CLINICAL THERAPEUTICS/NEW TECHNOLOGY—GLUCOSECATEGORY MONITORING AND SENSING

Table 1. Difference Between CES-D and DFCS Between Team Clinic and Standard Diabetes Clinic. Team Clinic Standard Diabetes Clinic p-value CES-D positive 13% 17% 0.77 CES-D score (±SD) 13.4±10.1 13.7±11.5 0.90 DFCS score (±SD) 27.7±10.4 30.4±11.1 0.18 Supported By: National Institutes of Health-National Institute of Diabetes and Digestive and Kidney Diseases 931-P Comorbid Depression and Diabetes Before and During the “Great 929-P Recession” of 2008 Patient Responses to Interim Data from Cardiovascular Outcomes EESHWAR K. CHANDRASEKAR, MOHAMMED K. ALI, KAI MCKEEVER BULLARD, Trials: Results from an Online Patient Survey Atlanta, GA MANU V. VENKAT, RICHARD S. WOOD, ADAM S. BROWN, PHIN YOUNGE, LISA Prior studies indicated that prescription rates of antidepressants in- S. ROTENSTEIN, KELLY L. CLOSE, San Francisco, CA, Boston, MA creased during the economic recession of 2008. However, estimates vary The disclosure of interim data from ongoing clinical trials is usually regarding the prevalence of depression among people with diabetes melli- discouraged, as it can alter participant behavior and threaten trial integ- tus (DM) around this time period. We used national data to estimate preva- rity. Current U.S. regulatory guidance requires long-term cardiovascular lence of depressive symptoms among persons with normal glycemic sta- outcomes trials (CVOTs) for new T2DM drugs, but allows interim data tus, pre-DM, and DM during 2005-2008 and 2009-2012. We analyzed data to be disclosed to support approval. The purpose of this study was to from 21,618 adults aged ≥18 years from the 2005-2012 National Health and examine how such disclosure could influence enrollment dynamics in Nutrition Examination Surveys. Using the Patient Health Questionnaire-9 a CVOT. An online survey from the diabetes market research company (PHQ-9), we defi ned clinically-signifi cant depressive symptoms, or “de- dQ&A was distributed to a panel of adult T2DM patients. Of the 1,984 pression”, as PHQ-9 score ≥10 or use of antidepressants. We categorized total respondents with T2DM, 1,542 reported a history of CVD and/or participants’ glycemic status using HbA1c: normal glycemic status (<5.7%), being told by their healthcare provider that they are at elevated CVD

pre-DM (5.7-6.4%), and DM (self-report of diagnosis or HbA1c ≥6.5%). We POSTERS risk. This represents a patient subgroup that is targeted for enrollment Therapeutics used logistic regression to compute predicted prevalence adjusted for age, in most diabetes CVOTs. In the survey, respondents were described a Clinical Diabetes/ sex, body mass index, race/ethnicity, poverty-to-income ratio, and aware- hypothetical CVOT. Next, they were randomized to receive scenarios in ness of DM or pre-DM. In 2009-2012, the crude prevalence of depression which evidence of either an increase or decrease in CVD incidence was among adults was 1.6 times higher for those with DM (22.9% [20.1-25.9]) disclosed during the trial. In both scenarios, the drug was approved. All than those with normal glycemic status (14.5% [13.0-16.1]) and 1.4 times participants selected one of four choices regarding their subsequent ac- higher than those with pre-DM (16.5% [14.4-18.9]). Crude prevalence in tions (see table below). each glycemic group remained relatively stable since 2005-2008, during Table 1. Patient Responses to the Disclosure of Interim CVOT Data. which the prevalence of depression among individuals with DM, pre-DM Interim data indicates Interim data indicates and normal glycemic status was 23.8% [21.3-26.5], 15.1% [13.0-17.4], and increased CVD risk decreased CVD risk 14.1% [12.9-15.3], respectively. In 2005-2008, adjusted prevalence ratios (n=816) (n=723) (normal glycemic status = reference) were 1.12 (0.93-1.34) for DM and 0.95 Remain in trial without any 26% 51% (0.82-1.09) for pre-DM. In 2009-2012, adjusted prevalence ratios (nor- major reservations mal glycemic status = reference) were 1.04 (0.83-1.31) for DM and 1.02 Remain in trial, ask doctor 41% 29% (0.87-1.92) for pre-DM. During 2005-2012, the prevalence of depressive about leaving trial during next symptoms remained stable across all glycemic groups. The prevalence of scheduled visit depressive symptoms did not increase around the “Great Recession” of Leave trial immediately, ask 4% 8% 2008. doctor to prescribe the newly approved therapy Leave trial immediately, return 30% 12% CLINICAL THERAPEUTICS/NEW TECHNOLOGY— to original diabetes therapy GLUCOSE MONITORING AND SENSING Our results indicate that interim data disclosure can meaningfully alter the behavior of T2DM patients enrolled in a CVOT, in ways that could endanger Guided Audio Tour: Glucose Monitoring—New Methods and Applications the trial’s integrity. Future work could examine the impact of interim data (Posters: 932-P to 939-P), see page 17. disclosure from real-world CVOTs. & 932-P 930-P Glycemic Effects of SGLT2 Inhibitor Canaglifl ozin in Type 1 Diabetes WITHDRAWN Using Dexcom G4 Platinum CGM NICHOLAS B. ARGENTO, KATHERINE NAKAMURA, Columbia, MD, San Diego, CA Limited information is available on the chronic use of sodium-glucose transporter 2 inhibitors in type 1 diabetes (T1D). We report on the glycemic, weight and systolic blood pressure (SBP) effect of canaglifl ozin 100 mg daily in T1D in a group of experienced Dexcom CGM (DCGM) users. In this retro- spective review, we examined records of T1D patients on DCGM > 1 yr (mean 4.6 yr) who were prescribed canaglifl ozin (CANA) and had a baseline DCGM 30 day download prior to and a second download after at least 1 month taking oral CANA 100 mg daily. 26 were identifi ed, 17 men, 25 white, T1D duration 12-48 yr average 30.3, 20 on pump and 6 on injections. All patients had an eGFR at baseline of 60 ml/min/1.73 m2 or higher. Average number of days/30 DCGM was worn was 29.3. Of the 26 patients, A1c data was avail- able in 25, and 22 had a baseline A1c of 7 or higher. The table shows results of selected outcomes. Total daily insulin dose (TDD) from pump downloads was available in 18 patients. In these patients, there was a reduction in TDD from 58.3 to 51.3 units (p=0.00012). There was no signifi cant change in serum creatinine or eGFR. Three females developed genital mycotic infections but continued therapy. Study concluded that the use of CANA in T1D resulted in signifi cant-

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A235 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—GLUCOSECATEGORY MONITORING AND SENSING

ly improved glycemic control with greater time in target, less hyperglycemia, due to chance, a large, pragmatic trial evaluating the effi cacy of intermittent and lower variability, with minimal increase in hypoglycemia, lower weight masked CGM in non-insulin treated patients with T2D is warranted. and SBP, and lower insulin use. Table. Table 1. Selected Outcomes of Baseline and Post CANA. CGM (N=17) SMBG (N=18) P-Value (Mean ± SD) Baseline Post p values Observed Mean (SD) CANA (paired t-tests) Baseline 7.7 (0.6) N=17 8.2 (0.5) N=18 DCGM mean glucose, mg/dL 169 ± 22 148 ± 16 <0.0001 Visit 5 Day 90 6.9 (0.6) N=14 7.2 (0.7) N=16 percent DCGM readings above 38 ± 12 25 ± 10 <0.0001 180 mg/dL Visit 10 Day 187 6.9 (0.7) N=15 7.5 (1.4) N=13 percent DCGM readings in target, 58 ± 12 69 ± 9 <0.0001 LOCF 6.9 (0.7) N=15 7.5 (1.3) N=16 70-180 mg/dL ANCOVA Least Squares percent DCGM below 70 mg/dL 4.1 ± 2.1 5.3 ± 3.7 0.0369 Mean (SE) Change from Baseline* DCGM standard deviation, mg/dL 67 ± 14 57 ± 11 <0.0001 Visit 5 Day 90 -1.03 (0.20) -0.73 (0.19) 0.271 Hemoglobin A1c,% 7.7 ± 0.9 7.2 ± 0.8 <0.0001 Visit 10 Day 187 -0.80 (0.33) -0.15 (0.39) 0.177 systolic blood pressure 122 ± 13/ 114 ± 15/ 0.0128/ LOCF -0.99 (0.31) -0.38 (0.31) 0.179 (mmHg)/weight (pounds) 206 ± 45 201 ± 46 0.0002 * Adjusting for baseline and site. Supported By: Medtronic, Inc.

& 933-P Triple-Goal Achievement in Patients with Type 2 Diabetes Mellitus & 935-P (T2DM) Improves Clinical Outcomes The Performance of an Orthogonally Redundant Glucose Sensor QIAN SHI, LIZHENG SHI, VIVIAN FONSECA, New Orleans, LA Compared with a Simply Redundant Electrochemical Glucose Sen- The impact of achieving 3 ADA goals: HbA1c (<7%) and LDL-C (<100 mg/dl) sor in Adults with Type 1 Diabetes and BP < 130/85 mmHg, has not been adequately evaluated in clinical trials, SYBIL A. MCAULEY, TRI T. DANG, JODIE C. HORSBURGH, ANUBHUTI BANSAL,

POSTERS GLENN M. WARD, ALICIA J. JENKINS, RICHARD J. MACISAAC, RAJIV V. SHAH, Therapeutics which usually examine only one or two. We therefore retrospectively exam-

Clinical Diabetes/ ined the incremental reduction of complication events in patients with T2DM DAVID N. O’NEAL, Melbourne, Australia, Northridge, CA achieving all 3 goals, compared with those achieving <3 goals. We identifi ed Orthogonally redundant sensors (ORS) integrating two distinct glucose 68,083 T2DM patients from the Veterans Affairs VISN 16 data warehouse sensing technologies, electrochemical and fl uorescence-based optical, with (2004-2011). Long-term outcomes were compared triple-goal achievers with independent failure modes potentially improve continuous glucose monitor- dual-goal, single-goal, and no-goal achievers (Table). Cox proportional hazard ing reliability. This study compares the performance of an ORS combining regression models were used to estimate the adjusted hazard ratio (aHR) redundant electrochemical plus optical sensing to a simply redundant elec- across goal achievement status. During the baseline period, 15.58% (10,597) trochemical comparator sensor (ECS). patients achieved all of the three goals, while 36.71% (24,979) and 34.53% Adults with type 1 diabetes are studied wearing an ORS and an ECS con- (23,494) patients achieved any two of the goals and any one goal, respec- currently for 7 days. Following sensor insertion, and on Day 4 with a stan- tively. Patients with less goal achievement had higher risks of all long-term dard meal, venous samples are collected for reference YSI plasma glucose outcomes complications, controlling for baseline conditions and demographic measurement at standardized intervals over 3 and 4 hours, respectively. characteristics (Table). In summary, the achievement of all 3 goals in diabe- Participants perform reference capillary blood glucose testing ≥ 8/day be- tes management leads to better outcomes than lesser achievement. Because tween study visits. Sensor glucose values are processed prospectively and this multi-faceted treatment strategy may reduce risks of complication events displayed only when sensor trace characterization algorithms determine the and mortality, a pragmatic prospective randomized trial targeting all goals is signal to be of adequate quality. Sensor glucose readings are compared to needed to confi rm the fi ndings, and may inform future guidelines. plasma and capillary glucose levels. This interim analysis is of 12 partici- pants who have completed the study to date. Reliability metrics: mean sensor display time is 86.9% for ORS vs. 74.2% for ECS (p=0.32), and mean sensor lifetime is 6.5 days for ORS vs. 5.4 days for ECS (p=0.29). Accuracy metrics: mean absolute relative difference (MARD) of ORS is 10.3% vs. 11.6% for ECS (p=0.39), and ISO 15197:2003 compliance is 87.4% for ORS vs. 83.3% for ECS (p=0.40). There has been no irritation or infection at any sensor insertion site. These preliminary results demonstrate the ORS is as accurate as the ECS and does not compromise insertion site health, though the difference in durability with the addition of orthogonal redundancy does not reach statistical signifi cance. Data collection is ongoing, and if combining opti- cal and electrochemical technologies signifi cantly enhances glucose sensing & 934-P reliability this may facilitate artifi cial pancreas development. Examining the Role of Continuous Glucose Monitoring (CGM) in Supported By: JDRF; The Leona M. and Harry B. Helmsley Charitable Trust Noninsulin Treated Type 2 Diabetes LAURA A. YOUNG, MICHELLE DUCLOS, ALISON MARQUIS, YANPING TENG, SO- NIA DAVIS, BRUCE W. BODE, JOHN B. BUSE, Chapel Hill, NC, Atlanta, GA & 936-P This two center pilot study aimed to determine whether periodic masked Glucose Poptest: Saliva Glucose Measurements Refl ect Blood Glu- continuous glucose monitoring (CGM) in patients with non-insulin treated cose Level in Diabetes Population (NIT) type 2 diabetes (T2D) can improve glycemic control. NIT T2D patients NEIL D. THEISE, REBECCA L. O’BRIEN, MYRON C. RAPKIN, RANDIECE L. ALT- (n=35) sub-optimally controlled (A1C 7.5%-9%) were recruited and con- SCHUL, Cliffside Park, NJ sented. Participants were randomized to self-monitoring of blood glucose Saliva glucose (SG) has long been considered a possible surrogate for (SMBG) 1-3 times/day or CGM with the iPro2 system with Enlite sensor every blood glucose (BG) screening or monitoring in diabetes mellitus (DM), though 6 weeks over 6 months. Subjects met with study staff at 6 week intervals to limited sensitivities of reported assays have so far prevented this option. review SMBG or CGM results from the prior 6 days. Therapy changes were We present a novel, rapid response, colorimetric, single-use, cost-effective guided based upon standardized treatment algorithms. Baseline characteris- Glucose PopTest (GPT) with suffi cient readability, sensitivity, and specifi city tics were not different between the groups (49% white, mean age 56, mean to accurately refl ect BG levels in diabetic and non-diabetic individuals. BMI 38 kg/m2). Though CGM participants exhibited a 0.61% (95% CI -0.30, Two devices were evaluated: GPT-1 (detecting down to 0.7 mg/dL SG) and 1.51) greater reduction in A1c from baseline to end of study (the primary end- a further optimized GPT-2 (detecting down to 0.25 mg/dL SG). Both can be point), this was not statistically different between the groups, perhaps due read semi-quantitatively (visual color chart comparison) or quantitatively to the small sample size. Similarly there were no signifi cant differences in (digital reader). GPT requires that the saliva sample be obtained >15 minutes diabetes related quality of life, self-effi cacy, or number of therapies utilized after food ingestion followed by a water mouth rinse. GPT evaluations of between the two groups over the course of the intervention. Retention was screening for DM (n=123) and from glucose challenge study (n=154) indicated 80% with no differences between the groups. While these fi nding may be that SG is consistently ~1% of BG, independent of dental hygiene.

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A236 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—GLUCOSE MONITORING AND SENSING

GPT-1 data: Accuracy/precision = 100/96 vs. reference SG method (BioAs- within the “no risk” zone, 2.46% were within the “slight, lower risk” zone say System Enzychrom Glucose Test) and 44.4/92.9 vs. BG test using paired and 0.5% fell within the “slight, higher risk” zone. IDE were calculated using plasma samples (YSI Glucose Analyzer). Comparison of novice vs. expert a computer-based model, as the differences in the dose determined using color-chart reads showed ≥ 93% agreement. Clarke error grid analysis in- the BGMS results and the dose determined using HK results. While FI and dicates 95.9% in zones A and B (“clinically accurate” and “benign Rx”, re- OV showed an IDE indicating a tendency to under-dose, the confi dence range spectively). for CNU was evenly distributed around -1.5 to 1.5 insulin units. Although GPT-2 data: Accuracy/precision = 100/100 vs. reference SG method and all BGMS fulfi lled ISO 15197:2013 accuracy limit criteria, differences were 90.0/93.2, vs. comparative plasma test using paired plasma samples. Re- seen in sub-analyses recommending them as further analysis parameters gression analysis of GPT-2 results showed r = 1.0 vs. SG ref standard and r = for BGM evaluations. Contour NEXT USB demonstrated high accuracy as evi- 0.822 vs. BG. (Clarke error grid analysis not performed). denced by lower MARD values, PEG and SEG analyses, as well as a smaller These data indicate that SG refl ects BG in diabetic and non-diabetic in- range of hypothetical IDE. dividuals independent of oral hygiene. The Glucose PopTest sensitively and specifi cally measures SG confi rming its viability for population screening for 939-P DM and possibly for pre-diabetes. These data also suggest that SG testing could reducing or eliminate needle-sticks for self monitoring for people with insulin dependent DM. WITHDRAWN Supported By: Pop Test LLC

& 937-P Evaluating Precision and Accuracy of FreeStyle Lite Test Strips Us- ing an OmniPod PDM Meter in Multiple Patient Situations CHRISTINE M. HAYDEN, MATTHEW STRUM, DAVID MURRAY, DONNA WEST STRUM, Oxford, MS Evidence for confounding factors in patient situations involving self- monitoring blood glucose (SMBG) is weak, due to lack of studies. Numerous

glucose monitors meet specifi c accuracy and precision requirements and POSTERS industry standards in order to aid patients with SMBG. This study evaluated Therapeutics precision and accuracy in OmniPod PDM® (O-PDM) meters with FreeStyle Clinical Diabetes/ Lite® (FSL) test strips when scented and unscented lotion residues were applied to testing sites prior to glucose monitoring. Twenty participants over the age of 18, without known diabetes mellitus were recruited as subjects. The forearm of each participant was divided into 3 quadrants_unscented lo- tion (top), control (middle), scented lotion (bottom). After testing each quad- rant with a lancet, the sites were cleansed with alcohol swabs and readings were taken a second time. Lotion residue BG readings means were: control (80.61 ± 1.861 mg/dL), unscented lotion (71.44 ± 3.080 mg/dL), scented lotion (73.00 ± 2.581 mg/dL). The alcohol cleaned quadrant BG means were: control (81.61 ± 2.456 mg/dL), unscented lotion (77.17 ± 2.614 mg/dL), scented lotion (80.42 ± 3.314 mg/dL). The O-PDM unscented lotion group had a statisti- cally signifi cant difference (p<0.05) when compared to its respective alcohol cleaned group; the O-PDM scented lotion group had a difference when com- pared to the alcohol scented group and a p-value of 0.07 was determined. The lotion residue quadrants had signifi cantly lower mean BG values. With tight accuracy and precision provided by the meters, the potential for patient and confounding factors is increased. By understanding potential sources of error, health care professionals, as well as patients may utilize SMBG more effectively. The results verify the importance of hand washing as well as cleaning testing sites before readings in hopes that both patients and health care professionals may identify common errors and work towards education and ultimately greater diabetes care.

& 938-P Comparative Evaluation of Contour® Next USB Blood Glucose Mon- itoring System, FreeStyle InsuLinx® and OneTouch® Verio™ IQ Using Error Grid Analyses and an Insulin Dosing Error Model JOSE LUIS BEDINI, JANE WALLACE, SCOTT PARDO, BEATRIZ FERNANDEZ-TRES- GUERRES, THORSTEN PETRUSCHKE, Barcelona, Spain, Mishawaka, IN, Whippany, NJ, Leverkusen, Germany This study compared the accuracy of 3 Blood Glucose Monitoring Systems (BGMS): Contour® Next USB (CNU), FreeStyle InsuLinx® (FI) and OneTouch® Verio™ IQ (OV) according to ISO 15197:2013 accuracy limit criteria, mean ab- solute relative difference (MARD), Parkes-Consensus (PEG) and surveillance 940-P error grid (SEG) analysis and an insulin dosing error analysis (IDE). Left-over Reduction of Hyper- and Hypoglycemia during Two Months with a blood samples (N=204) were analyzed with each BGMS using 2 strip lots and Wearable Artifi cial Pancreas from Dinner to Breakfast in Patients the hexokinase (HK) laboratory method (Dimension® EXL, Siemens AG). All with Type 1 Diabetes BGMS fulfi lled ISO 15197:2013 accuracy criteria. The percentage of results ERIC RENARD, J. HANS DEVRIES, CLAUDIO COBELLI, LALO MAGNI, JEROME within the limit was higher for CNU than for the other BGMS (CNU 99.75%, PLACE, JORT KROPFF, SIMONE DEL FAVERO, ROBERTO VISENTIN, MARCO MON- FI 97.55% and OV 97.55%). MARD was signifi cantly lower for CNU (3.44%) ARO, CHIARA TOFFANIN, FEDERICO DI PALMA, GIORDANO LANZOLA, MIRKO than for FI (4.23%) or OV (5.17%). Lower MARD indicates a smaller difference MESSORI, ANNE FARRET, FEDERICO BOSCARI, SILVIA GALASSO, DANIELA between HK method and BGMS. All results (100%) obtained with CNU were BRUTTOMESSO, ANGELO AVOGARO, AP@HOME CONSORTIUM, Montpellier, within Zone A of PEG. The FI and OV meters also had results in Zone B (1.7% France, Amsterdam, Netherlands, Padova, Italy, Pavia, Italy and 1.0 % respectively). SEG showed that results obtained with CNU and OV Wearable artifi cial pancreas (AP) at home from dinner to breakfast may be were mainly within the “no risk” zone (99.51% for both) with only 2 results an attractive fi rst routine use in patients with type 1 diabetes (T1D). (0.49%) within the “slight, lower risk” zone. For FI 97.04% of results were

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A237 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—GLUCOSE MONITORING AND SENSING

Thirty-fi ve adult T1D patients with insulin pumps were enrolled in a ran- A1c 7.0 -9.0%). Patients with type 1 diabetes, cardiac disease, renal and domized, crossover study for 2 periods of 2 months in free-life conditions hepatic impairment were excluded. comparing sensor-augmented pump (SAP) vs. AP use from dinner to wake-up Screened eligible patients continued their metformin alone regimen and time and SAP during day-time (HYBRID). A run-in of 2 weeks with SAP (Roche fi rst 72 hours CGM recording was performed. Patients were then randomised Spirit Combo and Dexcom G4 Platinum) and a wash-out of 4 weeks between on one to one basis to receive either vildagliptin 50 mg twice or sitagliptin periods were performed. AP was achieved by connecting the continuous glu- 100 mg once daily in addition to metformin. Second 72 hour CGM profi les cose monitor (CGM) and insulin pump to a smart-phone which ran an MPC was recorded after 12 weeks therapy. 30 patients of vildagliptin and 34 of algorithm (DiAs, University of Virginia). CGM data for the last 6 weeks of sitagliptin group completed the study. each period were analyzed on an ‘intention-to-treat’ basis with % time [70- 24 hours glucose variability measured by mean amplitude of glucose excur- 180 mg/dL] from 8PM to 8AM as primary endpoint. sions and standard deviation of mean glucose concentration showed similar Three patients dropped out (1 before randomization, 2 shortly after) due to improvement on both drugs in comparison to metformin alone. In contrast, poor system acceptance. In the 32 analyzed patients (initial A1c: 8.2±0.6%), parameters refl ecting daily glycaemic control, mean 24 hours blood glucose % time [70-180 mg/dL] was higher with HYBRID (mean±SD): 66.8±10.4 vs. concentration, time spent in the optimal glycaemic range (70-140 mg%) and 58.2±9.4 (p=0.001, 8PM-8AM), 68.5±14.0 vs. 57.6±10.5 (p=0.0009, 12AM- above the hyperglycaemic thresholds of 140 and 180 mg% together with the 7AM), 64.5±8.7 vs. 59.4±8.7 (p=0.009, 12AM-12AM). Percent time [>180 mg/ corresponding AUC values were signifi cantly improved from baseline only dL] and [<70mg/dL] were both lower with HYBRID (8PM-8AM): 31.5±10.2 in the vildagliptin arm. In addition, overall hyperglycaemia, (AUC [24h] > 100 vs. 38.4±9.8 (p=0.007) and 1.7±0.9 vs. 3.3±2.2 (p=0.0004), respectively. mg%) signifi cantly dropped from baseline on vildagliptin (-42%) but not on Percent time [80-140 mg/dL] was higher with HYBRID: 37.7±9.2 vs. 30.8±6.1 sitagliptin (-8%), while postprandial hyperglycaemic (AUC [0-4hr] x 3) was (p=0.001, 8PM-8AM), 38.7±12.3 vs. 30.2±7.2 (p=0.001, 12AM-7AM) and signifi cantly reduced on both. Basal hyperglycaemia was reduced only on 36.4±8.0 vs. 32.4±6.4 (p=0.03, 12AM-12AM). While mean blood glucose was vildagliptin (-45% & p=0.036). lower with HYBRID from 12AM to 7AM: 160±18 vs.169±15 (p=0.049), it was Addition of vildagliptin/sitagliptin signifi cantly reduced glycaemic variabil- similar from 12AM to 12AM: 162±15 vs. 165±15, although A1c was 0.16% ity with no difference between the two drugs. However, vildagliptin induced lower (p=0.047). better circardian glycaemic control than sitagliptin with a signifi cant decrease Our data shows that AP from dinner to wake-up time for 2 months in- on overall hyperglycaemia, mainly by reducing basal hyperglycaemia. creases % time in near-normal glucose range during this time period and over 24 hours. This supports AP from dinner to breakfast as a fi rst safe and

POSTERS 943-P Therapeutics benefi cial option for moving to the market. Evaluation of Increased Hypoglycemia Risk in Japanese Type 1 Dia- Clinical Diabetes/ Supported By: European Union (247138) betes by Average Daily Risk Range (ADRR) KOJI KASHIMA, HIROYUKI SHIMIZU, MICHIKO KAWASAKI, MASANOBU YA- 941-P MADA, Maebashi, Japan, Nasushiobara, Japan, Kiryu, Japan Time Lag of Glucose Appearance from Plasma to Interstitial Fluid Objective: Achieving a target of HbA1c less than 7% is generally recom- after Mixed Meal in Type 1 Diabetes mended to reduce microvascular complications, but hypoglycemic agent MICHAEL SLAMA, SIMMI DUBE, SONA VEETTIL, WALTER KREMERS, ANANDA often increases hypoglycemia risk. Hypoglycemia might be related to in- BASU, RITA BASU, Rochester, MN creased cardiovascular events and dementia. Simple and effi cient methods Time-lag for glucose to transfer from the plasma to interstitial fl uid (ISF) are required to evaluate the risk of hypoglycemia. We examined hypoglyce- is a critical factor in interpretation of continuous glucose monitor (CGM) mia risk by evaluating average daily risk range (ADRR) by using self-blood derived glucose concentrations and its accurate determination is vital glucose monitoring system in outpatients with Japanese type 1 (T1DM) and for informing open-loop and closed-loop algorithms for type 1 diabetes type 2 (T2DM) diabetes. (T1DM). We have recently reported a time-lag of 6.8 min in T1DM in the Research Design and Methods: In a total of 26 T1DM and 26 T2DM patients overnight fasted state. To determine the time-lag in the dynamic prandial were randomly enrolled in the study. All patients are using self-blood glucose state, we studied T1DM (n=10, age 49.1±10.4 yrs, BMI 27.7±3.2 kg/m2, HbA1c monitoring system. According to ADRR score, all patients were classifi ed into 7.9±0.7%, T1DM duration 24.2±14.9yrs) subjects on insulin pump therapy and three categories; low (1-19), moderate (20-39), and severe (40-60) ADRR score. healthy controls (HC) (n=10, age 47.3±8.6 yrs, BMI 26.2±5.4 kg/m2) on two Results: 1) 72.4% of T1DM patients who achieved HbA1c<7% were in randomized visits. During one visit a mixed meal (MM) containing 50 grams moderate and 27.3% in low ADRR score, whereas 11.8% of T2DM were 13C labeled glucose was ingested while on the other 13C labelled glucose was in moderate and 88.2% in low ADRR score. 2) In patients who achieved infused intravenously (IVM) to mimic the appearance of a 50g carbohydrate HbA1c<7%: HbA1c was not different between T1DM and T2DM (6.0±0.5% meal. Insulin was administered in T1DM subjects according to their custom- vs. 6.2±0.5%) but ADRR score was signifi cantly higher in T1DM (22.5±6.8 ary insulin:carbohydrate ratio at the start of MM and IVM. Microdialysis vs. 11.0±2.8: P<0.001), which refl ects the existence of hypoglycemia or hy- catheters were placed in the abdominal wall to sample ISF. Plasma and ISF perglycemia. Hypoglycemia (<70mg/dl) detected by themselves was more were sampled concurrently and periodically to measure 13C glucose enrich- frequent in T1DM (13.5±4.6% vs. 2.2±2.8%: P<0.001), lowest blood glucose ments for 6hrs. Time-lag of 13C glucose of >0.3% molar ratio (to account level was more severe in T1DM (39.3±7.5mg/dl vs. 68.6±13.7mg/dl: P<0.001), for assay sensitivity) to appear in ISF was calculated for each subject. We respectively. 3) ADRR score were positively correlated with HbA1c in both also accounted for the transit time through microdialysis catheter. Mean (sd) T1DM and T2DM (P<0.001). These correlation may indicate that when HbA1c time-lag of glucose appearance from plasma to ISF was 13.1 (6.5) min during level is lower, hypoglycemia risk is about two times higher in T1DM than that MM vs. 9.7 (5.5) min during IVM in T1DM (p=0.32). In contrast, time-lag of in T2DM. In addition, sub-analysis data indicate that GLP-1 analogue may glucose appearance was 11.2 (5.4) min during MM vs. 7.1 (2.7) min during reduce hypoglycemia risk in T2DM. IVM in HC (p=0.04). Time-lag did not differ between T1DM and HC. The MM Conclusion: ADRR score enables us to analyze the quantitative hypogly- results indicate the sum of the time taken for glucose absorption from the cemic risk which cannot be detected by HbA1c. Measurement of ADRR score gut, transport through the circulation with eventual fi rst appearance into the may help us to intensify the treatment by CSII or using GLP-1 analogue. ISF. Further studies are underway to determine the equilibration time and the time-lag of disappearance as glucose levels decline to refi ne next generation 944-P CGM algorithms. Accuracy Performance of Six Self-Monitoring Blood Glucose Supported By: The Leona M. and Harry B. Helmsley Charitable Trust Systems MAXWELL C. KUM, KALAYIL MANIAN MANESH, STEVEN CHIALIN WANG, 942-P TIMOTHY S. BAILEY, San Diego, CA Continuous Glucose Monitoring (CGM) Profi les with Vildagliptin vs. A clinical study was carried out to evaluate the system accuracy perfor- Sitagliptin in Addition to Metformin in Patients with Type 2 Diabe- mance of six different self-monitoring blood glucose (SMBG) systems (Accu- tes Mellitus Chek® Active, Accu-Chek® Performa, Contour®, FreeStyle Lite®, On Call® DEVENDRA P. SINGH, SHASHIKANT SINGH, SHASHI SEKHAR SINGH, ANAND Vivid, and OneTouch® Ultra® 2) with YSI 2300 STAT Plus as the comparison KUMAR SRIVASTAVA, KUNDAN SINHA, Varanasi, India method. We directly compare CGM profi les on vildagliptin and sitagliptin in pa- Capillary blood samples from 50 subjects were tested in duplicate on two tients with T2DM which was not optimally controlled on metformin alone. meters with 1 lot of strips for each SMBG system. The measurement results Patients included were > 21 yrs age, body mass index (BMI) of 20 to 43 kg / were then analyzed by calculating the percentage of results within ±15% m2, taking (>1500 mg/day) metformin alone and had inadequate control (Hb of the comparison method at results ≥100mg/dL or within ±15mg/dL of the

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A238 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—GLUCOSE MONITORING AND SENSING comparison method at results <100mg/dL (ISO 15197: 2013 system accuracy at 1 site and a positive bias (3.36% to 6.91%) at the other site. In Study 2 criterion). In comparison, the measurement results were also analyzed by (N=329), 97.8% of BGMS results were within the accuracy limits, and the calculating the percentage of results within ±20% of the comparison method serum controls showed minimal bias (<0.92%) at both sites. These fi ndings at results ≥75mg/dL or within ±15mg/dL of comparison method at results suggest that the ability of a BGMS to meet accuracy guidelines is infl uenced <75mg/dL (ISO 15197: 2003 system accuracy criterion). In addition, percent- by reference instrument accuracy. Since reference glucose analyzer technol- age of results within zone A and B of the Consensus Error Grid (CEG) was ogy has remained largely unchanged while BGMS technology has improved calculated (ISO 15197: 2013 system accuracy criterion). and meter accuracy guidelines have become more stringent, reference in- The results showed that more than 95% of results were within ±15% of strument measurement biases that were once considered negligible may the comparison method at results ≥100mg/dL or within ±15mg/dL of the now be consequential when assessing meter accuracy. comparison method at results <100mg/dL for Accu-Chek® Active, Accu- Supported By: Bayer HealthCare, LLC Chek® Performa, and On Call® Vivid, but less than 95% of results satisfi ed the same criteria for Contour®, FreeStyle Lite®, and OneTouch® Ultra® 2. 947-P All SMBG systems in the study showed 100% of results within zones A Habits of Highly Successful CGM Users and B of the CEG. JEREMY PETTUS, ERIC EBNER, STEVE EDELMAN, DAVID A. PRICE, La Jolla, CA, San Diego, CA 945-P A survey was collected from continuous glucose monitoring (CGM) users Mean Absolute Relative Difference (MARD) and Compliance with with T1 (N=222) and T2 diabetes (N=78) from across the U.S. to gain insight ISO 15197 Accuracy Limits: Which MARD Is Acceptable? into how CGM users derive benefi t. 120 (40%) of CGM users were retro- GUIDO FRECKMANN, STEFAN PLEUS, DELIA RITTMEYER, THOMAS LEUCHT, spectively defi ned as “Highly Successful CGM (HS-CGM) user” by meeting CORNELIA HAUG, Ulm, Germany criteria: 1) Most recent A1C ≤ 7%; and 2) A1C has decreased or stayed the The mean absolute relative difference (MARD) between the results of a same; or 3) Hypoglycemic events have decreased or stayed the same. blood glucose (BG) monitoring system (BGMS) and a comparison method is Relative to other users, HS-CGM users had: 1) Reduced daytime target sometimes used in the literature to describe the analytical accuracy of a glucose levels; 2) Lower CGM high alert settings; 3) Greater frequency of BGMS, and it is also very commonly used for continuous glucose monitoring CGM use; and 4) made lower percent changes to their correction or mealtime (CGM) systems. The question arises: which MARD corresponds to estab- insulin dose in response to a falling glucose. Specifi c to rate of change (ROC)

lished accuracy requirements like those specifi ed in ISO 15197? adjustments, both groups showed large (>100%) increases in their correction POSTERS In this retrospective analysis, data from system accuracy evaluations of insulin dose in response to rising glucose of 220mg/dl (one or two arrows Therapeutics 85 different test strip lots (69 different BGMS types) were used to calcu- up). However, in response to a falling glucose at 220mg/dl with one or two Clinical Diabetes/ late MARD between the BGMS results and the corresponding comparison arrows down, successful users would, on average reduce their correction method results. Additionally, the percentage of BGMS results within the dose less (38.5% vs. 55% p = .0004 and 42.9% vs. 57.1% reduction p=0.0038 system accuracy limits of ISO 15197:2003 (“2003 ISO accuracy limits”) and respectively. At a pre-meal glucose of 110mg/dl and 2 arrows up, successful ISO 15197: 2013 (“2013 ISO accuracy limits”) was calculated (±15 mg/dL for users would increase their bolus by 80.1% compared to a larger increase of glucose concentrations below 75 mg/dl (2013: 100 mg/dL) and ±20% (2013: 92.6% in the non-successful group(p=0.0306). ±15%) for glucose concentrations equal to or above 75 mg/dl (2013: 100 mg/ In summary, CGM users that report the greatest benefi t from the technol- dL)). The system accuracy data were then used to establish which MARD ogy generally wear the device all the time, have more aggressive glycemic results will likely lead to having at least 95% of results within ISO accuracy targets, and react more judiciously to glucose trends. limits. The MARD results for these 85 test strip lots ranged from 2.8% to 16.4%. The lowest MARD of a test strip lot that showed <95% of results within 2003 ISO accuracy limits was 7.5%, whereas the highest MARD of a test strip lot that showed ≥95% of results within ISO accuracy limits was 10.2%. For the 2013 ISO accuracy limits, the corresponding MARD values were 6.5% and 7.6%, respectively. Based on these data we conclude that a BGMS should achieve an MARD result of below 8% to likely have analytical accuracy acceptable with re- spect to ISO 15197. If its analytical quality should reach that of BG systems that have ≥95% of results within ISO 15197:2013 system accuracy limits, it is likely required to achieve an MARD result of 6.5% or less.

946-P Fundamental Importance of Reference Glucose Analyzer Accuracy for Evaluating the Performance of Blood Glucose Monitoring Sys- tems (BGMSs) TIMOTHY BAILEY, LESLIE J. KLAFF, JANE F. WALLACE, CARMINE GREENE, SCOTT PARDO, BERN HARRISON, DAVID A. SIMMONS, Escondido, CA, Renton, WA, Whippany, NJ As BGMS accuracy is based on comparison of meter and laboratory ref- erence glucose analyzer results, reference instrument accuracy is critical to BGMS accuracy evaluation. In 2 clinical studies, the performance of a new CONTOUR BGMS with an updated algorithm and currently available CONTOUR test strips was assessed. The CONTOUR meters, test strip lots, and study sites in both studies were identical. Untrained subjects performed a fi ngertip meter self-test and study staff obtained fi ngertip blood for YSI glucose analyzer measurement. Meter and YSI results were compared. The only testing differences between the studies involved reference instru- ment procedures: different YSIs, reference instrument tracking methods, and trained operators. YSI accuracy was monitored using National Institute of Standards and Technology traceable serum controls, with tighter limits in Study 2 vs. Study 1. The primary objective of both studies was to ana- lyze BGMS performance per International Organization for Standardization 15197: 2013 Section 8 accuracy criteria (% of results within ±15 mg/dL [<100 mg/dL] and ±15% [≥100 mg/dL] of the reference for persons with diabetes). In Study 1 (N = 136), 94.1% of BGMS results were within the accuracy limits, and YSI serum control results showed a negative bias (-0.64% to -2.48%)

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A239 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—GLUCOSE MONITORING AND SENSING

948-P day was reduced compared to insulin pump alone. In addition, we recorded Low-Carbohydrate Diet Did Not Affect the Behavior of Luseogli- an improvement of the score at the Diabetes Treatment Satisfaction Ques- fl ozin, a Selective SGLT2 Inhibitor, on Glycemic Control over 24 tionnaire, meaning an increase of patients’ satisfaction toward treatment. Hours Measured by Continuous Glucose Monitoring (CGM) in Japa- In conclusion, the insulin pump integrated with CGMS better improved nese Patients with Type 2 Diabetes glycemic control, glycemic variability and patients’ satisfaction in type 1 dia- RIMEI NISHIMURA, TAKESHI OSONOI, HIDEAKI JINNOUCHI, SHIGETO KANADA, betic patients compared to insulin pump alone. SOICHI SAKAI, YOSHISHIGE SAMUKAWA, Tokyo, Japan, Ibaraki, Japan, Kumamoto, Japan, Osaka, Japan 950-P No previous reports have studied the effect of SGLT2 inhibitors combined The Effi cacy of Continuous Glucose Monitoring to Improve BMI and with low-carbohydrate diet (LD) on glycemic control. This double-blind, pla- Glycaemic Control in Prediabetes: The OBIG Trial cebo-controlled, crossover study is the fi rst trial to compare 24-h glucose GIUSEPPE DEFEUDIS, CHIARA DI EMIDIO, ROCKY STROLLO, MARIA VERONA variability of Luseoglifl ozin (LUSEO) measured by CGM with normal diet (ND) RINATI, DARIO TUCCINARDI, ANDREA PALERMO, SILVIA ANGELETTI, SILVIA and LD. MANFRINI, PAOLO POZZILLI, Rome, Italy Patients with type 2 diabetes inadequately controlled with diet and exer- Body weight and blood glucose control are crucial elements for the man- cise were randomized into two groups in which patients fi rst received LUSEO agement of subjects with prediabetes and diabetes. Continuous glucose 2.5 mg QD then placebo (PBO) for 7 or 8 days each, or vice versa. All patients monitoring system (CGMS) may provide a more comprehensive assessment (n=37) took ND on Day 7. Part of them (n=18) took LD on Day 8. 24-h glucose of dysglycaemia and help to improve blood glucose control. The aim of the levels were measured by CGM on Days 7 and 8. The results of 18 patients OBIG trial was to investigate whether the use of CGMS improves blood glu- (age 62.8±7.7 years (mean ± SD), BMI 23.71±3.33 kg/m2) who took ND on Day cose control and reduce BMI in obese patients with prediabetes (defi ned 7 and LD on Day 8 were analyzed. as impaired fasting glycaemia and/or impaired glucose tolerance after Oral LUSEO 2.5 mg monotherapy with ND signifi cantly decreased 24-h mean Glucose Tolerance Test). Sixteen obese subjects with prediabetes, mean age glucose (MG) levels and 24-h AUC (difference vs. PBO: MG -23.22 mg/dL, 65.25±10.53 years, were randomly assigned to CGMS plus educational and 24-h AUC -555.6 mg/dL·hr, p< 0.001). Almost equally, LUSEO with LD showed dietary treatment (group A) or to educational + dietary treatment only (group lower MG levels and 24-h AUC than PBO (MG -27.61 mg/dL, 24-h AUC -660.7 B). CGMS was installed quarterly over a period of 9 months. Height, weight mg/dL·hr, p< 0.001). No hypoglycemia was observed over 24 hours, neither and waist circumference were registered and blood samples collected to with ND nor LD. However, special attention should be paid in case of taking POSTERS measure HbA1c levels at baseline (T0) and at the end of the obervational Therapeutics LUSEO with LD as marked increase in fasting ketones (Max: 3030 µmol/L in period (T9); glycaemic variability was also calculated as standard deviation Clinical Diabetes/ β hydroxybutyric acid) was observed. of glycaemic values registered by CGMS. No signifi cative differences were observed between groups at T0 or T9 for both BMI and HbA1c. When we analysed results at T0 and T9 within groups, in group A HbA1c (6.2%±0.48 vs. 6.09%±0.45, P=0.34) and BMI (36.86±5.18 vs. 36.49±5.32, P=0.15, respec- tively) did not signifi cantly change. Glycaemic variability also did not change signifi cantly over time. Conversely, in group B we found a signifi cative in- crease after 9 months of both HbA1c (5.75%±0.38 vs. 6.08%±0.12, P=0.003) and BMI (35.04±5.07 vs. 35.63±4.76, P= 0.017, respectively). These results suggest that a systematic use of CGMS may be useful to prevent progres- sion of dysglycaemia in obese patients with prediabetes and may support its use as an additional tool for the management of these subjects. Supported By: Medtronic, Inc.

951-P Blood Contamination of Unused Vial-Packed Glucose Test Strips in Multispeciality Hospitals MANOJ S. CHAWLA, AZEEM KATHAWALA, Mumbai, India Glucometers (point of care testing POCT) are widely used in hospitals and by patients. In hospitals, the same device is used on multiple patients. It is known that Hepatitis B virus, Clostridium diffi cile, methicllin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE) Supported By: Taisho Pharmaceutical Co., Ltd. and Acinetobacter baumannii survive on medical devices for many days mak- ing them reservoirs of fomites for transmission. 949-P The glucose testing strips (GTS) come in direct contact with blood. Though Effects on Glycemic Variability, Glyco-Metabolic Control, and Pa- presence of blood does not necessarily indicate infectivity, it can serve as tients’ Satisfaction of an Insulin Pump Integrated with Continuous a potential mode of transmission of nosocomial infections. This is the fi rst Glucose Monitoring System in Type 1 Diabetic Patients proof of concept study aimed to evaluate extent of blood contamination of PAMELA MAFFIOLI, DAVIDE ROMANO, ANGELA D’ANGELO, GIUSEPPE DEROSA, unused GTS from partially used vials. Pavia, Italy Vials containing GTS were placed in fi ve different wards of three multi- The aim of this study was to evaluate the effects of an insulin pump in- specialty hospitals in India. When at least half of strips in these vials were tegrated with continuous glucose monitoring system (CGMS) compared to used, they were sealed and sent to a government certifi ed forensic labora- insulin pump alone on glycemic control, and blood glucose variability in type tory to investigate for presence of blood. The phenolphthalein test having 1 diabetic patients, in a case-control clinical trial. We also evaluated the greater sensitivity than the leucomalachite green test was used to detect degree of patients’ satisfaction to treatment. the presence of blood. We enrolled 20 type 1 diabetic subjects, with an inadequate glycemic con- Blood contaminated strips were detected in 66.67% (10 of 15) of the vials. trol (glycated hemoglobin >7.5%), with an insulin pump from at least three Overall 9.32% (33 of 354) of strips were contaminated with blood. Average months. At baseline, patients were instructed to use a CGMS able to com- contamination rates varied from 4% to 14% between hospitals and 0% to municate with the insulin pump (Medtronic MiniMed Paradigm Veo) in an in- 33% between different wards of the same hospital. One of the hospitals had tegrated system. The function of suspension of insulin delivery, in case of hy- all its vials (100%) contaminated. Special care wards like ICCU (intensive poglycemia, was activated. We evaluated: anthropometric measurements, coronary care unit) showed a higher rate of contamination. glycated hemoglobin, fasting plasma glucose (FPG), post-prandial glucose Rate of blood contamination observed may be much less than the actual (PPG). These parameters were recorded at baseline, at 3 and 6 months after occurrence considering the fact that study vials were marked, making hospital the placement of the device. staff extra cautious while handling GTS. The use of a single vial for a single After 6 months since the placement of the integrated system, there was patient or individually packed test strips is one of the ways to reduce contami- a decrease of glycated hemoglobin. The daily blood glucose variability, ex- nation. Results of this study needs to be validated in a larger study involving pressed as mean amplitude of glycemic excursions, was reduced after the multiple hospitals to assess prevalence of blood contamination of GTS. placement of the integrated system. Also the glycemic variability from day to Supported By: Abbott Diabetes Care

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952-P vices (either retrospective CGM system or real-time CGM system) from 2007 to 2014. This study retrospectively analyzed 6,029 CGM data sets, which was selected from the type 1 and type 2 inpatients in endocrinology depart- WITHDRAWN ment in six major Chinese urban cities (Beijing, Shanghai, Wuhan, Kunming, Zhengzhou and Lanzhou). Six unique CGM parameters (Mean average CGM glucose, Mean maxi- mum glucose, Mean minimum glucose, Mean percentage time of blood glu- cose ≥200 mg/dL and ≥140mg/dL, Mean percentage time of blood glucose ≤70mg/dL and Mean glucose stand deviation) were analyzed from 6,029 data sets, and the results list in Table 1. Alarmly high percentage time val- ues in hyperglycemia (≥200mg/dL and ≥140mg/dL) were observed (23.7% and 55.5%, respectively). The glucose profi le analyzed from 6,029 CGM data sets provides more detailed glucose information for the Chinese urban diabetes population. POSTERS Therapeutics Clinical Diabetes/

953-P Balancing Reliability and Computational Effi ciency of the Dose Safety Hypoglycemia Prevention Module (HPM) ROBERT KIRCHER, DON MATHESON, RICHARD MAUSETH, Redmond, WA This research assesses the performance and computational effi ciency of the Dose Safety HPM. We followed the same test procedure described in our 2014 ATTD poster. 955-P The HPM prediction algorithm utilizes machine-learning techniques to build Extended Wear of a Next Generation of CGM Sensor a statistical model of the human glucoregulatory system. Glucose and insulin LUCAS BOHNETT, KATHERINE NAKAMURA, LAUREN JEPSON, JAKE LEACH, San dosing data from ten 24-hr in silico test runs; using different subjects from Diego, CA those used to generate the baseline model, were processed by the HPM. On- Real Time-CGM systems use body worn sensors that are limited in how line learning continuously personalized the baseline model for each subject. long they work. FDA approved CGM sensor wear times have incrementally The low threshold was set to 90 mg/dL. Of the 16 low glucose events in the improved over the years from 3 to 7 days while literature continues to show test datasets, 15 were predicted. In the baseline test, the mean prediction that long-term regularly CGM use provides clinical benefi ts to patients. The time before the events was 47 minutes (SD=30.7). Of the 6 false predictions, patch adhesion and bulkiness impact how long a sensor may be physically the mean actual glucose at the time was 98 mg/dL (SD=11.5). Note that false worn, but the sensor design assures the sensor will perform in an extended positives below 100 mg/dL are considered safe. duration. Both the sensor signal and the patch adhesiveness mainly decide To assess the impact of reduced computation, predictions and learning how reliable a CGM system is. were computed every third 5-minute glucose sample time, instead of every A next generation CGM sensor was evaluated over 14 days in 2 feasibility sample. trials enrolling diabetic subjects. Each subject wore 2 sensors and collected Of the 16 low glucose events in the test datasets, all 16 were correctly reference glucose measurements using the Bayer Contour SMBG meter to predicted. The mean prediction time before the events was 38 minutes assess sensor glucose response. Sensor life was estimated using the Ka- (SD=17.8). Of the 11 false predictions, the mean actual glucose at the time plan-Meier method by censoring non-sensor related CGM system failures. was 98 mg/dL (SD=4.6). 84 subjects wore a total of 175 sensors. 79 (94%) T1D, 5 (6%) T2D, and 46 Reducing algorithmic computation by 66% reduced the low glucose event (55%) male. The probability of sensor survival to day 10 was 94% [95% CI: prediction times by 9 minutes, but increased the number of accurate predic- 88%-97%], given 36 sensors were censored (Figure 1); this was reduced to tions to 100%. The accuracy of the predictions improved. The number of 79% [95% CI: 72%-85%] without censoring, i.e. at all cause stop-to-use. The false predictions of low glucose events increased however those predictions average change in glucose response from day 7 to day 10 for the 130 surviv- occurred when means actual glucose was < 99 mg/dL. More algorithmic in- ing sensors were small as -1% [95% CI:-3%- 1%]. vestigation and clinical validation is warranted. This new CGM system established stable performance for up to day 10. Supported By: National Institute of Diabetes and Digestive and Kidney Diseases Extended wear for next generation CGM sensors is feasible and may im- prove CGM utilization and patient satisfaction. 954-P Detailed Glucose Profi le Analysis of Chinese Urban Diabetes Using Continuous Glucose Monitoring Devices DAN WANG, GANG HAO, HUASHI ZHANG, Beijing, China 92.4 million adult diabetes were identifi ed in China by a recent study as in- dicated with their mean fasting plasma glucose level and mean 2-hr plasma glucose in oral glucose-tolerance test. In order to have better understanding and treatment of those large diabetes populations, more detailed glucose profi le information of those diabetes patients is needed. A large Continuous Glucose Monitoring (CGM) database was established from about 50,000 CGM users in China, who used SanMeditech’s CGM de-

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We studied 85 patients (50 men, 35 women; mean age 43.93±10.87 years, mean disease duration 21.91±6.07 years) with type 2 diabetes on differ- ent treatment regimens (31 on oral therapy, 33 on insulin mixtures, 21 on multiple insulin injections). Continuous glucose monitoring by using iProTM was performed for seven days and HbA1c was measured at the end of this period. High positive correlation was found between HbA1c (7.46±1.19%) and average blood glucose level during period of CGM (7.45±1.57mmol/l) (r=0.73), AUC above limit (r=0.75) and percentage of time spent with BG above 7.8mmol/l (38.26±26.38%, p<0.05, r=0.69). There was similar but negative correlation between HbA1c and percentage of time within the limit 3.9-7.8mmol/l (56.07±24.28%, p<0.05, r=-0.63). No correlations were found between HbA1c and number of excursions. These results stay the same in different treatment groups. Based on our data we conclude that performing CGM in patients with sta- ble glucose control as in type 2 could present the overall control and could be useful for assessment nevertheless short period of time that it refl ects.

958-P Hemodialysis (HD) Modalities May Affect Glycemic Indicator in Patients with Type 2 Diabetes (T2D): Underestimation of Glycated Albumin (GA) in Online-Hemodiafi ltration (OLHDF) 956-P JYUNICHIRO HASHIGUCHI, KOUHEI IKEDA, RICA ETOH, SATOSHI FUNAKOSHI, Performance of Two Continuous Glucose Measurement Devices, TAKASHI HARADA, YUTAKA MORI, KAZUNORI UTSUNOMIYA, Nagasaki, Japan, in Closed and Open Loop System, in Pediatric Patients with Type Komae, Japan, Tokyo, Japan

POSTERS A recent study indicated that, compared with glycated hemoglobin

Therapeutics 1 Diabetes (HbA1c), GA provides a more accurate assessment of glycemic control in HD

Clinical Diabetes/ ULRIKE SCHIERLOH, MALGORZATA E. WILINSKA, PETRA M. BAUMANN, THOM- AS AUGUSTIN, CARINE DE BEAUFORT, ROMAN HOVORKA, THOMAS PIEBER, patients with T2D. Meanwhile current hemodialysis therapy modalities such SPIDIMAN STUDY GROUP, Luxembourg, Luxembourg, Cambridge, United Kingdom, as online-hemodiafi ltration (OLHDF) attempt to remove over a wide molecu- Graz, Austria lar weight including albumin, which promotes turnover of albumin, resulting Closing the loop between continuous glucose measurement (CGM) and in possible underestimation of GA value compared with conventional HD. insulin pump, improving metabolic outcome and quality of life, is one of the The correlation between HbA1c and GA in both HD and OLHDF settings major focus areas of diabetes treatment in children with type 1 diabetes. were investigated. We recruited 117 patients on conventional HD and 31 We evaluated the performance of two CGM devices (Navigator II, Abbott patients on OLHDF, and then monitored monthly HbA1c and GA values for and Dexcom G4, Dexcom) during automated closed loop (CL) using Florence 3 months. D2 system (University of Cambridge, UK) versus open loop arm (OL) , in the As shown in fi gure, no signifi cant difference was obtained in HbA1c in clinic and at home. each modality over 3 month, whereas GA values were consistently larger 15 children, between 6 and 12 years, using insulin pumps, participated in in the group treated with OLHDF. There was no difference in these 2 groups this open-label single centre, randomized cross over study. They were admit- including serum albumin level. ted to a research facility for two overnight stays and two nights at home (CL GA may underestimated when treated with OLHDF presumably albumin and OL). Navigator CGM is part of the Florence D2 system and Dexcom G4 leakage, not serum albumin level. As OLHDF is being applied widely, the CGM was secondary CGM. interpretation of GA becomes important in HD patients with T2D. Complete data for 11 patients (6 females, age 10,6 years, HbA1c 8,2%, diabetes duration 5,6 years) were analyzed. Statistical analysis (Wilcoxon signed-rank test, t-test) comparing Naviga- tor data to Dexcom data was performed for time spent in target: glucose 3.9 to 8.0 mmol/l (CL: Navigator: 67,2%, Dexcom: 60,06%. OL: Navigator: 51,5%, Dexcom: 58,6%), time spent in hypoglycemia <3.3 mmol/l (CL: N: 1,1%, D: 0,8%. OL: Navigator: 2,1%, Dexcom: 6,7%) and <2.5 mmol/l (CL: Navi- gator and Dexcom: 0%. OL: Navigator: 0,02%, Dexcom: 2,0%), time spent in hyperglycemia > 10 mmol/l (CL: Navigator: 13,9%, Dexcom: 16,3%. OL: Navigator: 5,7%, Dexcom: 14,3%) and > 16.7 mmol/l (CL: Navigator: 2,2%, Dexcom: 1,4%. OL: Navigator and Dexcom: 0%), and the AUC < 3.3 mmol/l (CL: Navigator: 0,5%, Dexcom: 0,8%. OL: Navigator: 1,6%, Dexcom: 19,9% and AUC > 16.7 mmol/l (CL: Navigator: 2,5%, Dexcom: 11,9%. OL: Navigator, Dexcom: 0%). No statistically signifi cant difference was found between the two devic- es, neither in the clinic or at home , nor with closed or open loop. Further studies with larger patient populations including all age groups, are now needed to confi rm these preliminary results. Supported By: European Union 959-P Evaluation of the Relationship between Thyroid Hormone Level and 957-P Glucose Variability in Diabetic Patients Continuous Glucose Monitoring Systems (CGMS) as Control As- YAMEI ZHU, SHAN-JI PIAO, LEI ZHANG, ZONGYU QIU, HONGWEI YU, YANHU sessment Tool in Patients with Type 2 Diabetes DONG, Qingdao, China TZVETELINA TOTOMIROVA, IVONA DASKALOVA, Sofi a, Bulgaria Glucose variability is one of the major indicators of glycemic control. In- Glycated hemoglobin (HbA1c) and pre- and postprandial blood glucose creasing number of evidences suggest that glucose variability may cause (BG) level measurement are recommended for diabetes control assessment. diabetic complications. It is important to fully understand the parameters Continuous Glucose Monitoring is proved to be useful for insulin dose adjust- which cause glucose variability for preventing and management of diabetic ment in patients who are on multiple injection regimens or pump therapy. complications. Thyroid hormone levels may be infl uenced by glucose me- There are some other goals that could be achieved by using these devices. tabolism, but the mechanism remains unclear. The aim of this study was to We assessed the continuous glucose monitoring systems (CGMs) as con- evaluate the relationship between thyroid hormone levels and glycemic vari- trol assessment tool in patients with type 2 diabetes. ability in diabetic patients. A total of 55 patients with T1DM (17 males and 38 females) and 262 patients with T2DM (174 males and 88 females) were

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A242 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—GLUCOSE MONITORING AND SENSING included. Each subject underwent 72-hour continuous glucose monitoring 961-P system (CGMS) to document glucose profi le and variability. CGMS data was Infl uence of Initial Insulin Dosage on Blood Glucose of Children and analyzed using Medtronic MiniMed CGMS Solutions software. Glucose vari- Adolescents with Newly Diagnosed Type 1 Diabetes Mellitus ability was assessed using mean amplitude of glycemic excursion(MAGE) of YI WANG, CHUNXIU GONG, XI MENG, Beijing, China glucose during CGMS. And the levels of TSH, FT3, FT4, TT3 and TT4 were To study the infl uence of the initial insulin dosage on blood glucose (BG) determined. Multiple linear regression analyses were used to assess the dynamics, β-cell protection, short- and long-term BG control. Sixty newly infl uence of thyroid hormone on the glucose variability. The FT4 level, even diagnosed type 1 diabetes mellitus patients were randomly assigned to within the normal range, was positively and linearly correlated with MAGE, continuous subcutaneous insulin infusions of 0.6±0.2 U/kg/day (Group 1); which is most commonly used to assess glucose variability (Beta =0.44, 1.0±0.2 U/kg/day (Group 2); or 1.4±0.2 U/kg/day (Group 3) for 3 weeks. BG P =0.032 ). But correlation between FT3 level and MAGE was not signifi cant was monitored continuously for the fi rst 10 days and the last 2 days of weeks (P=0.096). Also TT3, TT4 and TSH were not correlated with MAGE. It implies 2 and 3. Twenty-four hour urinary 8-iso-PGF2α was assayed on days 8, 9, that FT4 is one of parameters which cause glucose variability. These data and 10. The occurrence and duration of honeymoon period were recorded. support that management of thyroid hormone, especially FT4, is necessary Fasting C-peptide and glycosylated hemoglobin (HbA1c) were assayed after in all diabetic patients. 1, 6, and 12 months of insulin treatment. BG concentrations decreased to the target range by the end of week 3 (Group 1), week 2 (Group 2), or week 960-P 1 (Group 3). The actual insulin dosage over the 3 weeks, frequency of hypo- Regular-Life Use of Patient Real-Time CGM Data glycemia on weeks 1 and 2, and median BG at the end of week 1, but not KATHERINE NAKAMURA, TYLER KENT, TOM HALL, JORGE VALDES, ANDREW 8-iso-PGF2α differed signifi cantly in the three groups. Age-group compari- BALO, San Diego, CA sons revealed that younger patients needed a lower insulin dosage. Severe While many RCTs have reported signifi cant clinical benefi t from real-time hypoglycemia was not observed in any patient, but there were signifi cant CGM (RT-CGM) use in diabetes management, there is no published informa- group differences in the time at which hypoglycemia fi rst occurred.Differ- tion for patients’ regular-life use of RT-CGM. This is the fi rst look at a CGM ences in initial insulin dosage produced different BG dynamics in week 1, data repository collected via Dexcom technical services. equivalent BG dynamics on weeks 2 and 3, but had no infl uence on short- and Patients volunteered their RT-CGM data seeking diagnostic support. A long-term BG control and β-cell function. Choice of insulin dosage should be total of 300 patients uploaded their Dexcom G4 Platinum CGM data over guided by BG monitoring.

several months of 2014, of which half of were male. POSTERS Approximately 5.8 M records of CGM data revealed an average of 75 days Therapeutics

962-P Clinical Diabetes/ CGM use, with a daily average of 161 mg/dL and a CV of 32%. These patients Continuous Glucose Monitoring (CGM) Data Mining for Sensor Glu- spent 1.2 hrs (±1.9 hrs) per day in Hypoglycemia (CGM ≤ 70mg/dL), half of cose Prediction—A Machine Learning Perspective which were nocturnal; and spent 3.4hrs (±4.8 hrs) in hyperglycemia (CGM≥ JIN YAN, LANE DESBOROUGH, WEI CHEN, Northridge, CA, New York, NY, Berke- 240 mg/dL). The majority of patients have their low alert set at 80 mg/dL, ley, CA and high alert set at 200 mg/dL, the same as the manufacturer defaults. On Background: The large volume of sensor glucose (SG) data available from average, patients reviewed their CGM screens 41(±32) times a day. Multi- CGM system motivates the development of methods to investigate short- variate analyses indicated that glycemic control variables, including mean, term blood glucose predictions in type 1 diabetes mellitus. Machine Learn- variance, CV of CGM glucose, time in hypoglycemia, and time in hyperglyce- ing (ML) techniques are widely used for data analysis and pattern discovery. mia were associated with the duration of CGM use, meal time, time of day ML applications on SG data can provide opportunities to improve the ef- as well as interactions with CGM. fi cacy and quality for sensor-augmented pump therapy. The study suggests that the patients’ glycemic controls were well main- Methods: A discrete-time model of short-term glucose predictor is devel- tained with frequently interactions with their CGM. The upcoming con- oped as a function of carbohydrate intake and insulin infusion. The model nected CGM solution for patient regular daily use would further advance includes six individualized parameters and we performed recursive least diabetes management. square (RLS) to optimize these parameters. Performance of this new algo- rithm was assessed using CGM data over a 24 h duration. Results: Refer to Figure 1. Conclusions: The simulation results demonstrate the potential of this ma- chine learning method, which could serve as a sensor glucose data mining approach for producing personalized short-term glucose predictions, improv- ing the decision making for insulin delivery and meal bolus compensation/in- take, and standardizing personalized real-time therapy based on CGM data.

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A243 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—GLUCOSE MONITORING AND SENSING

963-P 965-P Electrical Attachment of a Glucose Oxidase Molecule on a Carbon The Effect of Self-Monitoring Blood Glucose among Inmates with Nanotube as a Component of an Artifi cial Pancreas Diabetes GORDON A. THOMAS, SONALI KAMATH, REGINALD FARROW, ALOKIK KAN- ROBIN N. HUNTER BUSKEY, Raleigh, NC WAL, Newark, NJ The increasing prevalence and risk for complications from diabetes neces- Our long term goal for this research project is to make an implantable, ar- sitate patient participation and attentiveness to select appropriate foods, tifi cial pancreas which can administer insulin based on the glucose concen- perform regular physical activity and be active in diabetes management and tration measured in interstitial fl uid. As an initial step toward making a very self-maintenance. Only one-third of individuals with diabetes achieve treat- small and implantable glucose detector using individual glucose oxidase ment targets. Inmates are a unique population challenged by the increased molecules, a microcircuit was made containing wires covered by an insulat- prevalence of chronic conditions such as diabetes. The correctional setting ing later with 30 nm diameter holes that provided access from a solution to presents clinical management limitations. Diabetes clinical practice guide- external electronics. Next, charged carbon nanotubes in suspension were lines for inmates incorporate personal glucose monitoring for insulin users. directed using electrophoresis toward the holes. The connection between In 2009, the Federal Bureau of Prisons initiated a self-monitoring glucose two wires through the media solution produced no voltage within our noise program for inmates requiring insulin. Glucose meters were distributed to limit. However, an applied voltage of 0.2V produced a current 43 thousand inmates to facilitate self-monitoring of blood glucose. times larger than for the empty holes (1.3micro-A). We sought to evaluate the effectiveness the self-monitoring program had Next, the protocol was to use a similar electrophoretic technique to attempt on the hemoglobin A1c (HbA1c) values of diabetic inmates requiring insulin. to attach a glucose oxidase on the tip of one nanotube and a laccase mol- A group of 61 insulin-using inmates were randomly selected for a retrospec- ecule on an adjacent nanotube. As a test, the pair was immersed in a solution tive medical record review. containing glucose, oxygen and the media. When the circuit through the pair Average baseline and follow-up HbA1c values were compared over 30 and the solution was completed electrically, the voltage rose rapidly up to 1V, months starting on the glucose meter issuance date. A change in the HbA1c producing a peak current of 32 electrons/ms. After the initial fl ow of ions, the was evaluated by 2-tailed t test. The sample was divided into three groups voltage decreases with time in a quasi-exponential form, indicative of a deple- by glycemic control: group one - target, group - two mild to moderate, and tion of the ionic concentration around the proteins and that the region spreads group three - poor. Statistically signifi cant HbA1c increases were observed with time. At times longer than 600s, the equilibrium voltage approaches a in the mild to moderate group and statistically signifi cant decreases were stable average value of 200mV or 7 electrons/ms with fl uctuations of about observed in the poor group. Possible infl uential factors on HbA1c included POSTERS Therapeutics 20mV. These results indicate that the proteins are electrically connected to co-morbidities, medications, and ethnicity. Although glucose monitoring Clinical Diabetes/ the nanotubes and to the glucose solution, demonstrating that this molecular was not demonstrated to decrease HbA1c levels in the mild to moderate confi guration is a potential component of a small glucose monitor. group, glucose monitoring was associated with decreased levels in the poor Supported By: National Science Foundation group, indicating the importance of promoting self-monitoring blood glucose among this population. 964-P Periodic CGM in T2DM: Exploring Benefi ts across Various Therapy Choices 966-P The Use of CGM to Identify Type 1 Diabetic Patients with Hypo- JOTHYDEV KESAVADEV, PRADEEP BABU SADASIVAN PILLAI, ARUN SHANKAR, glycemia Problems and Its Impact for Avoidance of Biochemical GEETHU SANAL, JAYASREE LALLY, GOPIKA KRISHNAN, SUNITHA JOTHYDEV, Hypoglycemia Trivandrum, India We assessed glycemic patterns and A1c across various regimens in T2DM NORBERT HERMANNS, BERNHARD KULZER, DOMINIC EHRMANN, THOMAS using Professional Continuous Glucose Monitoring (CGM). 432 were ran- HAAK, Bad Mergentheim, Germany domized; 301 (77% male) with age 54 (SD=12.7) underwent CGM at base- This cross-over study used a CGM system (DexCom SEVEN PLUS CGM). line and 6 months. We noted their glycemic patterns (Table 1) and made In a randomized order, participants had either no access (CGM blind) or real suitable changes to diet, exercise and treatment (Table 2) aided by SMBG time access to current glucose data (CGM open). One objective was to ana- and telemedicine. Paired-samples t-test was conducted to compare A1c at lyze if type 1 diabetic patients with hypoglycemia problems (at least one the time of initial CGM and at 6 months. There was signifi cant difference in episode requiring third party assistance) could be identifi ed by the use of the initial (M=7.5%, SD=1.4) and fi nal A1c (M=7.0%, SD=0.9); t (300)=11.54, p = blinded CGM data. We also analyzed the impact of CGM use on biochemi- <0.0001. Repeat CGM at 6 months showed signifi cant improvement in GV. cal hypoglycemia. Type 1 diabetic patients with hypoglycemia problems had Of the different treatment categories, CSII showed biggest difference in A1c signifi cant longer diabetes duration (17.0 vs. 11.0 yrs.), a higher unawareness (-0.5%), followed by basal bolus (-0.4), biphasic (-0.3), and basal (-0.2). Peri- score (4.0 vs. 2.0) and lower thresholds for detecting hypoglycemia (50.0 odic CGM in T2DM may offer benefi ts in safely reaching glycemic targets. vs. 65.0 mg/dl) than patients without hypoglycemia problems. During the blinded CGM phase patients with hypoglycemic problems had a signifi cant Table 1. longer duration of low glucose phases 248 vs. 153 minutes per day (p=.037; Patterns Detected in CGM. <70 mg/dl) respectively 173 vs. 96 minutes per day (p=.041; <60 mg/dl). Area Hypoglycemia Nocturnal 65 (22%) under the receiver operating curve (ROC 0.72 p=.03) indicated a suffi cient screening performance of the duration of low glucose periods (< 70 mg/dl) Early morning 25 (8%) for the identifi cation of patients with hypoglycemia problems. A cut-off of Pre-lunch 12 (4%) 170 minutes per day of time spend in the low glucose range had a sensitivity Evening 21 (7%) of 75% and a specifi city of 70.3%; the positive predictive value was 52.9%, Hyperglycemia Dawn phenomenon 1 (0%) the negative predictive value was 86.4%. A comparison of blind vs. open CGM showed that time spend in a low glucose range could be signifi cantly Post-meal spike 136 (45%) more reduced in patients with hypoglycemia problems than in patients with- Both hypo & hyperglycemia Somogyi phenomenon 5 (2%) out hypoglycemia problems during CGM open (< 60 mg/dl; - 67.8 min per day Other excursions 137 (46%) p=.040; < 50 mg/dl; -50.6 min per day, p=.038; < 40 mg/dl; -41.4 min. per day, p=.03). This study shows that CGM has an unused potential for identifying Table 2. type 1 diabetic patients at risk for hypoglycemia problems in clinical practice Interventions Made after CGM. as well as for avoidance of biochemical hypoglycemia, which plays a pivotal role for the development of hypoglycemia associated autonomic failure. Interventions N (%) Supported By: Dexcom Dietary modifi cations 298 (99%) Exercise modifi cations 289 (96%) Change in OHA dose/regimen 114 (38%) Change in insulin dose 161 (53%) Change in insulin time 30 (10%) Change in insulin type 42 (14%) Recommended CSII 56 (19%)

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A244 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—GLUCOSE MONITORING AND SENSING

967-P 969-P Early Endobarrier Glucometrix Premix Insulin Analogs Preserve Good Glycemic Control in Patients GABRIELLA SEGAL-LIEBERMAN, ALON LANG, MAOR LAHAV, NICKY LIEBER- with Type 2 Diabetes Previously Treated with Premix Human Insu- MAN, AYANA PASTER, NOA KONVALINA, HANNAH KANETY, RINA HEMI, JA- lin: A CGM Study COB ILANI, OHAD COHEN, Ramat Gan, Israel, Tel Aviv, Israel TRIANTAFYLLOS DIDANGELOS, CHARALAMPOS MARGARITIDIS, FOTIOS ILI- The Endobarrier (by GI Dynamics®) is a device that shields the duodenum ADIS, ARETI HITOGLOU, KALI MAKEDOU, CHRISTOS SAVOPOULOS, APOSTOLOS and upper jejunum from contact with chyme, thereby mimicking in part a HATZITOLIOS, Thessaloniki, Greece Roux-en-Y gastric bypass (RYGB) operation, which has been shown to de- The aim of the study was to establish if good glycemic control could be crease plasma glucose in an acute, weight-independent fashion. The Endo- preserved with premix insulin analogs (type 30/70, PIA) in patients with type barrier device, provides a unique opportunity to help decipher the contribu- 2 diabetes (DM) previously well controlled with premix human insulin (type tion of duodenal bypassing to the effect of RYGB on glucose homeostasis. 30/70, PHI) with the use of continuous glucose monitoring (CGM). An Endobarrier device was placed in the duodenum of 45 obese, uncon- We studied 14 patients with DM type 2 (8 men, 6 women), aged 63.8±10.7 trolled diabetic subjects with a mean diabetes duration of 11 years, baseline years, on PHI treatment and good glycemic control (HbA1c 6.7±0.1%). A 7-day HbA1c of 9.5% and a BMI of 37.6 kg/m2. CGM (iPro2 Medtronic) was placed on all patients. After a month, the treat- Acute effects of the Endobarrier on glucose homeostasis were evalu- ment was changed to PIA instead of PHI and a 7-day CGM was placed again. ated using a Continuous Glucose Monitoring (CGM) recording device for We measured Glycated Albumin (GA) and Fructosamine (FRU) as indices of one week, as of two days prior to Endobarrier insertion until four days after glycemic control. the procedure. CGM data revealed a signifi cant decrease in average daily PIA compared to PHI preserved good glycemic control (average glucose glucose levels within 24h after insertion. Four days after the procedure, a 139.9±21.3 vs. 140.0±19.3 mg/dl, p=0.988). The changes before and after decrease of 39±44 mg/dL in average daily glucose levels, a decrease of over in the two 7-days CGM time periods between PIA vs. PHI were similar in 50% in high glucose values (>180 mg/dL) and an increase of 63% in the time GA and in FRU (GA, -3.8±34.1 vs. 2.9±59.1 µmol/L, p=0.695, FRU -6.5±32.4 spent within range (70-180 mg/dL) were observed. vs. 3.2±34.4 µmol/L, p=0.413 ) and there was no signifi cant difference in This improvement in glucose tolerance occurred despite a signifi cant re- all parameters of glucose variability in CGM (standard deviation: 48.6±20.0 duction in diabetes treatment. Among patients treated with insulin (71% vs. 45.6±13.2 mg/dl; p=0.583). Mean absolute difference percent between of the cohort), average daily insulin dose decreased by 49% (from 88 to 45 paired blood and sensor glucose values was calculated: 10.5±6.7 vs. units per day). 13.1±5.1%; p=0.080). Area under the curve (AUC) for sensor glucose<70 mg/ POSTERS Appetite, evaluated by a visual analog scale (VAS), has shown a signifi - dl was similar too (5.0±3.5 vs. 3.4±3.5, p=0.250). Moreover, there was no Therapeutics cant reduction after 12 weeks of Endobarrier treatment (p<0.003) despite difference in total insulin units (49.5±14.5 vs. 47.9±13.1, p=0.064). Only, be- Clinical Diabetes/ the fact that participants have lost an average of 11.2 kg during this time. En- tween 11.00 pm and 3.00 am, AUC above 130 mg/dl of sensor glucose was dobarrier therapy in advanced uncontrolled obese diabetic subjects seems signifi cantly more with PHI compared to PIA (47.4±30.1% vs. 34.0±24.9%, to have an early glucose lowering effect, supporting the concept of duodenal p=0.049). There was a positive correlation between average glucose and bypassing mediating the acute improvement in glucose homeostasis seen GA, FRU (0.696, p=0.008, 0.777, p=0.002). after RYGB. In addition to glucose lowering, duodenal bypassing seems to Premix insulin analogs preserve good glycemic control in patients with be an important player in weight loss as well as appetite suppression, both type 2 diabetes previously treated with premix human insulin and also allow seen after RYGB. These observations render Endobarrier a promising treat- fl exible injection timing, relative to meal timing, thus improving adherence, ment for “diabesity.” compliance and quality of life. Supported By: Clalit Health Services; Israel Diabetes Association 970-P 968-P Effect of Acarbose on Blood Glucose Fluctuations in Patients with Insulin Pump Therapy Directed Only by a Continuous Glucose Moni- Type 2 Diabetes on Insulin Therapy toring System in Type 1 Diabetes in Everyday Life JIANHUA MA, FENGFEI LI, Nanjing, China MICHAEL MUELLER-KORBSCH, Vienna, Austria Objective: Postprandial glucose fl uctuations may increase oxidative Eight patients treated for their diabetes type 1 with insulin pump therapy stress, and increase cardiovascular risk in type 2 diabetes mellitus (T2DM). were switched from the common fi ngerstick glucose measurements to a Addition of acarbose to patients with T2DM who are inadequately controlled continuous glucose monitoring system (CGM) fi ngersticks blood glucose are with insulin may lower HbA1c levels. The present study aims to evaluate the only taken once a day during a steady state glucose level to calibrate the effect of adding acarbose on glycemic excursions measured by Continuous system. The CGM values and the trends were used to charge the preprandial Glucose Monitoring System (CGMS) in patients with T2DM already on insu- insulin doses and to correct higher glucose levels by the bolus calculator. In lin therapy. addition the patients received an algorithm to respond to rising and falling Patients and Methods: A randomized, parallel-group study of 34 T2DM trends shown on the CGM. If the CGM trends were rising patients had to give patients (HbA1c range, 7.5-9.0%) was carried out. After therapy with con- a supplement insulin dose, if the trends were falling the insulin pump were tinuous subcutaneous insulin infusion for 7 d, patients were randomized to stopped and sometimes additional carbohydrates have to be taken. The receive acarbose plus Pre-mixed 30/70 insulin or Pre-mixed 30/70 insulin amount of hypoglycemic values below 55 mg/dl was 2% with the CGM. 5% therapy only, for 2 weeks. CGMS was used to measure glucose fl uctuations of the values lies in the range between 56 to 69 mg/dl and 50% of the values for 3 days. The primary endpoint was the 24 h mean amplitude of glycemic lies in the target area with 70- 130 mg/dl. The HbA1c decreased about 0, 5 excursions (MAGE). The secondary endpoints included the 24 h mean blood and 1% from the basic values. The mean glucose levels lies between 117 and glucose (MBG), the standard deviation of the MBG, the percentage time 152 mg/dl and the standard deviation between 46 and 65. The HbA1c values duration (%) of hyperglycemia (glucose > 10.0 mmol/L) and hypoglycemia goes from 5, 5 tol 7, 5%. The fi nal observation period for all patients will be 6 (glucose < 3.9 mmol/L), the incremental AUC of blood glucose above 10.0 months. With this new way of routing the insulin pump therapy by the CGM mmol/L, the AUC of glucose below 3.9 mmol/L, as well as hyperglycemia no unexpected glucose values appeared and if the values raise up or down and hypoglycemia episodes. The AUC of severe hypoglycemia (glucose < 2.8 the patients have the opportunity to change the ongoing process in a better mmol/L) was also analyzed. Data were expressed as mean ±SD or medians way. Therefore it is not necessary to count the carbohydrates exactly. (25th, 75th quartiles) values. Results: Although the MBG did not differ signifi cantly between the two groups, the addition of acarbose improved MAGE of glucose levels (P = 0.044). Acarbose signifi cantly decreased the AUC of blood glucose above 10.0 mmol/L (P = 0.037). Furthermore, severe hypoglycemia (< 2.8 mmol/L) was signifi cantly reduced in the acarbose group. Conclusions: Addition of acarbose to insulin therapy improves glucose fl uctuation in patients with T2DM.

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A245 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—GLUCOSE MONITORING AND SENSING

971-P a month. Many classical diabetes assays, such as ivGTT, oGTT, ITT, clamp, Glycemic Variability Correlates with 1.5-anhydroglucitol (1.5-AHG) were tested with this remote method and compared with the conventional but Not with Markers of Oxidation, Infl ammation, and Endothelial glucometer assay (Fig. 1). Our data demonstrate the 1st success of remote, Function: Baseline Characteristics of the CAROLINA® CGM Sub- continuous monitoring of blood glucose in conscious, stress-free NHPs and study its potential advantages bringing to diabetes research and drug discovery. ROGER S. MAZZE, RICHARD M. BERGENSTAL, ELLIE STROCK, XI MIN, KYLE THOMPSON, SARAH K. BORGMAN, KARIN HERMANSSON, MICHAELA MAT- THEUS, HANS-JUERGEN WOERLE, ODD ERIK JOHANSEN, Shorewood, MN, Min- neapolis, MN, Stockholm, Sweden, Ingelheim am Rhein, Germany, Asker, Norway DPP4-inhibitors enhance glucose-induced insulin secretion, decreases glucagon secretion and might effectively reduce blood glucose variability. This is investigated in the CGM substudy of CAROLINA®, an ongoing, CV outcome trial comparing linagliptin with glimepiride. To explore potential relationships between glycemic variability (assessed with CGM, Dexcom SEVEN PLUS) and circulating markers of glucose variability (1.5-AHG), oxi- dative stress, endothelial function and systemic infl ammation we analyzed the baseline glucose excursion patterns and assessed whether glycemic variability was correlated with fi ve vascular markers. Specifi cally, we char- acterized the baseline ambulatory glucose profi les with glucose exposure (by total area under the curve), glucose variability (by inter-quartile range) and glucose stability (by the average hourly absolute change) of all CGM readings in 2-week periods. Mean±SD age of the 44 patients with T2D was 66±9 years and HbA1c 7.0±0.4%. A modest, signifi cant negative correlation between glycemic variability and 1.5 AHG was observed, but not for the vas- cular markers (Table). Future analysis of the prospective CAROLINA® CGM substudy will determine if glimepiride and linagliptin have differing impact POSTERS Therapeutics on glycemic excursions patterns. Clinical Diabetes/

973-P Self-Assessment of Glucose Levels in the Real World Is Less Fre- quent than Proposed in Major Guidelines RICHARD HELLMUND, Alameda, CA Adherence to guidelines for glucose monitoring in diabetes is essential to manage the risk of serious fl uctuations in glucose and achieve glycaemic control. Three retrospective studies which assessed the frequency of glu- cose monitoring via prescription data have been identifi ed. They showed many patients tested less often than recommended by major guidelines. This gap in monitoring frequency could contribute to the growing clinical and economic burden of diabetes. A U.S. cohort analysis of insulin-dependent patients in the IMS LifeLink database from 2007-2009 indicated the median number of test strips per day was 1.43 (519/year, n = 45,555). A Canadian cohort study using the IMS Brogan Inc. Drug plan database from 2006-2010 showed patients receiving insulin used a mean of 3.0 strips/day (1094/year, n = 142,551). A recently published UK study of the IMS LifeLink EMR-Europe Database for 2009-2010 indicated a median of 1.65 strips/day (600/year) for 2,676 insulin-dependent patients. This evidence contrasts with guidelines such as ADA (2014) which call for 6 to 8 tests per day for many patients on intensive insulin regimens. Also the European Consensus Statement (Schnell 2009) calls for 2 to 4 tests per day for patients receiving basal or pre-mixed insulin. The studies suggest a large number of patients may be testing less frequently than recommended, Supported By: Boehringer Ingelheim despite payers reimbursing for suffi cient strips to meet guidelines. Hence many patients and their healthcare professionals may have less information 972-P than they need to make informed decisions. Long-Term Continuous Glucose Monitoring in Conscious Stress- It is plausible that insuffi cient glucose monitoring is associated with an Free Nonhuman Primates with Implanted Telemetry Device increased rate of hypoglycemia and diabetic complications. Therefore new BINGDI WANG, GUOFENG SUN, XIAOLI WANG, XUNHUA DING, WEIMIN TANG, options in glucose monitoring that provide more actionable information on YI-XIN (JIM) WANG, YONG-FU XIAO, Jiangsu, China patients’ glycaemic profi les, may help manage the escalation in the clinical Diabetes becomes a global epidemic issue. Aging nonhuman primates and economic burden of diabetes. (NHPs) develop insulin resistance and high blood glucose in a way similar to the progression and onset of type 2 diabetes in humans, which makes them 974-P an excellent model for diabetes research. The conventional tests of blood BTI-320, a Nonsystemic Novel Drug to Control Glucose Uptake into glucose are by handheld glucometer, clinical chemistry analyzer or analox the Bloodstream, Functions as a Competitive Inhibitor of Sugar Hy- analyzer. These methods require periodical blood sampling with potential drolyzing Enzymes subject stress and ethical volume limitation, especially during research. KEVIN H. MAYO, AURELIO DREGNI, MICHELLE C. MILLER, BEN RIVNAY, DAVID This study investigated HD-XG transmitter, a Data Sciences International PLATT, Minneapolis, MN, Manchester, NH implantable device, for continuous monitoring of blood glucose in conscious Ingestion of sugars results in generation of glucose, and its uptake into NHPs. The glucose sensor was implanted into a femoral artery and the refer- the blood, causing a spike to which diabetics are sensitive. BTI-320 is a ence electrode plus its device body was implanted subcutaneously nearby. novel, non-systemic therapy that safely reduces postprandial glucose excur- A small receiver/amplifi er was carried in the monkey jacket for remote signal sions with reduced side effects compared with acarbose. BTI-320 is com- collection from outside cage. Blood glucose, body temperature and physi- posed of non-glucose-containing polysaccharides, essentially a composite cal activity were monitored wirelessly and recorded continuously for over of two modifi ed galactomannans: GM-α and GM-β. A number of enzymes

For author disclosure information, see page A810. & Guided Audio Tour poster ADA-Funded Research

A246 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULINS are responsible for sugar hydrolysis in the body. The present study was de- Faster aspart vs. IAsp had signifi cantly faster onset of appearance (LSmean, signed to assess the molecular mechanism of action of BTI-320 in the inhi- min: children, 5.2 vs. 9.8; adolescents, 5.3 vs. 11.0; adults, 5.5 vs. 12.3). Insu- bition of several sugar hydrolyzing enzymes (α-amylase, maltase, sucrose, lin exposure within 1 h was higher for faster aspart vs. IAsp (greatest diff. and lactase). We used nuclear magnetic resonance (NMR) spectroscopy to within 15 min; Table). Faster aspart had a greater glucose-lowering effect investigate interactions between BTI-320 components, GM-α and GM-β, vs. IAsp (ΔPGav, signifi cant in children; Table). PG1h treatment diff. (faster and these enzymes, as well as the effects that GM-α and GM-β have on aspart–IAsp; estimates [95% CI], mmol/L): children, –1.87 [–3.71; –0.04]; the rates of enzyme-mediated sugar hydrolysis to glucose. Results were adolescents, –0.64 [–2.26; 0.97]; adults, –1.10 [–2.64; 0.44]. Treatment ef- compared with those on acarbose. Chemical shift changes in NMR spectra fect did not differ signifi cantly between age groups (PG1h, P=0.56; ΔPGav,0–1h, demonstrated that GM-α interacts with the enzymes. Using a colorimetric P=0.15; ΔPGav,0–2h, P=0.32). There were no safety/tolerability issues. Faster assay with para-nitrophenyl-glucose as substrate, we demonstrate with onset and higher early insulin exposure with faster aspart vs. IAsp led to a Michaelis-Menten plots that GM-α functions as a competitive inhibitor larger glucose-lowering effect, though only signifi cant for children, who are with maltase, sucrase and lactase. In the presence of 2 mg/ml GM-α, Km prone to rapidly fl uctuating glucose levels and unplanned food intake. values of this substrate for all three enzymes were increased by up to a factor of three. Using the starch-iodine assay, we also found that the rate of α-amylase-mediated starch hydrolysis is decreased by about a factor of two in the presence of 2 mg/ml GM-α. The effect on the rate of starch hydro- lysis with acarbose is similar but at concentrations of about 100-fold less. Although GM-β also shows some activity against these enzymes, it is about 5 to 10-fold less effective, suggesting that GM-α is the active ingredient in BTI-320. Our fi ndings provide insight into how BTI-320 may function in vivo and support the potential viability of BTI-320 as an alternative to acarbose therapy. Supported By: Boston Therapeutics, Inc.

975-P

Our Experience of Using Sensor Augmented Insulin Pump (Minimed POSTERS 620G) Therapeutics Clinical Diabetes/ YUKO HOTTA, TOMOYUKI KAWAMURA, KAYAKO HASHIMURA, MASAHIKO JOO, YONEO KASHIHARA, TOMOMI HASHIMOTO, MASAKAZU HIROSE, TAKASHI HI- GASHIDE, MAYUMI AONO, SHIGEO AONO, HARUO SHINTAKU, Osaka, Japan, & 977-P Kitakyushu, Japan, Nishinomiya, Japan, Toyonaka, Japan Postmeal Glycemia following U-400 Ultra-Rapid-Acting/Basal In- In October 2014, we introduced sensor augmented insulin pumps (SAP: sulin BIOD-531 vs. Premixed and U-500 Insulins in Patients with Minimed 620G with Entitle®) for patients with type 1 diabetes for the fi rst Type 2 Diabetes time in Japan. LINDA MORROW, LAURIE HAN-CONRAD, LORI CANNEY, PHILIP PICHOTTA, Twenty one patients with type 1 diabetes in our hospital (age 2-41, HbA1c MARCUS HOMPESCH, ALAN KRASNER, ERROL DE SOUZA, Chula Vista, CA, Dan- 7.2±1.2%) started to use SAP. Three patients has changed from MDI and 18 bury, CT changed from Paradigm 722 without real-time CGM. Fifteen were inpatient BIOD-531, a 400 U/ml formulation of recombinant human insulin, EDTA, and 6 were outpatient. We examined how long they could use one sensor citrate, and magnesium sulfate is associated with a biphasic time-action without exchange, the frequency of the self- monitoring of blood glucose profi le characterized by rapid onset and a basal duration of action. In this level (SMBG), and so on. randomized, four-period crossover trial, glucose responses after baseline Sometimes sensors got out of skin by accident and patients had to ex- glucose normalization and injections of test insulins (0.6 U/kg) given with change a sensor for another one within six days. So two patients needed a standardized solid breakfast (921 kcal) were evaluated over a 12 hour pe- more than fi ve sensors for a month. The other patients needed only fi ve sen- riod in 12 patients with type 2 diabetes treated with 50-150 units of insulin/ sors for a month. One patient could continue to use a sensor for 14 days day. BIOD-531 was administered before or after the breakfast. Humalog® without exchange. The frequency of SMBG decreased signifi cantly (7.6 times Mix 75/25 (HMix) and Humulin® R U-500 (U-500) were administered before per a day to 3.5 times per a day). Minimed 620G has much better operability breakfast. Subjects also received a standardized lunch (669 kcal) 5.5 hours than Paradigm 722. The improvement of frequency of sever hypoglycemia after breakfast without additional insulin. Glycemic responses are shown in and HbA1c were also observed by using SAP. Figure 1. BIOD-531 resulted in superior glycemia during the post-breakfast All patients who used Minimed 620G with Entitle® were satisfi ed with period and over the course of the entire day. Overall, pre-meal BIOD-531 it and wanted to continue to use it. However Japanese Health Insurance resulted in average glucose concentration of 177.8 ± 11.9 mg/dl compared to System allows only fi ve sensors per a month, but some sensors cannot be 225.1 ± 10.7 mg/dl with HMix (p < 0.001) and 197.2 ± 8.8 mg/dl with U-500 kept for six days. Therefore, the patients have to try to use one sensor for (p=0.042). BIOD-531 dosed after breakfast also resulted in superior glucose more than six days. control relative to the comparators. All insulins were well tolerated. In sum- mary, BIOD-531 provided superior prandial control compared to either HMix or U-500 in patients with type 2 diabetes. CLINICAL THERAPEUTICS/NEW TECHNOLOGY— INSULINS

Guided Audio Tour: Working to Improve Mealtime Insulin Therapy (Posters: 976-P to 983-P), see page 15.

& 976-P Earlier Onset and Higher Early Exposure of Faster-Acting Insulin Aspart vs. Insulin Aspart in Adults Is Retained in Children and Ado- lescents with T1D THOMAS DANNE, TORBEN BIESTER, MARYAM FATH, LARS THORSSON, TORD RIKTE, OLGA KORDONOURI, HANNE HAAHR, Hannover, Germany, Søborg, Denmark Faster-acting insulin aspart (faster aspart) is insulin aspart (IAsp) in a new formulation, with faster absorption after s.c. injection. Twelve children (mean age 10.4 y), 13 adolescents (mean age 15.1 y) and 15 adults (mean age 20.2 y) received 0.2 U/kg single dose (mean: 8.3 U, 12.8 U, and 15.6 U, respectively) of faster aspart or IAsp before a meal test (68% carbohydrates; adjusted for body weight) in a randomized, double-blind, crossover design.

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A247 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULINS

& 978-P early exposure and higher glucose infusion rates (GIR) in the fi rst hour post- Dance-501 Inhaled Human Insulin Has a Dose-Linear Response and dosing than LIS at 0.2 U/kg (AUCINS(0-1h) 71 vs. 48 h*mU/L, AUCGIR(0-1h) 205 vs. Similar Within-Subject Variability as Rapid-Acting Insulin Lispro 122 mg/kg, all comparisons p <0.001). Late effect was signifi cantly lower for ERIC ZIJLSTRA, TIM HEISE, LESZEK NOSEK, HANS-VEIT COESTER, KATHRIN BC LIS (AUCGIR(3-8h) 357 vs. 446 mg/kg, p=0.0115). Dose-proportionality was LÜCKEMEYER, LISA PORTER, SAMANTHA MILLER, ANDY VICK, JAMES B. FINK, established for early and total exposure of BC LIS (AUCINS(0-12h) 102 vs. 205 JOHN PATTON, Neuss, Germany, Brisbane, CA, Ashland, OH vs. 444 h*mU/kg, 0.1 vs. 0.2 vs. 0.4 U/kg) and dose-linearity for pharmacody- This study investigated the pharmacokinetic (PK) and pharmacodynamic namics (AUCGIR(0-12h) 726, 1357 and 2422 mg/kg for 0.1, 0.2 and 0.4 U/kg). BC (PD) properties of Dance 501, a novel inhaled human insulin liquid formula- LIS was well tolerated; no injection site reactions were observed. tion (INH) and device. Conclusion: BC LIS shows dose-linear absorption and action at clinically rele- Twenty-four subjects with type 2 diabetes received 3 INH doses: low (70 vant doses of up to 0.4 U/kg in subjects with type 1 diabetes. Because of its ultra- IU), medium (140 IU) and high (210 IU) and 1 equivalent medium dose (18 U) of fast action BC LIS has the potential to improve postprandial glucose control. s.c. insulin lispro (LIS). The medium dose was repeated to determine within subject variability. PD was investigated during a 12-h euglycemic clamp. Mean PK/PD profi les (fi gure) show a more rapid absorption for the medium INH dose versus LIS (TMAX 54 ± 31 vs. 89 ± 32 min, [mean ± SD]), resulting in a faster initial effect (T50%-GIRmax 49 ± 30 vs. 61 ± 20 min). Relative bioavail- ability and biopotency were 12.2 ± 8.1% and 13.6 ± 5.9%. A linear dose- response was observed for the primary PK parameters (AUC0-8h, CMAX) and a dose-dependent increase for the primary PD parameters (AUCGIR0-12h, GIR- MAX). Within subject variability was comparable between insulins for AUC0-8h (15.5 vs. 12.0%), CMAX (16.9 vs. 24.5%) and GIRMAX (25.7 vs. 21.4%), but higher with INH for AUCGIR0-12h (29.9 vs. 17.0%). No safety issues were identifi ed; cough was observed only in 3 out of 462 inhalations. In conclusion, Dance 501 inhaled insulin shows promising PK/PD charac- teristics with rapid absorption and onset of action and may therefore be-

POSTERS come a clinically meaningful alternative to rapid-acting insulin injectables. Therapeutics Clinical Diabetes/

& 980-P Probing the Mode of Action of Nicotinamide in Faster-Acting Insulin Aspart: Is Local s.c. Blood Flow Affected? JONAS KILDEGAARD, HANNE H.F. REFSGAARD, HELLE B. OLSEN, CLAUS B. JEPPESEN, SVEND LUDVIGSEN, JEPPE STURIS, ULLA RIBEL, Måløv, Denmark Faster-acting insulin aspart for s.c. injection is insulin aspart (IAsp) in a new formulation containing two additional excipients (nicotinamide (NA) and arginine) relative to NovoLog®. This new formulation brings a faster initial absorption of IAsp after s.c. injection. Temporary increased local blood fl ow is a hypothetical mechanism of action by which NA may act on absorption. Xenon 133 (133Xe) washout has been shown to correlate with blood fl ow (Larsen et al 1965). We here investigate if NA when injected s.c. together with 133Xe infl uences 133Xe washout. Plasma IAsp profi les and 133Xe washout were studied in pigs after s.c. injection of formulations including NA and/or 0.6 mM IAsp. Prostaglandin E1 (PGE1) was included as positive control. Formulations were injected at 5 mm depth and 133Xe radioactivity above the depot recorded for 4 hours. Blood was drawn frequently to measure plasma glucose and IAsp. Plasma IAsp profi les revealed increased early absorption with both NA and PGE1. Over the course of the 4 hours, 133Xe washout was clearly enhanced by PGE1, while NA did not have a clear effect. We evaluated the change in 133Xe signal during the fi rst 15 min for the vehicles using linear regression and evalu- ated the slopes as a representation of the early washout. The mean±SD slopes were: NovoLog® vehicle -0.71±1.30 (%/min), NA vehicle -1.24±1.12 (%/min) and PGE1 vehicle -2.47±0.82 (%/min). PGE1 vehicle was signifi cantly different from both NovoLog® and NA vehicles (p<0.002 and P<0.05). NA vehicle was not signifi cantly different from NovoLog® vehicle (p=0.31). & 979-P Faster-acting insulin aspart or IAsp formulated with PGE1 exhibits in- Ultra-Rapid BioChaperone Insulin Lispro (BC LIS): Linear Dose-Re- creased early absorption compared to NovoLog®. 133Xe washout (early and sponse and Faster Absorption than Insulin Lispro (LIS) overall) was signifi cantly affected by PGE1, but not by NA alone. A direct GRIT ANDERSEN, BERTRAND ALLUIS, GRÉGORY MEIFFREN, AYMERIC RAN- effect of NA on local s.c. blood fl ow is therefore considered unlikely to play a SON, CYRIL SEROUSSI, MARTIN GAUDIER, OLIVIER SOULA, ANNELIE FISCHER, major role in the increased early absorption of faster-acting insulin aspart. LESZEK NOSEK, TIM HEISE, Neuss, Germany, Lyon, France Background and Aims: This double-blind, randomised, four period cross- & 981-P over study investigated the dose-response relationship of BC LIS, a novel Effect of Short-Term Intensive Insulin Therapy on Post-challenge ultra-rapid insulin. Hyperglucagonemia in Early Type 2 Diabetes: The Role of Beta Cell Materials and Methods: Thirty-eight male patients with type 1 diabetes Function received single doses of 0.1, 0.2 and 0.4 U/kg of BC LIS and 0.2 U/kg of LIS CAROLINE K. KRAMER, BERNARD ZINMAN, HAYSOOK CHOI, RAVI RETNAKARAN, under automated euglycaemic clamp conditions (ClampArt®, clamp duration Toronto, ON, Canada 12h post-dosing). Hyperglucagonemia is a characteristic feature of type 2 diabetes (T2DM) Results: Mean baseline adjusted insulin (INS) profi les are given in the fi g- that has been postulated to be due to beta-cell dysfunction and the resultant ure. Ultra-rapid properties of BC LIS were confi rmed with signifi cantly greater loss of insulin-mediated alpha-cell suppression. Since short-term intensive

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A248 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULINS insulin therapy (IIT) can improve beta-cell function when administered in ear- & 983-P ly T2DM, we sought to determine whether IIT can reduce hyperglucagone- Higher Early Exposure and Greater Early Glucose-lowering Effect mia. In this study, 62 patients (age 59±8.3 yrs, A1c 6.8±0.7%, T2DM 3.0±2.1 with Faster-Acting Insulin Aspart vs. Insulin Aspart in Japanese yrs duration) underwent 4 weeks of IIT (basal detemir and pre-meal aspart). Patients with T1D Glucagon response was measured by area-under-the-glucagon-curve (AUC- MASANARI SHIRAMOTO, TOMOYUKI NISHIDA, ANN KATHRINE HANSEN, glucagon) on oral glucose tolerance test at baseline and 1-day post-IIT. Beta HANNE HAAHR, Fukuoka, Japan, Tokyo, Japan, Søborg, Denmark cell function before and after IIT was assessed by (i) Insulin Secretion- Faster-acting insulin aspart (faster aspart) is insulin aspart (IAsp) in a new Sensitivity Index-2 (ISSI-2) and (ii) ΔISR0-120/Δglucose0-120*Matsuda index formulation, with faster initial absorption after s.c. injection. This trial inves- (where ISR is the prehepatic insulin secretion rate determined by C-peptide tigated the pharmacokinetic (PK) and pharmacodynamic (PD) properties of deconvolution). Following IIT, both measures confi rmed improvement in faster aspart vs. IAsp after s.c. injection in Japanese patients with T1D. For- beta-cell function (both mean increase ≥25%, P<0.02). Of note, there was a ty-three patients (mean age ± SD: 39.4 ± 9.4 yrs) received a single dose (0.2 marked reduction in AUCglucagon (P<0.001) (Fig). However, the decrease in U/kg s.c.) of faster aspart or IAsp under glucose-clamp conditions (STG-22; AUCglucagon was not associated with the change in either beta-cell mea- blood glucose target 100 mg/dL; duration 12 h post-dose) in a double-blind, sure (both r<0.10, p>0.44). Thus, short-term IIT can reduce post-challenge randomized, crossover design. Onset of appearance and t50%Cmax with faster hyperglucagonemia in early T2DM but this effect does not appear to be due aspart occurred 58% and 35% earlier than with IAsp, and faster aspart had to improved beta cell function. greater early insulin exposure during the fi rst 2 h (2-fold greater exposure than IAsp in the fi rst 30 min post-dose); total exposure was similar (Table). Faster aspart had greater glucose-lowering effect within 2 h post-dose vs. IAsp (greatest diff. in the fi rst 30 min), and earlier onset of glucose-lowering effect (Table). Earlier onset of action with faster aspart vs. IAsp was sup- ported by ~10 min shorter t50%GIRmax (37.5 vs. 47.4 min; treatment diff. [95% CI]: -9.97 min [-12.78; -7.15]). Both treatments were well tolerated. Earlier onset and greater early insulin exposure with faster aspart led to a greater early glucose-lowering effect vs. IAsp in Japanese T1D patients. POSTERS Therapeutics Clinical Diabetes/

& 982-P The Signifi cance of Obtaining Single-Patient Evidence for the Best Insulin Treatment in Patients with Type 1 Diabetes with Recurrent Severe Hypoglycemia—Lessons from the HypoAna Trial ULRIK PEDERSEN-BJERGAARD, PETER L. KRISTENSEN, HENNING BECK-NIELS- EN, KIRSTEN NØRGAARD, HANS PERRILD, JENS S. CHRISTIANSEN, TONNY JENSEN, HANS-HENRIK PARVING, BIRGER THORSTEINSSON, LISE TARNOW, Hillerød, Denmark, Odense, Denmark, Hvidovre, Denmark, Copenhagen, Denmark, Guided Audio Tour: Development in Basal Insulin (Posters: 984-P to 991-P), Aarhus, Denmark see page 17. The scientifi c evidence for the benefi t of insulin analogs on a single patient level in type 1 diabetes is sparse. We made a post-hoc analysis of data from & 984-P the HypoAna cross-over trial to test the hypothesis that obtaining single- Superior HbA1c Reduction with Basal Insulin Peglispro (BIL) vs. In- patient evidence for the superior treatment can improve overall treatment sulin Glargine (GL) Alone or with Oral Antihyperglycemic Medica- outcomes compared to grouped treatment approach, based on either human tions (OAMs) in T2D Patients (Pts) Previously Treated with Basal insulin or analog insulin. Insulin: IMAGINE 5 In a two-year, multicentre, prospective, randomised, open, blinded end- JOHN B. BUSE, HELENA W. RODBARD, CARLOS TRESCOLI SERRANO, JUNXIANG point (PROBE) trial, 114 patients with type 1 diabetes and recurrent severe LUO, TIBOR IVÁNYI, JULIANA BUE-VALLESKEY, MARK L. HARTMAN, MICHELLE hypoglycemia were treated with basal-bolus therapy based on analog A. CAREY, ANNETTE M. CHANG, Chapel Hill, NC, Rockville, MD, Valencia, Spain, (detemir/aspart) and human (NPH/regular) insulin in a balanced cross-over Indianapolis, IN, Budapest, Hungary, Blue Bell, PA design aiming at maintenance of baseline HbA1c. For each patient the su- The novel basal insulin analog BIL has a fl at activity profi le and reduced perior treatment was considered that resulting in fewest events of severe peripheral effect resulting in a hepato-preferential action. This Phase 3, hypoglycemia defi ned by ADA criteria, or in case of similarity, that eventually open-label, treat-to-target 52-week study in T2D pts (HbA1c ≤9%) on basal resulting in a more than 0.4% lower HbA1c. insulin alone or with up to 3 OAMs, assessed noninferiority of BIL to GL in A higher proportion of the patients (n= 56; 49%) had superior outcome reducing HbA1c at 26 wks (margin=0.4%) when added to prestudy OAMs. Pts with analog insulin compared with equal outcome (n=30; 26%) and better were randomized 2:1 to BIL (N=307) or GL (N=159); 162 pts underwent MRI outcome on human insulin (n=28; 25%) (p=0.0016). The overall rate of severe to assess liver fat content (LFC). Superiority of BIL vs. GL was demonstrated hypoglycemia during the superior treatment for each patient of 0.67 episode for change in HbA1c at 26 and 52 wks. In addition, more BIL pts reached per patient-year was lower compared to the 1.1 and 1.6 episode per patient- HbA1c <7% and lab FSG was lower with BIL. BIL pts had a 60% rate reduc- year with analog insulin and with human insulin, respectively (p<0.0001). tion vs. GL in nocturnal hypoglycemia (hypo) and more pts reaching HbA1c There was no clinically signifi cant difference in HbA1c between the three <7% without nocturnal hypo over 52 wks. BIL-treated pts had a lower total groups. hypo rate, higher basal insulin dose, and numerically less weight gain. BIL We conclude that in patients with type 1 diabetes and recurrent severe pts had higher triglycerides (TGs), lower LDL-C and HDL-C, no difference in hypoglycemia treatment based on analog insulin resulted in better outcome non-HDL-C, and higher ALT and AST. More BIL pts had ALT ≥3x ULN (2.3 vs. in twice as many patients as treatment based on human insulin. Individu- 0%, p=.101), with no cases of Hy’s law. LFC increased from baseline in pts alized treatment selected according to single-patient evidence may result on BIL vs. GL with stable LFC from wks 26 to 52. In summary, in patients in clinically signifi cant further improvement of outcomes compared to a previously treated with conventional basal insulins, BIL provided superior grouped treatment approach. reduction in HbA1c, less nocturnal and total hypo, and higher TGs, ALT, and Supported By: Novo Nordisk A/S LFC compared to GL.

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A249 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULINS

Table. less bolus insulin. With BIL, LDL-C and triglycerides (TG) increased and HDL-C decreased. More BIL pts had ALT ≥3x ULN (4.8 vs. 2.0%, p=.021) with no cases of Hy’s law. Liver fat content (LFC), assessed by MRI in 182 pts from 2 studies of BIL vs. GL in T1D, increased with BIL. Pts on BIL were more likely to have injec- tion site reactions (13.3 vs. 0.2%, p<.001). In conclusion, treatment with BIL vs. GL in patients with T1D gave superior HbA1c reduction, lower nocturnal hypo, and weight loss, with increases in ALT, TG, LFC, and injection site reactions. Table.

Supported By: Eli Lilly and Company

& 985-P Superior HbA1c Reduction with Basal Insulin Peglispro (BIL) vs. In- sulin Glargine (GL) and Preprandial Insulin Lispro in a Double-Blind Supported By: Eli Lilly and Company Study in Patients (pts) with Type 2 Diabetes (T2D): IMAGINE 4 THOMAS BLEVINS, THOMAS R. PIEBER, GILDRED COLÓN VEGA, SHUYU ZHANG, & 987-P

POSTERS EDWARD J. BASTYR III, ANNETTE M. CHANG, Austin, TX, Graz, Austria, San Juan,

Therapeutics Sustained Glycemic Control and Less Nocturnal Hypoglycemia with PR, Indianapolis, IN

Clinical Diabetes/ New Insulin Glargine 300 U/mL compared with Glargine 100 U/mL The novel basal insulin BIL has a fl at activity profi le and reduced periph- over 12 Months in Japanese People with T1DM (EDITION JP 1) eral effect resulting in a hepato-preferential action. In this 26-wk, Phase 3, MUNEHIDE MATSUHISA, MASAYOSHI KOYAMA, XI CHENG, MARIKO SUMI, blinded, treat-to-target trial, 1369 pts with T2D (HbA1c ≥7.0 and <12.0% on ≥1 TAKAHISA HIROSE, ON BEHALF OF THE EDITION JP 1 STUDY GROUP, Tokushima, insulin injection/day) were randomized to bedtime BIL (N=691) or GL (N=678). Japan, Tokyo, Japan, Beijing, China Pts could continue metformin. A wireless electronic diary system facilitated In EDITION JP 1, Japanese people with T1DM receiving new insulin communication of SMBG, hypoglycemia (hypo), and insulin dosing. At Wk 26, glargine 300 U/mL (Gla-300, n=122) showed comparable glycemic control pts on BIL vs. GL demonstrated superior HbA1c reduction (baseline (B/L): 8.4%; and less hypoglycemia over 6 mo compared with glargine 100 U/mL (Gla- Wk 26: 6.8 vs. 7.0%; treatment difference -0.21%, p<.001). BIL-treated pts had 100, n=121). Participants continued to receive Gla-300 or Gla-100 for an addi- lower FSG (125 vs. 132 mg/dL, p=.015), and more reached HbA1c <7% (63 vs. tional 6 mo. The 12-mo study period was completed by 228 participants; 114 53%, p<.001). The improved glycemic control with BIL vs. GL was achieved (93.4%) receiving Gla-300 and 114 (94.2%) receiving Gla-100. HbA1c and FPG with a 45% lower rate of nocturnal hypo and more pts reaching HbA1c <7% levels decreased from baseline to mo 12 with Gla-300 (mean [SD] change without nocturnal hypo over 26 wks (24 vs. 12%, p<.001). Total hypo relative −0.20 [0.80]% and −14.0 [86.5] mg/dL) and Gla-100 (mean [SD] change −0.25 rate was 1.10 (BIL/GL, p=.053); severe hypo rate and incidence did not differ [0.72]% and −7.0 [93.2] mg/dL). At mo 12, mean daily Gla-300 dose was 24 between treatments. With BIL, basal insulin dose was 11% higher, but bolus U/day (0.36 U/kg/day) and Gla-100 dose was 18 U/day (0.28 U/kg/day), with and total insulin doses were similar at 26 wks. The BIL group had greater re- little change in dose observed between mo 6 and 12. Daily mealtime insulin duction in within-day and between-day fasting & 9-point SMBG variability, doses were comparable in the Gla-300 (29 U/day [0.45 U/kg/day]) and Gla- and less weight gain (change from B/L,1.3 vs. 2.2 kg, p<.001). BIL treatment 100 (29 U/day [0.47 U/kg/day]) groups at the end of the study period. Over was associated with higher triglycerides (TG, change from B/L: 24 vs. -3 mg/ 12 mo, rates (events per participant-year) and percentage of participants dL, p<.001), lower HDL-C (change from B/L: -2 vs. 0 mg/dL, p<.001), and similar experiencing ≥1 nocturnal confi rmed (≤70 mg/dL) or severe hypoglycemic LDL-C, with no difference in cardiovascular or other serious adverse events. At event were comparable between groups. At the lower <54 mg/dL threshold, Wk 26, ALT mean change from B/L was 7.6 vs. -0.6 IU/L (p<.001); more BIL pts a reduction in event rate was observed with Gla-300 compared with Gla-100 had ALT ≥3x ULN (1.9 vs. 0.9%, p=0.16), with no cases of Hy’s law. There were during the night (2.39 vs. 3.85; rate ratio 0.62; 95% CI: 0.39 to 0.97). Consis- no signifi cant differences in effi cacy or safety in pts with anti-BIL treatment- tently the percentage of participants experiencing ≥1 nocturnal event at this emergent antibody responses. In pts with T2D, BIL vs. GL, in combination with threshold was also reduced with Gla-300 compared with Gla-100 (52.5 vs. insulin lispro, provided improved glycemic control with less nocturnal hypo, 66.1; relative risk 0.79; 95% CI: 0.64 to 0.98). Severe hypoglycemia occurred less weight gain, and increases in TG and ALT. in 12 and 11 participants receiving Gla-300 and Gla-100. Similar numbers of Supported By: Eli Lilly and Company adverse events were reported for each treatment group. To conclude, Japa- nese people with T1DM achieved sustained glycemic control with less noc- & 986-P turnal confi rmed (<54 mg/dL) or severe hypoglycemia over 12 mo with Gla- Superior Reduction of HbA1c in a Double-Blind, Randomized Study 300 vs. Gla-100. Gla-300 was well tolerated over the 12-mo study period. of Basal Insulin Peglispro (BIL) vs. Insulin Glargine (GL) in Patients Supported By: Sanofi (NCT01689129) (pts) with T1D: IMAGINE 3 RICHARD M. BERGENSTAL, HELEN LUNT, EDWARD FRANEK, FLORENCE TRAVERT, & 988-P JIANI MOU, MARK L. HARTMAN, MYRIAM ROSILIO, EDWARD J. BASTYR III, Effect of Baseline Total Daily Dose on Clinical Outcomes of 2 Dosing FOR THE IMAGINE 3 STUDY GROUP, Minneapolis, MN, Christchurch, New Zealand, Algorithms of Human Regular U-500 Insulin in Patients with Type 2 Warsaw, Poland, Paris, France, Indianapolis, IN, Neuilly sur Seine, France Diabetes BIL, a basal insulin analog with a fl at PK profi le, has reduced peripheral ac- CAROL WYSHAM, ROBERT C. HOOD, MARK L. WARREN, TAO WANG, JEFFREY tivity resulting in hepato-preferential action. In this Phase 3, 52-wk, blinded A. JACKSON, Spokane, WA, Beaumont, TX, Greenville, NC, Indianapolis, IN study of BIL vs. GL, 1114 adults with T1D (39% female) and HbA1c <12% (mean We stratifi ed results from a 24-week prospective study randomizing 325 7.86%) were randomized 3:2 to bedtime BIL or GL with prandial insulin lispro. severely insulin resistant patients (baseline [BL] total daily dose [TDD] >200 U) An electronic diary facilitated data capture and insulin dosing decisions. At 52 with uncontrolled type 2 diabetes to thrice daily (TID) or twice daily (BID) human wks, BIL vs. GL provided superior reduction of HbA1c (difference -0.22%; 95% regular U-500 insulin. The effect of BL TDD (≤300 U: n=224, 69%; >300 U: n=101, CI: -0.32, -0.12). More pts on BIL achieved HbA1c <7%. With BIL, pts had less 31%) on effi cacy and safety was evaluated. Demographics were similar between glucose variability, a 47% lower rate of nocturnal hypoglycemia (hypo, SMBG subgroups except for injection number (P < .001) and weight (P=.008), both lower ≤70 mg/dL), and weight loss. The total hypo rate was 11% higher with BIL and for ≤300 U TDD patients. At 24 weeks, no TID/BID differences in change from BL may be associated with daytime bolus insulin dosing; severe hypo rates were within subgroups or subgroup-treatment interactions were found for A1C, TDD, similar. While total insulin dose was similar, BIL patients used more basal and or weight, but the >300 U TDD subgroup had signifi cantly greater A1C reduc-

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A250 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULINS tion (P=.04). Severe and nonsevere hypoglycemia (hypo) rates (0-24 weeks) were & 990-P similar between treatments in both subgroups, though a trend toward lower Lipid Changes during 26-Wk Treatment with the Novel Basal Insulin rates for nonsevere (overall and by visit) was noted for TID. In the >300 U TDD Peglispro (BIL) vs. Insulin Glargine (GL) or Insulin NPH in 6 IMAGINE subgroup, signifi cantly higher overall rates were seen for severe (P=.04) and non- Trials severe (≤70 mg/dL) hypo (P < .001). Hypo rates over 24 hours were higher for >300 HENRY GINSBERG, BERTRAND CARIOU, TREVOR J. ORCHARD, LEI CHEN, U TDD patients from 3 to 6 AM. These rates were lower for TID patients around JUNXIANG LUO, EDWARD J. BASTYR III, JULIANA BUE-VALLESKEY, ANNETTE noon and BID patients around 6 PM in both subgroups. These results indicate M. CHANG, TIBOR IVÁNYI, SCOTT J. JACOBER, JENNIE G. JACOBSON, BYRON that either regimen is effective and safe across the TDD spectrum in this popula- J. HOOGWERF, New York, NY, Nantes, France, Pittsburgh, PA, Indianapolis, IN, Bu- tion, though higher hypo rates were observed in the >300 U TDD subgroup. dapest, Hungary We analyzed fasting lipid data from 6 Phase 3 trials of the hepato-pref- erential insulin BIL (Figure Legend), including apolipoproteins (apo) and free fatty acid (FFA) from subgroups in 5 trials. By wk 26, in insulin-naïve T2D pts, triglycerides (TGs) decreased with GL and NPH (-11 and -15 mg/dL, p<.05) but were unchanged from baseline with BIL (-1 to +4 mg/dL, p=NS). In T1D and T2D pts previously treated with insulin, TGs were stable with GL (p=NS) and increased 19 - 24 mg/dL (15 - 25%) with BIL (p<.001). After BIL discontinua- tion TGs decreased to pre-study levels (Figure). In all trials, with BIL, HDL-C changed 0 to -5 mg/dL; LDL-C changed 0 - 7 mg/dL. With GL, HDL-C and LDL-C changed 0 to -1 and 1 - 5 mg/dL respec- tively. Apo A1 and B were mostly unchanged with BIL. Among pts previously treated with insulin, there were no treatment differences in FFA (p=NS); in insulin-naïve T2D pts, FFAs decreased more with GL than BIL (p=.002). In conclusion, lipids, FFAs and apos A1 and B had little or no change with BIL in insulin-naïve T2D pts; in contrast, GL and NPH lowered TGs. When BIL replaced conventional insulin treatments, increases in TG were observed.

Increased hepatic de novo lipogenesis, increased adipose tissue release of POSTERS FFA, or decreased adipose tissue lipoprotein lipase activity, either alone or Therapeutics in combination, may also be the basis for differences in TG levels between Clinical Diabetes/ BIL and other insulins.

& 989-P Liver Enzyme Results from 7 Basal Insulin Peglispro (BIL) Clinical Trials in T1D and T2D MARK L. HARTMAN, SHUYU ZHANG, EDWARD J. BASTYR III, ANNETTE M. CHANG, SCOTT J. JACOBER, MELVIN J. PRINCE, Indianapolis, IN BIL, a basal insulin analog with a fl at PK profi le, has reduced peripheral activity resulting in hepato-preferential action. To monitor hepatic safety in the BIL registration studies, liver enzymes and total bilirubin (TBL) were measured at 0, 4, 8, 12, 16, 26, 39, 52, 65, and 78 wks, depending on study duration, and 4 wks following study basal insulin withdrawal. Data were integrated for studies comparing BIL with insulin glargine (GL) in patients (pts) with T1D (1 Phase 2 and 2 Phase 3 trials; 1026 BIL and 676 GL) and T2D (1 Phase 2 and 3 Phase 3 trials; 2194 BIL and 1464 GL). Mean alanine aminotransferase (ALT) increased from baseline in BIL pts and pla- teaued after 4 wks in T1D and 26 wks in T2D (median increase up to 5 IU/L for T1D and 3 IU/L for T2D) but did not increase in GL pts. ALT was higher in BIL than GL pts at all time points (p<.05) and decreased after discontinuation of BIL. Aspartate aminotransferase (AST) results were similar. No clinically meaningful changes in mean TBL occurred. More BIL pts had ALT ≥ 3X upper limit of normal (ULN) than GL (T1D: BIL 4.4% vs. GL 1.5%, T2D: BIL 2.0% vs. GL 0.6%, both p<.005). AST ≥ 3X ULN was more common in BIL than GL pts for T2D (1.2% vs. 0.4%, p=.009) but not for T1D. TBL ≥ 2X ULN was similar for BIL vs. GL. No pt had ALT ≥ 3X ULN with a TBL ≥ 2X ULN that was considered causally related to BIL; thus Hy’s Law criteria were not met. Of the pts taking BIL with ALT ≥ 3X ULN (44 in T1D, 44 in T2D), all pts with T1D and 40 (90.9%) with T2D returned to or trended toward baseline while continuing BIL (37 in T1D, 22 in T2D) or after discontinuing BIL (7 in T1D, 18 in T2D). Four T2D patients had insuffi cient follow-up to adequately assess the ALT trend. Liver fat content (LFC) was measured by MRI in 3 subsets of pts and was higher in BIL (change from baseline: BIL [-1% to 5%] vs. GL [-4% to 0%], p≤.002) at 26 and 52 wks, in both T1D and T2D. In summary, no acute, severe, hepatocellular drug-induced liver injury was observed with BIL treatment for up to 78 wks. Further research/analysis will help in assessment of these fi ndings of increased ALT and LFC. Supported By: Eli Lilly and Company

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A251 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULINS

& 991-P These high percentages are only partly explained by transient intensive insu- Older People with Type 2 Diabetes: Glycemic Control and Hypogly- lin regimens in acutely-ill patients identifi able in the database. cemia Risk with New Insulin Glargine 300 U/mL We observed high rate of early discontinuation of insulin in T2DM patients JEAN-FRANÇOIS YALE, VANITA R. ARODA, BERNARD CHARBONNEL, ROBERT (but lower with basal insulin scheme). Further real-world studies are war- RITZEL, ANA MERINO-TRIGO, PETER STELLA, MARIE-LISE GRISONI, ALAN J. ranted to identify factors associated with this poor persistence. SINCLAIR, Montreal, QC, Canada, Hyattsville, MD, Nantes, France, Munich, Ger- many, Paris, France, Levallois-Perret, France, Droitwich Spa, United Kingdom In people with T2DM, a patient-level meta-analysis of EDITION 1, 2 and 3 has shown Gla-300 provides comparable glycemic control with less hypogly- cemia over 6 months vs. glargine 100 U/mL (Gla-100). In this post hoc analysis, we investigated these outcomes, as well as an extended and clinically defi ned window of nocturnal hypoglycemia (22:00 h-pre-breakfast SMPG) and com- posite endpoints, in those aged ≥65 yrs (n=659). Gla-300 showed comparable glycemic control to Gla-100 (LS mean [95% CI] difference in HbA1c change from baseline to month 6: 0.00 [-0.14 to 0.15]%). There was less confi rmed (≤70 mg/dL) or severe hypoglycemia during the night irrespective of the nocturnal window analyzed and a trend towards less any time (24 h) events for Gla-300 vs. Gla-100. More Gla-300-treated participants reached HbA1c targets or had HbA1c reduction ≥0.5 % without confi rmed (≤70 mg/dL) or severe nocturnal hypoglycemia. Those on Gla-300 were 55-70% more likely to achieve HbA1c <7 % with no nocturnal hypoglycemia (signifi cant using both windows). In sum- mary, the comparable glycemic control plus hypoglycemia benefi t of Gla-300 is confi rmed in a potentially more vulnerable subgroup aged ≥65 yrs, with more people reaching HbA1c targets without hypoglycemia on Gla-300 vs. Gla-100. The nocturnal hypoglycemia benefi t of Gla-300 was also confi rmed when an Supported By: Sanofi

POSTERS extended window (22:00 h-pre-breakfast SMPG) was considered. Therapeutics 993-P Clinical Diabetes/ Similar Counterregulatory Hormone Responses to Hypoglycemia with Basal Insulin Peglispro (BIL) vs. Insulin Glargine (GL) in Type 1 Diabetes TIM HEISE, CHRISTOPH KAPITZA, LESZEK NOSEK, ERIC CHEN QUIN LAM, SIAK LENG CHOI, PARAG GARHYAN, SCOTT J. JACOBER, NIELS PORKSEN, MELVIN J. PRINCE, HELLE LINNEBJERG, Neuss, Germany, Singapore, Singapore, Indianapolis, IN BIL is a novel basal insulin with a fl at pharmacokinetic and glucodynamic pro- fi le and hepatic and peripheral action more like endogenous insulin. The effects of BIL and GL on the counter-regulatory response to hypoglycemia and recovery were assessed in this open-label, randomized, 2-period, crossover study. After once-daily, individualized, subcutaneous doses of BIL or GL for ≥14 days, 13 patients (mean [±SD] age, 41.0 ± 10.4 years; duration of diabetes, 19.0 ± 8.7 years) underwent a hypoglycemic clamp by infusion of human in- sulin (0.5 mU/kg/min) to achieve sequential blood glucose (BG) targets of 72, 58, and 45 mg/dL (BG nadir). The amount of glucose infusion required to recover from 45 to 72 mg/dL was also compared. There was no statistically signifi cant difference between treatments in the counter-regulatory response of epinephrine (Table; see also norepinephrine, cor- tisol, and growth hormone data). Mean baseline glucagon was higher following BIL than GL; this statistically signifi cant difference was maintained during the clamp. There were no statistically signifi cant differences between BIL and GL in the mean amount of glucose required to reach a BG concentration of 72 mg/dL. BIL and GL showed similar counter-regulatory responses to and recovery from hypoglycemia, indicating that the hepato-preferential action of BIL Supported By: Sanofi (NCT01499082, NCT01499095, NCT01676220) does not impair counter-regulation. Table. 992-P High Rates of Early Discontinuation of Insulin Therapy in Type 2 Diabetes: A Nationwide Study RONAN ROUSSEL, BERNARD CHARBONNEL, MOURAD BEHAR, JULIE GOUR- MELEN, CORINNE EMERY, BRUNO DETOURNAY, Paris, France, Nantes, France, Villejuif, France, Bourga-la-Reine, France A retrospective cohort study was conducted on a random sample of ≈ 600,000 patients registered in the French national health insurance data- base. Newly insulin treated (no insulin in the previous 12 months) T2DM pa- tients were included. Persistence was defi ned as remaining on insulin (what- ever the scheme used) without discontinuation (no insulin over 12 months). Among 1,909 initiations identifi ed in 2012/2013 (basal scheme: 61.8%, basal/rapid: 15%, other schemes: 23.2%) the average age (SD) at initiation was respectively 67.5 (14.2), 61.8 (18.1) and 63.2 (18.4) years. Insulin was initiated by GPs in 39.3% (47.7% for basal scheme) and prescribed without other antidiabetic drugs in 21.1%. Persistence was studied on 1,969 patients initiating insulin in 2011/2012. Among survivors, nearly 25% stopped insulin in the fi rst year (18.4% for bas- al scheme). Patients discontinuing insulin were younger (64.7 (18.5) vs. 67.3 (14.3) p=0.0003) and less often male (45.8% vs. 55.7%, p<0.0001). 20.2% did not receive any antidiabetic drug over 12 months after discontinuation.

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A252 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULINS

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994-P Improved Postprandial Glycemic Control with Faster-Acting Insulin Aspart in Subjects with Type 1 Diabetes Using CSII BRUCE BODE, LISELOTTE HYVELED, SØREN CAN TAMER, PATRIA YBANEZ, MAREK DEMISSIE, Atlanta, GA, Søborg, Denmark A double-blind, randomized, crossover, active-controlled trial compared 14 days of continuous subcutaneous insulin infusion (CSII) of two formulations of faster-acting insulin aspart (faster aspart) with CSII of insulin aspart (IAsp) in 43 adults with T1D. Only data for the faster aspart formulation undergoing further development are presented. The primary endpoint was postprandial glucose response 2 h after a standardized meal test (individualized insulin Supported By: Sanofi U.S. dosing by bolus calculator), as evaluated by mean change in plasma glucose (ΔPGav,0-2h). Faster aspart provided statistically signifi cant lower ΔPGav,0-2h 996-P compared with IAsp (3.03 mmol/L vs. 4.02 mmol/L; Table). Subjects had Effect of Exercise on Pharmacokinetics (PK) of Basal Insulin Peg- blinded continuous glucose monitoring (CGM) during the trial. The greater lispro (BIL) and Insulin Glargine (GL) in Type 1 Diabetes Mellitus glucose-lowering effect at meals with faster aspart vs. IAsp was confi rmed (T1DM) Patients by interstitial glucose (IG) profi les, with the largest differences at breakfast HELLE LINNEBJERG, ERIC CHEN QUIN LAM, SIAK LENG CHOI, MARY P. KNA- (Table). The duration of low IG (≤3.9 mmol/L per 24 h) was signifi cantly lon- DLER, NIELS PORKSEN, VIKRAM P. SINHA, PARAG GARHYAN, OLIVER KLEIN, ger for IAsp (2.45 h) than faster aspart (2.03 h; mean difference [95% CI]: LESZEK NOSEK, TIM HEISE, Indianapolis, IN, Singapore, Singapore, Silver Spring, POSTERS -0.42 [-0.72; -0.11]. No new safety fi ndings were observed with faster as- MD, Neuss, Germany Therapeutics part compared with IAsp. In summary, faster aspart had signifi cantly greater BIL is a novel basal insulin that has a prolonged duration of action related Clinical Diabetes/ glucose-lowering effect than IAsp after a standardized meal, with fi ndings to a delay in insulin absorption and a reduction in clearance. As exercise confi rmed by CGM for all meals, and less time spent with low glucose levels, may potentially affect insulin absorption, this study investigated the effect as measured by IG. of exercise on PK of BIL and GL. Forty patients with T1DM received 0.5-U/kg subcutaneous doses of either BIL or GL once daily in the thigh for 20 days. In each treatment arm, patients were randomized to 1 of 2 sequences, provid- ing an intra-subject comparison: a 45-minute exercise challenge at 50-70% VO2 max (17 hours postdose; ~6 hours after a meal) on Day 17 and no exercise on Day 20, or vice versa. On both days, PK samples were collected for 24 hours after insulin dosing, with frequent blood sampling for PK and blood glucose (BG) conducted from 17 to 20 hours postdose (0-3 hours after start of the exercise). Mean BIL concentrations increased during exercise, reaching a peak at 1 hour and returning to pre-exercise levels within 3 hours after starting ex- ercise. BIL AUC0-24,ss was increased by 13% with exercise compared to no exercise. BIL area under the concentration curve for 3 hours after the start of exercise (AUC0-3) and Cmax,ss were increased by 63% and 64%, respectively, with exercise compared to no exercise. These differences were statistically 995-P signifi cant. In contrast, for GL, these PK parameters were not affected by Exploratory Study of a Dose-Response Curve for Basal Insulin exercise. CHARLES SHAEFER, LOUISE TRAYLOR, LING GAO, TERRY DEX, PRISCILLA SEPE, Mean baseline BG levels were comparable (BIL: 138 vs. 122; GL: 145 vs. NEIL SKOLNIK, Augusta, GA, Bridgewater, NJ, Somerset, NJ, Jenkintown, PA 148 mg/dL, with/without exercise). Over the 3-hour period after exercise The decision about moving from basal insulin (BI) alone to basal plus pran- start, mean (±SD) BG levels were similar with or without exercise following dial therapy is a challenging one for many primary care physicians (PCPs), BIL or GL dosing (BIL: 86.0 ± 26.5 mg/dL with exercise vs. 90.7 ± 30.2 mg/dL who often continue to titrate BI; resulting in inadequate A1C control, and no exercise; GL: 113 ± 31.8 mg/dL vs. 125 ± 48.9 mg/dL). increased risk of hypoglycemia and weight gain. While exercise transiently increased systemic exposure following BIL but not To guide PCPs in proper BI dosing, a post hoc analysis of 3 insulin glargine GL dosing, this did not appear to affect BG to a clinically signifi cant extent. titration studies of ≥ 24 weeks was performed to assess if there is a di- Supported By: Eli Lilly and Company minishing response to increasing basal insulin dose. A total of 458 patients were included; mean age 56 years, male 50%, mean BMI 33 kg/m2, mean 997-P A1C 8.7%, mean fasting plasma glucose (FPG) 199.6 mg/dL. Ratios for FPG Hypoglycemia Association with Hospitalization and Mortality change:insulin dose change from baseline to various time points were cal- in Older Patients with T2DM Initiating Basal Insulin (BI) in a U.S. culated. Medicare Advantage Population We found that FPG reduction becomes proportionally smaller with in- JAVIER ESCALADA, LAURA LIAO, CHUNSHEN PAN, HONGWEI WANG, Pamplona, creasing dose of BI, leveling at ~0.5 IU/kg (Figure). Spain, Bridgewater, NJ, Boca Raton, FL These results illustrate that a dose-response curve exists with BI. As BI A retrospective U.S. health insurance claims database analysis assessed dose approaches 0.5 IU/kg, PCPs should consider possibly initiating prandial comorbidities, healthcare utilization and mortality in older patients (mean therapy. Decreases in the glucose-lowering response in patients requiring age 72 y) with T2DM initiating BI (2006–13). Patients who had used OADs/ high BI doses may be indicative of either a dose-response curve or a greater GLP-1s and had 2 y continuous Medicare Advantage coverage (1 y pre- and degree of insulin resistance. Like any dose-response curve seen at a popula- post-BI initiation) were included. A Cox proportional hazard model evaluated tion level, individualization of therapy and response is important in determin- risk of hospitalization and death, with medically attended hypoglycemia ing appropriate treatment decisions for patients. (HG) as the time-varying covariate, adjusting for demographic, comorbidities and medication history. Of 31,035 patients analyzed, 16,534 (53%) experi- enced hospitalization and 4414 (14%) died during a mean follow-up of 2.8 y. A greater proportion of patients with HG required hospitalization than those without HG (75.6% vs. 50.8%), experiencing 1.43 and 0.65 hospitalization episodes/patient-year, respectively. Patients with HG were more likely to die

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A253 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULINS

than those without HG (21.1% vs. 13.4%). After mutual adjustment, HG was associated with an elevated risk of all-cause hospitalization (HR 1.60; 95% CI: 1.53–1.66) and death (HR 1.50; 95% CI: 1.41–1.61) (Figure). In a large U.S. Medicare Advantage population with T2DM, HG is a strong independent risk factor for hospitalization and death following BI initiation, suggesting the need for a new BI with a favorable HG profi le in this older population.

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999-P Risk Factors and Economic Burden of Hypoglycemia in Older Pa- tients with Type 2 Diabetes Mellitus (T2DM) Initiating Basal Insulin (BI) in a U.S. Medicare Advantage Population JAVIER ESCALADA, LAURA LIAO, CHUNSHEN PAN, HONGWEI WANG, Pamplona, Spain, Bridgewater, NJ, Boca Raton, FL A retrospective U.S. health insurance claims database analysis assessed risk factors for hypoglycemia (HG) and its cost burden in older patients (mean age 72 years) with T2DM on OADs/GLP-1s and initiating BI (2006–2013). 31,035 patients with 2 years’ continuous Medicare Advantage coverage (1 year pre- and post-BI initiation) were included, of whom 9.9% (n=3066, HG group) experienced ≥1 episode of medically attended HG during the 1-year POSTERS Therapeutics of follow-up (FU).

Clinical Diabetes/ At baseline, the HG group were more likely to have non-diabetes comor- bid conditions (Charlson Comorbidity Index 2.6 vs. 1.7, p<0.001) and incurred higher total annual healthcare costs ($54,057 vs. $30,249, p<0.001) than the group who did not experience HG during FU (n=27,969, non-HG group). The HG group were more strongly associated with baseline macrovascular (OR=1.27, 95% CI: 1.05–1.54) and microvascular (OR=1.34, 95% CI: 1.11–1.62) complications, mental illness (OR=1.21, 95% CI: 1.01–1.46) and foot disease (OR=2.10, 95% CI: 1.63–2.70), rates of which increased by 8.0–9.3% in the FU period (rates were lower and relatively stable in the non-HG group). After BI initiation, overall total annual healthcare costs fell slightly, from $32,601 at baseline, to $32,460. However, in the HG group, annual healthcare costs increased by 39% to $75,398, mainly driven by outpatient ($28,097) and in- patient ($37,930) costs. This contrasts with a modest (9%) decline to $27,753 in the non-HG group. The HG group was associated with substantially higher diabetes-related healthcare costs (adjusted annual costs $19,938 and $8,539, for the HG and non-HG groups, respectively) and also incurred $5,337 HG-related costs. Older T2DM patients with comorbidities are at greater risk of HG after BI Supported By: Sanofi initiation. This group of fragile patients is associated with increased health- care utilization and costs, highlighting the need for a BI with a reduced risk 998-P of HG. Reduced Nocturnal Hypoglycemia (Hypo) with Basal Insulin Peglis- Supported By: Sanofi pro (BIL) Compared with Insulin Glargine (GL): Pooled Analyses of 5 Randomized Controlled Trials 1000-P JULIO ROSENSTOCK, MICHEL MARRE, YONGMING QU, SCOTT J. JACOBER, Insulin Injection into Regions with Lipohypertrophy (LHT) Worsens MELVIN J. PRINCE, ANNETTE M. CHANG, EDWARD J. BASTYR III, Dallas, TX, Postprandial (PP) Blood Glucose (BG) vs. Injections into Normal Paris, France, Indianapolis, IN Adipose Tissue (NAT) Nocturnal hypo is a signifi cant safety concern and limits optimization of ULRIKE HÖVELMANN, SUSANNE FAMULLA, LIDIA HERMANSKI, ANNELIE FIS- basal insulin dosing to achieve glycemic goals. We compared the novel basal CHER, LUTZ HEINEMANNN, MATTHIAS KALTHEUNER, LAURENCE HIRSCH, TIM insulin analog BIL, with its fl at PK profi le and hepato-preferential action, to HEISE, Neuss, Germany, Leverkusen, Germany, Franklin Lakes, NJ GL for glucose control in 5 global studies in 3 patient (pt) groups (type 2 We compared the effects of subcutaneous insulin (INS) injection into LHT diabetes (T2D) basal only, T2D basal-bolus, and type 1 diabetes (T1D)). We and NAT on postprandial BG control and insulin (INS) absorption in 13 pa- conducted integrated analyses to assess HbA1c change and hypo events tients with type 1 diabetes and LHT (confi rmed by physical exam and ultra- (SMBG ≤70 mg/dL) across studies. sound). Patients received two identical mixed meals (75 g CHO) separated Patients (N=4927) were randomized to bedtime BIL or GL in 26-, 52- and by at least 6 h, each covered with 0.15 U/kg insulin lispro injected at meal 78-week treat-to-target trials. In all studies, pts treated with BIL met sta- start into LHT or NAT, in random order. Pre-meal BG was adjusted to 100±20 tistical superiority in the primary outcome of reduction in HbA1c, and had mg/dL. BG and INS (lispro-specifi c radioimmunoassay) were measured over 37-45% lower nocturnal hypo rates. Total hypo rates were not signifi cantly 5 hours after each meal. INS injection into LHT led to reduced INS exposure different in T2D pts. In T1D pts, total hypo rate was higher with BIL and versus injection into NAT (AUCINS 0-5h 46% lower, p=0.053). Mean PP BG con- associated with higher rates of daytime hypo when bolus insulin was ad- centrations were signifi cantly increased (17% higher in the fi rst 2 hours, 58% ministered. There were no treatment differences in severe hypo rates. For higher from 2 to 5 h, 39% higher over 5 h, all p<0.05) and to a 25% increase symptomatic hypo events, the mean SMBG values were not different with in max. BG (193 vs. 154 mg/dL, p=0.043) (Figure). PP hypoglycemia (BG≤50 BIL vs. GL. Continuous glucose monitoring in a subset of T1D and T2D pts mg/dL) occurred slightly less frequently with LHT injection (2 vs. 6 patients, showed similar mean duration of individual hypo events by treatment. p=0.20). In conclusion, treatment with BIL compared to GL was associated with In conclusion, insulin injection into LHT regions has a pronounced nega- greater HbA1c reductions and fewer nocturnal hypos in pts with T1D or tive effect on insulin absorption and postprandial blood glucose control com- T2D. pared with injection into NAT. The data reinforce the importance of good

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A254 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULINS injection technique, particularly site rotation, and provide the rationale for a reliable tool to predict requirement of hypoglycemic agents for optimum patients to avoid injecting insulin into areas with LHT. control of blood glucose during GC treatment.

1002-P Effi cacy and Safety of IDegLira (Combination of Insulin Degludec + Liraglutide), in Insulin-Naïve Patients with T2D Uncontrolled on GLP-1 Receptor Agonist (GLP-1RA) Therapy SULTAN LINJAWI, BRUCE W. BODE, LOUIS B. CHAYKIN, JEAN-PIERRE COUR- REGES, YEHUDA HANDELSMAN, LUCINE LEHMANN, ABHISHEK MISHRA, RICH- ARD W. SIMPSON, Coffs Harbour, Australia, Atlanta, GA, Bradenton, FL, Narbonne, France, Los Angeles, CA, Søborg, Denmark, Bengaluru, India, Box Hill, Australia In this 26-week open-label trial, patients (pts) with T2D uncontrolled on maximum dose GLP-1RA therapy (liraglutide OD or exenatide BID) + met- formin ± pioglitazone ± sulfonylurea were randomized 2:1 to IDegLira (com- bination of insulin degludec and liraglutide) OD (n=292) or unchanged GLP- 1RA therapy (n=146); previous OADs were continued. Mean A1c decreased from baseline (7.8%/7.7%) to 6.4% (IDegLira) and 7.4% (unchanged GLP-1RA) (p<0.001). 75% of pts on IDegLira achieved A1c <7% vs. 36% on unchanged GLP-1RA (p<0.001); 63% on IDegLira vs. 23% on unchanged GLP-1RA at- tained A1c ≤6.5% (p<0.001). FPG and 9-point SMBG profi les improved signifi - cantly more with IDegLira than unchanged GLP-1RA (Table). Weight change was +2.0 kg with IDegLira and -0.8 kg with unchanged GLP-1RA. Confi rmed hypoglycemia rates were low (Table) but higher with IDegLira vs. unchanged GLP-1RA. Mean IDegLira dose at 26 weeks was 43 dose steps (i.e. 43 U degludec, 1.55 mg liraglutide). Safety profi le of IDegLira was consistent with

previous fi ndings; both treatments were well tolerated. POSTERS Consistent with previous fi ndings on GLP-1RA intensifi cation with insu- Therapeutics lin-containing therapy, IDegLira OD provided superior glycemic control vs. Clinical Diabetes/ unchanged GLP-1RA and represents an effi cacious approach to intensifying therapy in patients uncontrolled on GLP-1RAs. Table.

1001-P Development and Validation of a Scoring System to Predict Re- quirement of Hypoglycemic Agents for Optimum Control of Blood Glucose during Glucocorticoid Treatment in Patients with Autoim- mune Diseases HIROYUKI MORITA, ICHIRO MORI, MOTOCHIKA ASANO, KOICHIRO TAGUCHI, YOSHIHIKO KITADA, KEI FUJIOKA, TAKAHIDE IKEDA, MASAHIRO YAMAUCHI, KAZUO KAJITA, TATSUO ISHIZUKA, Gifu, Japan Supported By: Novo Nordisk Long-term glucocorticoid (GC) treatment may be necessary for patients with various autoimmune diseases. The purpose of the present study is to develop and validate a scoring system to predict requirement of hypoglyce- 1003-P mic agents for optimum control of GC-induced hyperglycemia. We retrospec- IDegLira in Insulin-Naïve Patients with Type 2 Diabetes (T2D) Inad- tively evaluated 230 patients with autoimmune diseases admitted between equately Controlled on Sulfonylureas (SU) Alone or in Combination 2004 and 2013 to develop a prediction score. Inclusion criteria indicated that with Metformin: The DUAL IV Study the dosage of prednisolone treatment should be more than 5 mg/day for 4 HELENA W. RODBARD, BRUCE W. BODE, STEWART B. HARRIS, LUDGER ROSE, weeks. Exclusion criteria included hypoglycemic therapy before GC adminis- LUCINE LEHMANN, HENRIK JARLOV, JERRY THURMAN, Rockville, MD, Atlanta, tration. Forty-three percent of GC-administered patients required treatment GA, London, ON, Canada, Münster, Germany, Søborg, Denmark, St. Charles, MO with hypoglycemic agents. A logistic regression analysis revealed that risk This 26-week, multinational, double-blind trial assessed an insulin deglu- factors of requirement of hypoglycemic therapy during GC administration dec/liraglutide combination (IDegLira) in adults (n=435) with T2D (A1c 7.0- should be raised for age, HbA1c, FPG, and starting dose of prednisolone 9.0%). Patients were randomised 2:1 to receive once-daily IDegLira or place- (sPSL). ROC analyses showed that cutoff values of age, HbA1c, FPG and sPSL bo added to SU ± metformin, and started at 10 dose steps (10 units IDeg/0.36 were 58 years old, 6.3%, 101 mg/dl, and 0.74 mg/kg, respectively. We scored mg Lira), with titration to a fasting glycemic target of 72-108 mg/dL. patients profi les as follows; age (years), 40-59, 1 point, 60-79, 2 points, more Mean A1c decreased from 7.9% (both groups) to 6.4% with IDegLira than 80, 3 points; HbA1c (%), 6.0-6.4, 1 point, 6.5-6.9, 2 points, more than and to 7.4% with placebo, estimated difference 1.02%, p<0.001. A1c <7% 7.0, 3 points; FPG (mg/dl), 90-99,1 point, 100-109, 2 points, more than 110 was achieved by 79.2% of IDegLira patients vs. 28.8% receiving placebo, mg/dl, 3 points; sPSL (mg/kg), 0.50-0.74, 1 point 0.75-0.99, 2 points, more p<0.001 (for A1c ≤6.5%: 64.0% vs. 12.3%, p<0.001). Mean fasting plasma than 1.00, 3 points. Sum of the scores was 6.2±2.1 for patients treated with glucose decreased from 164 mg/dL (both groups) to 117 mg/dL with IDegLira hypoglycemic agents vs. 3.6±1.7 for others. When 4 points was defi ned as and to 159 mg/dL with placebo, estimated difference 41.4 mg/dL, p<0.001. the cut-off value of the sum of the scores, the sensitivity, specifi city and At 26 weeks, a self-monitored 9-point blood glucose profi le showed reduc- accuracy were 89%, 51% and 67%, respectively. We validated the scoring tions in the profi le mean of 39.6 vs. 12.6 mg/dL with IDegLira and placebo, system to another 42 patients admitted in 2014. The sensitivity, specifi city respectively, with an estimated difference in mean glucose of 27.9 mg/dL, and accuracy were 89%, 70% and 74%, respectively. The scoring system is p<0.001. Blood glucose was signifi cantly lower with IDegLira at all 9 time-

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A255 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULINS

points (post hoc analysis). Mean IDegLira dose at 26 weeks was 28 dose 1005-P steps (28 units IDeg/1.0 mg Lira). Faster-Acting Insulin Aspart Using Continuous Subcutaneous Insu- Confi rmed hypoglycemia (severe or plasma glucose <56 mg/dL) occurred lin Infusion (CSII): Earlier Onset of Exposure and Greater Early Phar- in 41.7% and 17.1% of IDegLira- and placebo-treated patients, respectively, macokinetic (PK) and Pharmacodynamic (PD) Effects than Insulin with rates of 3.5 vs. 1.4 events/patient year (estimated rate ratio: 3.74, Aspart p<0.001). Mean weight change was +0.5 kg with IDegLira vs. -1.0 kg with TIM HEISE, ERIC ZIJLSTRA, TORD RIKTE, LARS THORSSON, LESZEK NOSEK, placebo (p<0.001). HANNE HAAHR, Neuss, Germany, Søborg, Denmark IDegLira signifi cantly improved glycemic control in combination with SU. Faster-acting insulin aspart (faster aspart) is insulin aspart (IAsp) in a new Hypoglycemia rates were low, but, as expected given the use of SUs, more formulation with a faster initial absorption after subcutaneous (s.c.) injec- common than in previous trials where IDegLira was used in combination with tion. This randomized, double-blind, crossover trial evaluated the PK/PD other oral anti-diabetic agents. Treatment was well tolerated, with overall properties of faster aspart during CSII in 48 patients with T1DM (mean ± SD adverse event rates comparable to previous IDegLira trials. age: 46.3±8.6 y; HbA1c: 7.4±0.6%). Patients received faster aspart or IAsp as Supported By: Novo Nordisk a CSII bolus dose (0.15 U/kg) on top of basal CSII (0.02 U/kg/h) under glucose clamp conditions (ClampArt; target 100 mg/dL; duration 27 h, 13 h run-in, 14 1004-P h post bolus dosing). After the bolus dose t50% Cmax and tmax occurred 36% (12 Basal Insulin Peglispro (BIL) Provides Clinically and Signifi cantly min) and 31% (26 min) earlier and early insulin exposure in the fi rst 2 h was Better HbA1c Control with Less Nocturnal Hypoglycemia (Hypo) greater with faster aspart than IAsp, eg, 3-fold greater exposure in the fi rst than NPH when Used in Combination with Oral Agents in Insulin- 30 min (Table); total exposure was similar. Faster aspart had earlier t50% GIRmax Naïve T2D Patients (Pts): IMAGINE 6 (21%; 11 min) and tGIRmax (14%; 19 min) and a greater glucose-lowering effect GEORGE GRUNBERGER, LEI CHEN, ÁNGEL RODRÍGUEZ, FRANCISCO J. TINA- during the fi rst 2 h after bolus dosing vs. IAsp; total glucose-lowering effect HONES, SCOTT J. JACOBER, JULIANA BUE-VALLESKEY, Bloomfi eld Hills, MI, was similar (Table). Both treatments were well tolerated. In summary, faster Indianapolis, IN, Alcobendas, Spain, Málaga, Spain aspart showed enhanced early exposure and action compared with IAsp in BIL is a novel basal insulin with a fl at profi le and hepatic/peripheral gradi- CSII. Improvements in onset of exposure and action were more pronounced ent more like endogenous insulin. This Phase 3, open-label, treat-to-target than those previously reported for s.c. injection of faster aspart (Diabetes (TTT) study assessed if BIL was non-inferior (margin=.4%) to NPH in reducing 2014;63(Suppl.1):A233).

POSTERS HbA1c when added to prestudy oral agents (26-wk endpoint). Therapeutics Pts were randomized to bedtime NPH (n=213) or BIL (n=428; n=213 morn- Clinical Diabetes/ ing and n=215 bedtime dosing). HbA1c at endpoint was lower for BIL vs. NPH (6.8 vs. 7.1%; p<.001). A greater proportion of BIL pts achieved HbA1c <7% (63.1 vs. 43.4%; p<.001) and HbA1c <7% without nocturnal hypo (36.7 vs. 12.3%; p<.001). Weight gain did not differ between groups; insulin doses were higher in BIL pts. Nocturnal hypo rates (events/pt/30 d) were lower for BIL vs. NPH (.31 vs. .61; p<.001) and total hypo rates were similar (BIL: 1.46 vs. NPH: 1.73; p=.092). No signifi cant differences between groups were observed at endpoint for any lipid variables. At endpoint, ALT increased with BIL, but pts with ALT ≥3X ULN did not differ between groups, with no cases of Hy’s law. Injection site reactions were infrequent. In this TTT study, BIL treatment showed clinically relevant improvements in glycemic control and a signifi cant reduction in nocturnal hypo compared to NPH, consistent with a hepato-preferential action and reduced peripheral activity. 1006-P Table. Meta-analysis of Clinical Outcomes According to Age in T2DM Patients Initiating Insulin Glargine THOMAS J. HAAK, LOUISE TRAYLOR, WOLFGANG LANDGRAF, DAVID R. OW- ENS, Bad Mergentheim, Germany, Bridgewater, NJ, Frankfurt, Germany, Swansea, United Kingdom This meta-analysis compared effi cacy and safety outcomes by age in patients with T2DM initiating insulin. Standardized patient-level data were pooled from 15 RCTs (fasting plasma glucose [FPG] target < 100 mg/dL) of ≥ 24 weeks duration. Patients were insulin-naïve adults with T2DM, adding insulin glargine to their current oral therapy. Data were examined by age: < 65 years (y) versus ≥ 65 y. Outcomes included A1C, FPG, weight, insulin dose, and hypoglycemia. Overall, 3,188 patients were included (< 65 y, n=2,411; ≥ 65 y, n=777); 53% male, mean age 57.7 y. Mean age was 53.8 y and 69.8 y, respectively. Baseline mean T2DM duration and weight differed in patients < 65 y and ≥ 65 y (8.2 vs. 11.6 y; and 87.5 vs. 81.4 kg, respectively). Patients aged < 65 y had slightly greater mean reductions in A1C (−1.5% vs. −1.4%) and FPG (−73.9 vs. −72.8 mg/dL), and greater weight gain (2.0 vs. 1.5 kg) from baseline to Week 24. Similar percentages of patients < 65 y and ≥ 65 y achieved A1C < 7.0% at endpoint (46% vs. 44%); however, insulin dose was higher in patients < 65 y (0.46 vs. 0.35 U/kg). Overall, nocturnal and severe hypoglycemia incidences, and event rates were comparable in age groups (Table). Insulin glargine use in T2DM patients aged ≥ 65 y results in similar clinical outcomes as those in patients aged < 65 y, but at lower insulin doses and with less weight gain. Severe hypoglycemia was rare and not increased in older patients.

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A256 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULINS

glucose management in non-cardiac surgery (≥ 3 hours duration). Intraop- Table. Hypoglycemia Incidence and Event Rate in Patients Initiating Insulin erative glycemic levels and variability (measured in standard deviation - SD) Glargine by Age. were compared against ICU length of stay, incidences of surgical infections, Hypoglycemia defi nition Incidence (%) Rate and pulmonary & cardiovascular complications (Figure). Compared against (events/patient year) a reference set of cases with low mean glycemic levels < 140 mg/dL, cases < 65 y ≥ 65 y < 65 y ≥ 65 y with high mean glucose levels > 180 mg/dL was associated with increased (n = 2,411) (n = 777) (n = 2,411) (n = 777) ICU length of stay (β = 2.17, p =0.01) and higher odds of surgical infections Overall with PG < 70 mg/dLa 47.62 46.98 5.74 6.13 (OR = 3.87, p=0.004) and pulmonary complications (OR = 5.20, p=0.02) in Overall with PG < 56 mg/dLa 29.45 29.99 1.93 1.91 patients without diabetes. Compared with a reference set of cases with low glycemic variability (SD < 15), cases with high glycemic variability (SD > Nocturnal with PG < 70 mg/dLb 19.87 17.76 1.17 1.08 35) was associated with increased ICU length of stay (β = 1.82, p =0.03) and Nocturnal with PG < 56 mg/dLb 11.20 9.14 0.48 0.42 higher odds of pulmonary complications (OR = 8.70, p=0.04) in patients with Severe (assistance required) 2.07 2.06 0.08 0.11 diabetes. These results indicate that in diabetic patients, high intraopera- aIncluding severe events; bOccurring between 0:01 AM and 5:59 AM. PG, tive glycemic variability, and in non-diabetic patients, high intraoperative plasma glucose. glycemic levels are associated with poor surgical outcome. Supported By: Sanofi Table.

1007-P Infl uence of Gender on Glycemic Control and Hypoglycemia in T2DM Patients Initiating Insulin Glargine ALEXANDRA KAUTZKY-WILLER, LOUISE TRAYLOR, WOLFGANG LANDGRAF, BERNARD CHARBONNEL, Vienna, Austria, Bridgewater, NJ, Frankfurt, Germany, Nantes, France Previous studies suggest females with T2DM are less likely to reach treat- ment targets and have a higher risk of hypoglycemia with insulin therapy. POSTERS In a meta-analysis, patient-level data from 15 RCTs (fasting plasma glu- Therapeutics cose [FPG] target < 100 mg/dL) of ≥ 24 weeks duration were standardized, Clinical Diabetes/ pooled, and examined by gender. Patients were insulin-naïve adults with Supported By: University of Washington T2DM adding insulin glargine to existing oral therapy. Week 24 outcomes included A1C, FPG, weight, insulin dose, and hypoglycemia. Overall, 3,188 patients were included (1,508 female, 1,680 male) with 1009-P similar mean age (57.7 years) and T2DM duration (9 years). Females weighed Incidence of Gastrointestinal Side Effects Similar between IDeg- less (80.3 vs. 91.0 kg) but had higher body mass index (31.2 vs. 29.9 kg/m2). Lira and Non-GLP-1RA Comparators Despite a similar mean baseline A1C of 8.7%, A1C reduction was less in VANITA R. ARODA, ELMAR JAECKEL, HENRIK JARLOV, TRINE JULIE ABRAHA- females (−1.4% vs. −1.6%) and endpoint FPG similar (117.3 vs. 118.7 mg/dL). MSEN, TINA VILSBØLL, Hyattsville, MD, Hannover, Germany, Søborg, Denmark, Endpoint insulin dose was similar (0.45 vs. 0.42 U/kg). Weight change was Hellerup, Denmark low and similar (1.7 vs. 2.0 kg). Overall and nocturnal hypoglycemia rates IDegLira is a novel fi xed-ratio combination of insulin degludec (IDeg), a with plasma glucose < 70 mg/dL were signifi cantly higher in females (Table). basal insulin with an ultra-long duration of action, and liraglutide (Lira), a Fewer females achieved A1C < 7.0% at endpoint (42% vs. 49%) and A1C < glucagon-like peptide-1 receptor agonist (GLP-1RA), which has previously 7.0% without severe hypoglycemia (41% vs. 48%). demonstrated advantages in glycemic control compared with IDeg and Lira. As with previous observations, our analysis shows that female T2DM pa- In this post-hoc analysis of 2 double-blind 26-wk phase 3 trials: DUAL IV tients achieve less glycemic control at a slightly higher risk of hypoglycemia (IDegLira vs. placebo in subjects inadequately controlled on oral antidiabetic with basal insulin therapy. Gender differences should be considered in treat- drug [OADs]) and DUAL II (IDegLira vs. IDeg in subjects inadequately controlled ment decisions. on basal insulin and OADs) in which IDegLira was initiated at 10 and 16 dose steps, respectively (1 dose step=1 unit of IDeg and 0.036 mg Lira), we compared Table. Hypoglycemia Incidence and Event Rate in Patients Initiating Insulin Glargine Stratifi ed by Gender. the proportion of subjects experiencing gastrointestinal (GI) side effects, often associated with GLP-1RAs during the fi rst 12 wks of treatment. Hypoglycemia defi nition Incidence (%) Event rate The proportions of subjects with GI side effects are presented in Figure 1. (events/patient year) There was no statistically signifi cant difference between the odds of expe- Female Male P Female Male P riencing GI side effects for subjects on IDegLira vs. pooled non-GLP-1RA at (n = 1,508) (n = 1,680) value (n = 1,508) (n = 1,680) value wks 4, 8, 12 or during entire trial period (odds ratios DUAL II: 2.0, 1.1, 1.1, 2.0; Overall with PG < 70 mg/dLa 44.90 41.28 0.047 4.83 3.69 < 0.001 DUAL IV: 1.0, 2.0, 0.4, 0.9, respectively). Overall with PG < 56 mg/dLa 24.82 24.03 0.597 1.35 1.19 0.123 A similar proportion of patients treated with IDegLira experienced GI side ef- Severe (assistance required) 2.36 1.67 0.163 0.10 0.06 0.146 fects vs. IDeg or placebo. This may be explained by the slow and steady titration Nocturnal with PG < 70 mg/dLb 16.21 14.86 0.265 0.89 0.65 0.003 of IDegLira leading to improved tolerability without losing glycemic control. Nocturnal with PG < 56 mg/dLb 7.86 6.99 0.280 0.32 0.27 0.195 Nocturnal severe 1.12 0.56 0.076 0.05 0.02 0.070 (assistance required)b Results derived from a generalized linear model including age, gender, duration of T2DM, body mass index, A1C, FPG, and insulin dose at baseline and concomitant oral therapy as factors. aIncluding severe events; bOccurring between 0:01 AM and 5:59 AM. PG, plasma glucose. Supported By: Sanofi

1008-P Association between Intraoperative Glycemic Levels and Postop- erative Complications in Non-cardiac Surgery Patients BALA G. NAIR, MAYUMI HORIBE, MONI B. NERADILEK, Seattle, WA Studies associating hyperglycemia with poor surgical outcome have thus far focused on cardiac surgery patients and postoperative glucose levels. We undertook a retrospective cohort study of adult patients (N = 995, 455 diabetic – both type 1 & 2 and 540 non-diabetic) that required intraoperative Supported By: Novo Nordisk

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A257 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULINS

1010-P Table. Key Glucose Lowering and Safety Outcomes Comparisons—No Related Factors of Insulin Dose Setting in Type 2 Diabetic Patients Statistically Signifi cant Differences. Treated with Continuous Subcutaneous Insulin Infusion WEN XU, XIUZHEN ZHANG, SIHUI LUO, YANHUA ZHU, JINHUA YAN, BIN YAO, LTHome EUT JIANPING WENG, Guangzhou, China, Shenzhen, China All Initiation Titration All Initiation Titration Short-term continuous subcutaneous insulin infusion (CSII) has been (n=48) (n= 18) (n= 30) (n=48) (n= 18) (n= 30) proved to improve glucose control and beta-cell function in T2DM. Optimal Baseline A1c - Mean (SD) 8.6 (1.2)% 9.2 (1.4)% 8.3 (1.0)% 8.9 (1.6)% 9.3 (1.9)% 8.7 (1.3)% insulin dose setting is indispensable for successful CSII therapy. However, 12-week Post-randomization A1c - 7.7 (1.0)% 7.7 (1.0)% 7.7 (1.1)% 7.6 (0.7)% 7.3 (0.6)% 7.8 (0.7)% limited data is available in T2DM population. This study is aimed to explore Mean (SD) the related factors of insulin dose setting to achieve glycemic control with Proportion of subjects achieving 21% 28% 17% 44% 50% 40% CSII in T2DM. composite primary target (at least A total of 327 T2DM patients (male: 59.6%; age: 53±13 years; diabetes 4 out of 7 FPGs and mean FPG for 3 duration: 4.5±5.7 years; BMI, 24.4±3.1 kg/m2; HbA1c: 10.6±2.4%) were consecutive prior FPGs in the target enrolled, who were admitted to hospital for 1-2 weeks of CSII therapy. range + no severe hypoglycemia) Insulin was adjusted according to the fasting (FBG) and postprandial Proportion of subjects achieving 29% 28% 32% 19% 50% 0% capillary blood glucose (PBG). After achieving normoglycemia (defi ned as 12-week A1c < 7% FBG≤7mmol/L and PPG≤10mmol/L), the insulin requirement profi les were Hypoglycemia (% of subjects with 35% 22% 43% 46% 33% 53% analyzed. documented hypoglycemia episode) A biphasic pattern with the maximum basal rates of CSII at 3AM-7AM Nocturnal Hypoglycemia (% of sub- 8% 6% 10% 15% 6% 20% and 5PM-10PM, and the minimum rates at 0AM-3AM and 10PM-0AM were jects with documented nocturnal revealed. Total daily insulin dose per kilogram (TDD/kg) was 0.77±0.26 IU/ hypoglycemia episode) kg. The ratio of total basal insulin dose to TDD (%TBa) was 40%. Patients with baseline HbA1c ≥8% needed more insulin than those with HbA1c <8% Supported By: Sanofi (0.79±0.25 IU/kg versus 0.65±0.26 IU/kg, p <0.05). TDD/kg and %TBa in female patients were higher than those in male (TDD/kg: 0.84±0.27 IU/ 1012-P kg versus 0.72±0.24 IU/kg; %TBa: 41.9±8.4% versus 39.0±9.4%, p <0.05).

POSTERS Low Levels of Unmodifi ed Insulin Glargine in Plasma of People with Therapeutics Further multiple regression showed that gender (p<0.05), FPG (p<0.001), Type 2 Diabetes Mellitus Requiring High Doses of Basal Insulin Clinical Diabetes/ HbA1c (p<0.05) and waist to hip ratio (p<0.05) were signifi cantly and in- PAOLA LUCIDI, FRANCESCA PORCELLATI, HANNELE YKI-YÄRVINEN, MATTHEW dependently related to TDD/kg; gender (p<0.05) and disease duration C. RIDDLE, PAOLA CANDELORO, ANNA MARINELLI ANDREOLI, GEREMIA B. BOL- (p<0.05) were independently associated with %TBa, while body weight LI, CARMINE G. FANELLI, Perugia, Italy, Helsinki, Finland, Portland, OR was not associated with either TDD/kg or %TBa. After s.c. injection, insulin glargine (M0) is cleaved to metabolites M1 and %TBa is around 40% in Chinese T2DM treated with CSII when glycemic M2 in glargine treated subjects with type 2 diabetes (T2DM). The aim of this control is achieved. In this population, female, patients with larger waist study was to establish glargine metabolism in T2DM subjects requiring very to hip ratio or poor glycemic control need higher TDD/kg. Higher %TBa high doses of glargine. might be considered in female or patients with longer disease duration. Ten T2DM subjects on stable treatment with >1.2 U/kg glargine were studied 12±1 h after last s.c. glargine injection. Mean insulin glargine dose was 162±63 U/day (1.49±0.28 U/kg/day). Fasting blood samples were ana- 1011-P lyzed for M0, M1 and M2 (LC-MS/MS method) and plasma free insulin (FIRI) Long-Acting Insulin Glargine Titration Web Tool (LTHome) vs. En- by radioimmunoassay after antibody precipitation. hanced Usual Therapy of Glargine Titration (INNOVATE Trial) M1 was present in all subjects with a mean concentration of 457±337 HARPREET S. BAJAJ, KARRI VENN, CHENGLIN YE, RONNIE ARONSON, Bramp- pmol/L, representing 100% (84 to 100%, 10th to 90th percentiles) of total ton, ON, Canada, Toronto, ON, Canada insulin. M2 was not detected in any subject. M0 was detected only in 4 out Basal insulin initiation and titration in the real-world is often prolonged of the 10 subjects with a mean concentration 78±19 pmol/L representing and unsuccessful, due to titration complexity and hypoglycemia. LTHome 0% (0 to 16%) of total insulin (Figure 1). M1 was >500 pmol/L, and corre- - a web tool - applies a rules engine-based algorithm (based on prior dose, lated with M0 (r=0.69, p<0.025). FIRI was correlated with M1 concentration fasting plasma glucose (FPG) and hypoglycemia), providing insulin titration (r=0.95, p<001). Glargine dose injected s.c. was not correlated to M0, neither advice directly to the patient. M1 or FIRI. This randomized, investigator-initiated trial evaluates the safety and In T2DM subjects on very high glargine dose, glargine is nearly totally effi cacy of LTHome compared to Enhanced Usual Therapy (EUT, by physi- metabolized to M1. M0 is detected only in 40% of subjects at a concentra- cian and with diabetes educators) to reach FPG goal over 12 weeks among tion <100 pmol/l. Thus, glargine metabolism in people taking high doses of 138 patients. Inclusion criteria for patients scheduled to initiate or titrate glargine is similar to that for people with T1DM and T2DM on lower glargine basal insulin were: type 2 diabetes, 18-75 years, computer literacy and doses. HbA1c >7.0%. INNOVATE protocol was approved by ethics board. We pres- ent the pre-planned interim results. Ninety six patients, with comparable baseline characteristics, were ran- domized to LTHome vs. EUT. There was no severe hypoglycemia during the trial. Both titration approaches were equally effective in glucose lowering with similar safety outcomes - no signifi cant differences were seen at the end of 12-week trial period (Table). Similar results were observed with LTHome vs. EUT, regardless of subgroups i.e. patients initiating or titrating glargine insulin. LTHome may offer an effective and safe real-world alternative to EUT, for each of basal insulin initiation and titration.

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A258 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULINS

1013-P defi ned as the Index. All patients had a minimum of 1 year continuous coverage Sustainable Glucometric Trends in High-Risk Diabetic Patients: prior to (Q1–4) and 1 year after (Q5–8) Index. Of 8335 patients analyzed, 15% Two Years On were hospitalized during Q4. Quarterly rates of medical claims for HG were ANDRE TAN, CHEE CHIN PHANG, SUAN TEE LIM, HAI DONG LUO, GRAEME MA- stable (~1.1%) during Q1–3, increasing to 3.1% in Q4. This sharp increase is CLAREN, KRISTINE TEOH, DODDABELE S. DEEPAK, Singapore, Singapore postulated to correspond to sample- or hospital-prescribed BI. Rates of medi- Patients with diabetes mellitus (DM) undergoing coronary artery bypass cal claims for HG remained elevated during the 2-year follow-up (FU) period, surgery (CABG) have excess postoperative morbidity and mortality that may approximately double that in Q1–3 (Figure). Use of metformin, sulfonylurea, be reduced with optimal glycemic control. Since August 2012 a structured and DPP-4 fell by about 5–15% over the 2-year FU period; however, a high pro- glucose management protocol has been in use for all type 2 DM patients portion of patients discontinued BI over the same period (43%), with the high- post-CABG during transition from intravenous to subcutaneous therapy. This est proportion (22%) occurring in the fi rst quarter after BI disbursement (Q5). consists of scheduled basal insulin [Insulin glargine (Lantus®)], prandial and These results suggest that HG risk is greatest around BI initiation and that supplemental insulin [insulin aspart (Novorapid®)] targeting fasting and pre- BI discontinuation is a treatment challenge, highlighting the need for a new meal capillary blood glucose [CBG, mmol/L] of 4.0-8.0 and any CBG of 4.0-10.0. BI with a better HG profi le in this population. Data on baseline characteristics, glucometrics and postoperative outcomes were collected for T2DM patients who underwent CABG in the second year (Y2) of protocol use (Sep 2013 - Aug 2014) and this was compared against pa- tient data from the fi rst year (Y1: Aug 2012-2013) and pre-protocol use (Jan- Aug 2012). Glucometric outcomes were analyzed using the population and patient-day model. Glucometric data showed sustained reduction of overall mean CBG in Y2 (8.9 + 3.2) vs. Y1 (9.0 + 3.1, p=0.079) vs. baseline (9.4 + 3.2, p <0.0001); increased on-target CBG (4.0-10.0) in Y2 (68%) vs. Y1 (66%, p=0.034) vs. baseline (64%, p<0.0001) and lower mean patient-day CBG in Y2 (8.9 + 2.1) vs. baseline (9.3 + 2.3, p = 0.0001). There was no excess hypoglycemia per 100 patient-days [all episodes (6.05 vs. 7.75 vs. 5.68, p=0.147, 0.737) and severe episodes {CBG<2.2} (0.083 vs. 0.08 vs. 0.26, p=0.404, 0.328)] comparing Y2 vs. Y1 vs. baseline respectively. There was a trend towards further reduction POSTERS in hospital length of stay (days) in Y2 (14.6 + 11.8) vs. Y1 (15.3 + 10.6, p=0.62) Therapeutics vs. baseline (17.6 + 15.3, p = 0.08). Surgical site infections were lower in Y2 Clinical Diabetes/ compared to Y1 (3.7% vs. 6.6%, p=0.2) with a signifi cant reduction compared to baseline (3.7% vs. 15.9%, p=0.0003). Protocol implementation in the second year shows consistently improving glucometric and postoperative outcomes in post-CABG T2DM patients without increasing hypoglycemia. Supported By: Sanofi 1014-P Safety, Pharmacokinetics (PK), and Pharmacodynamics (PD) of 1016-P Once-Weekly Dulaglutide in Elderly Patients with Type 2 Diabetes Ultra-Rapid-Acting Concentrated Insulin BIOD-531 Suitability for (T2D) Continuous Subcutaneous Insulin Infusion (CSII) Therapy CORINA LOGHIN, KAREN B. SCHNECK, XUEWEI CUI, JENNY Y. CHIEN, Indianapo- RODERIKE POHL, ALAN KRASNER, BRYAN R. WILSON, MING LI, MARY GUIN- lis, IN NESS, PRAGATI RAVULA, ERROL DE SOUZA, Danbury, CT The aim of this study was to evaluate the safety, PK, and PD of dulaglutide BIOD-531, a U-400 formulation of recombinant human insulin, EDTA, cit- in elderly patients after subcutaneous doses (0.5, 0.75, 1.5 mg) for 6 weeks. rate and MgSO4, has accelerated absorption and onset of action compared In this parallel design, double-blind study, 37 male and female patients to Humulin® R U-500 and Humalog® Mix75/25™ and a basal duration profi le with T2D (≥65years [y]) were randomized to placebo or dulaglutide. Blood when delivered by subcutaneous (sc) injection. The feasibility of BIOD-531 samples were taken for PK and PD evaluations. PD analyses, including glu- for CSII therapy was evaluated in miniature diabetic swine (n=8) using a cose, C-peptide, insulin and glycosylated hemoglobin (A1C), were performed crossover study design following Animas Ping® pump bolus or sc injection of on absolute and change from Day -1 values. 0.25 U/kg BIOD-531; plasma samples were obtained over the next 8 hours. Patients were aged between 65 and 76y (26 aged 65 to 69y; 10 aged 70 Accelerated rates of absorption (T50%max early and Tmax, min) of BIOD-531 were to 75y; 1 aged >75y). Dulaglutide doses were safe and well tolerated. The similar following pump bolus (9.9±2.2 and 42.5±7.8) and sc injection (9.6±1.8 majority of adverse events (AEs) was gastrointestinal, mild in severity and and 64.4±17.9) resulting in rapid lowering of glucose (see Figure). Further- resolved without intervention. The incidence of AEs was generally similar more, there were no signifi cant differences in several other pharmacokinetic across all dose levels and comparable to placebo. Dulaglutide PK in elderly (Cmax or AUC0-480min) or glucose lowering measures following pump bolus and patients with T2D were consistent with those previously reported in pa- sc injection. However, the duration of late insulin exposure was signifi cantly tients <65y; characterized by a slow absorption phase and a long elimination (p <0.05) shorter (T50%maxlate, 94.4±10.1 vs. 155.7±18.0 min; AUC120-480min, half-life. Systemic exposure of dulaglutide was generally dose-proportional 1809±370 vs. 4711±761 µU/mL*min) and the return of glucose to baseline and accumulation at 6 weeks was approximately 1.5-fold compared to Day 1. was signifi cantly faster following pump bolus vs. sc injection (see Figure). With 1 exception, statistically signifi cant reductions in the area under the The ultra-rapid-acting profi le with a shortened duration of action along with serum glucose response curve (-98.0 to -197 mg·h/dL), fasting glucose (-13.9 to its high concentration make BIOD-531 a promising candidate for CSII and -27.7 mg/dL), and 2-hour postprandial glucose concentrations (-26.3 to -59.5 artifi cial pancreas therapy. mg/dL) compared to placebo occurred on Days 3 and 38 for all doses. All dose levels of dulaglutide had a signifi cant reduction in A1C compared to placebo. Based on safety, PK, and PD, dulaglutide 1.5 mg once weekly can be ad- ministered to patients ≥65y without dose adjustment.

1015-P Hypoglycemia Rates and Concomitant Medications after Basal In- sulin (BI) Initiation in Patients with Type 2 Diabetes Mellitus (T2DM) in a U.S. Managed Care Setting ENGELS CHOU, LAURA LIAO, HONGWEI WANG, HSING-WEN CHUNG, JAVIER ESCALADA, Bridgewater, NJ, King of Prussia, PA, Pamplona, Spain Patients with T2DM in a U.S. health insurance claims database from 2006 to 2012, who initiated BI on top of oral antihyperglycemic drugs, were followed for up to 2 years to assess quarterly hypoglycemia (HG) rates and the use of Supported By: National Institute of Diabetes and Digestive and Kidney Diseases concomitant antihyperglycemic drugs. Patients who subsequently added pran- (R43DK096604) dial insulin were excluded. The fi rst BI disbursement through pharmacy was

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A259 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULINS

1017-P Pts were mostly Caucasian (96%), approximately 43 y old with diabetes Age, BMI, and Diabetes Duration: Effect on Glycemic Control and duration about 20 y. During 12-wk lead-in, mean ± SD HbA1c decreased from Hypoglycemia with Insulin Glargine 300 U/mL in Type 2 Diabetes 7.5 ± .8 to 6.8 ± .7%; fasting serum glucose (FSG) decreased from 162 ± 69 (T2DM) to 123 ± 59 mg/dL. STEPHEN M. TWIGG, JAVIER ESCALADA, MARIE-LISE GRISONI, PETER STELLA, VT and FT groups were similar in HbA1c, FSG, glucose variability, total and ANA MERINO-TRIGO, FERNANDO J. LAVALLE GONZÁLEZ, BERTRAND CARIOU, nocturnal hypoglycemia, and basal and bolus insulin doses (Table). Self-mon- LUIGI F. MENEGHINI, Sydney, Australia, Pamplona, Spain, Levallois-Perret, France, itored FBG was slightly lower with FT than VT (p=.014). Treatment-emergent Paris, France, Monterrey, Mexico, Nantes, France, Dallas, TX adverse events (AEs) and serious AEs were similar for both groups. Over 36 The EDITION 1, 2 and 3 clinical trials showed that insulin glargine 300 wks, LS mean ± SE weight decreased 1.2 ± .3 kg (p<.001) and mean triglyc- U/mL (Gla-300) provided comparable glycemic control to glargine 100 erides, ALT, and AST increased signifi cantly (all p<.05) but trended toward U/mL (Gla-100) and less hypoglycemia in people with T2DM, over 6 months baseline levels by 4 wks after BIL discontinuation. No pts met criteria for Hy’s law. of treatment. The effects of Gla-300 vs. Gla-100 on HbA1c reduction and hypoglycemia were investigated in different subgroups (age [<65 and ≥65 BIL permits 8-40 h dosing intervals with similar HbA1c compared to fi xed years], BMI [<30 and ≥30 kg/m2] and diabetes duration [<10 and ≥10 years]) in time dosing in T1D. a post hoc patient-level meta-analysis of EDITION 1, 2 and 3. HbA1c reduction Table. remained comparable between the Gla-300 and Gla-100 arms, regardless of age, BMI or disease duration (Table). The lower risk of confi rmed (≤70 mg/dL) or severe hypoglycemia with Gla-300 vs. Gla-100 was not affected by age or BMI (Table). For the diabetes duration subgroup analysis no signifi cant heterogeneity of treatment effect was seen for nocturnal hypoglycemia, whereas the benefi t of lower risk of confi rmed (≤70 mg/dL) or severe hy- poglycemia at any time of day with Gla-300 was seen in those with longer duration of diabetes (Table). In conclusion, comparable glycemic control was observed with Gla-300 and Gla-100, and less nocturnal hypoglycemia was seen for Gla-300 regardless of the subgroup. POSTERS Therapeutics Clinical Diabetes/

Supported By: Eli Lilly and Company

1019-P Lipohypertrophy (LHT) Leads to Blunted, More Variable Insulin Ab- sorption and Action in Patients with Type 1 Diabetes (T1DM) SUSANNE FAMULLA, ULRIKE HÖVELMANN, ANNELIE FISCHER, HANS-VEIT COESTER, LUTZ HEINEMANN, LARS KALTHEUNER, LAURENCE HIRSCH, TIM HEISE, Neuss, Germany, Leverkusen, Germany, Franklin Lakes, NJ We investigated insulin (INS) exposure and pharmacodynamics (PD) of insulin lispro (LIS) injected into abdominal areas with LHT or normal adipose tissue (NAT). Thirteen T1DM with LHT (confi rmed by palpation and ultra- sound) received single doses of 0.15 U/kg LIS approximately every 6 hours, twice into a region with LHT and twice into NAT in random order, under automated Glucose clamp conditions (ClampArt, blood glucose target 100 mg/dL). Mean INS and glucose infusion rate (GIR) profi les are shown. Comparing Supported By: Sanofi (NCT01499082, NCT01499095, NCT01676220) LHT with NAT injection, LS-mean INS concentrations were comparable dur- ing the fi rst 30 min (AUCINS0-0.5h 8.8 vs. 9.4 h*mU/L), but signifi cantly lower thereafter (AUC 29.3 vs. 41.5 h*mU/L, AUC 97 vs. 154 h*mU/L, 1018-P INS0-1h INS.0-4h all p<0.02). Maximum INS exposure was reduced by 34% (CINSmax 49.7 vs. Similar HbA1c Reduction and Hypoglycemia with Variable Time 75.4 mU/L, p<0.002). The PD effect in the fi rst 4 h was 27% lower with LHT (VT) and Fixed Time (FT) Dosing of Basal Insulin Peglispro (BIL) in injection (AUC : 529 vs. 720 mg/kg, p<0.05), whereas maximum GIR was Type 1 Diabetes (T1D): IMAGINE 7 GIR0-4h comparable (GIRmax 5.5 vs. 6.0 mg/kg/min, p=0.378). Intra-subject variability SATISH K. GARG, JEAN-LOUIS SELAM, ANUJ BHARGAVA, NANETTE C. SCHLOOT, was substantially higher after dosing into LHT (coeffi cients of variation 52 JUNXIANG LUO, QIANYI ZHANG, JENNIE G. JACOBSON, BYRON J. HOOGWERF, vs. 11% [AUCINS.0-4h] and 57 vs. 23%, [AUCGIR0-4h], all p<0.002). Aurora, CO, Tustin, CA, Des Moines, IA, Bad Homburg, Germany, Indianapolis, IN This fi rst glucose clamp study in patients with LHT explains clinical experi- BIL is a novel basal insulin with a fl at profi le and hepatic and peripheral ence that both insulin absorption and action are substantially blunted and action more like endogenous insulin. The fl at profi le may allow fl exible timing considerably more variable when insulin is injected into areas with LHT. of BIL insulin dosing. In this Phase 3 crossover study, patients (pts; N=212) received BIL (evening dosing) for 12 wks (lead-in phase); 182 pts were then randomized to two 12- wk treatment periods comparing FT (evening) and VT (dosing intervals: 8-40 h, AM [M, W, F] or PM [T, Th, Sa, Su]). Primary outcome was noninferiority (margin=.4%) of VT vs. FT for HbA1c after 12 wks.

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A260 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULINS

1021-P Switching from Twice-Daily Basal Insulin to Once-Daily New Insu- lin Glargine 300 U/mL (Gla-300): An Analysis in People with T2DM (EDITION 1 and 2) RONAN ROUSSEL, MICHAEL C. D’EMDEN, MILES FISHER, FRANCISCO JAVIER AMPUDIA-BLASCO, PETER STELLA, MARIE-LISE GRISONI, ANNA M.G. CALI, CAROL H. WYSHAM, Paris, France, Brisbane, Australia, Glasgow, United Kingdom, Valencia, Spain, Levallois-Perret, France, Spokane, WA In EDITION 1 (basal + mealtime insulin) and EDITION 2 (basal + OADs), people with T2DM receiving new insulin glargine 300 U/mL (Gla-300) achieved compa- rable glycemic control with less hypoglycemia vs. glargine 100 U/mL (Gla-100). This post hoc analysis explored the effect of switching from twice-daily basal insulin to once-daily Gla-300 or Gla-100. At randomization, 16.9% and 19.8% of people were receiving twice-daily basal insulin in EDITION 1 and EDITION 2, re- spectively. In these subgroups, glycemic control was comparable over 6 months in people who switched to Gla-300 or Gla-100 (LS mean difference in HbA1c change from baseline to month 6 −0.01 [95% CI −0.27 to 0.24]% in EDITION 1 and 0.16 [−0.25 to 0.57]% in EDITION 2). As in the overall study cohorts, Gla-300 dose was higher than Gla-100 at month 6 in this analysis. Participants switching from twice- to once-daily basal insulin in EDITION 1 had lower risk of confi rmed (≤70 mg/dL) or severe hypoglycemia with Gla-300 vs. Gla-100 at night, but not at any time (24 h; possibly infl uenced by mealtime insulin use), while in EDITION 2, the risk was reduced both at night and at any time (24 h; Table). To conclude, as seen overall in EDITION 1 and 2, people with T2DM switching from twice-daily basal insulin to once-daily Gla-300 achieved comparable glycemic control with less hypoglycemia vs. those switching to Gla-100. POSTERS Therapeutics Clinical Diabetes/

1020-P Determinants of Insulin Sensitivity Recovery with Short-Term In- tensive Insulin Therapy in Patients with Newly Diagnosed Type 2 Diabetes Mellitus WAN XUESI, ZHIMIN HUANG, LIEHUA LIU, JUAN LIU, LIJUAN XU, YANBING LI, Guangzhou, China Insulin resistance is considered a signifi cant predisposing factor for the development of type 2 diabetes mellitus (T2DM). The aim of this study was to analyze the improvements of insulin resistance by continuous subcutane- ous insulin infusion (CSII) and the determinants underlying the improvements in insulin sensitivity. We pooled data from randomized controlled trial in which 160 patients with newly diagnosed T2DM (n=160,103 male, aged 49.8±10.4 ys, HbA1C 11±2.1%) underwent 2 weeks of CSII alone or with either rosiglitazone 4 mg QD, or metformin 500mg TID, or α-lipoic acid 600 mg QD. HOMA -IR and Supported By: Sanofi (NCT01499082, NCT01499095) intramyocellular lipid (IMCL), quantifi ed by MRS, were compared before and after discontinuation of CSII. 1022-P After short-term CSII treatment, HOMA IR improved significantly in all Comparative PK and PD of the Rapid-Acting Insulin Lispro Product groups while IMCL were ameliorated except for those on CSII with metform- SAR342434, and U.S.- and EU-approved Humalog® in Subjects with in. The decrease of IMCL in the soleus was greater in the CSII + TZD group T1DM than in the CSII-alone group (4.45±4.15 vs. 1.72±3.26mmol/kg, p = 0.022). IRENE NOWOTNY, CHRISTOPH KAPITZA, ANNE LEHMANN, HOOTAN KHATAMI, There were strong positive correlation between pre-intervention value and KARIN BERGMANN, BAERBEL ROTTHAEUSER, REINHARD BECKER, Frankfurt, themselves corresponding change in both HOMA-IR and IMCL (p< 0.01). The Germany, Neuss, Germany, Bridgewater, NJ multivariate regression analysis was developed. The change of BMI and PPG SAR342434 solution and Humalog® are both rapid-acting insulin lispro were independent predictor of the decrease of ln HOMA-IR (standardized products. Despite identical AA sequences, protein-based therapeutics coeffi cients were 0.216 and 0.211, F=4.023, p=0.021). IMCL in the soleus manufactured by distinct processes must be shown to be pharmacologically muscle decreased with the increment of average daily insulin dosage/unit similar to be approved as biosimilars. body weight (F=7.54, p=0.007). The average daily insulin dosage, but not BMI Exposure (PK) to and activity (PD) of SAR342434 (T) and U.S.(R1)- and EU(R2)- (p=0.208), was an independent predictor of the decrease of IMCL in the tibi- approved Humalog® were compared in a single-center, randomized, double-blind, alis muscle (F=15.25, p<0.001). 3-treatment, 3-period, 6-sequence, crossover, euglycemic clamp study. Thirty In conclusion, short-term CSII is very effective in improving insulin sensi- male T1DM subjects (20-59 years) were randomized to receive 0.3 U.kg-1 T, R1 and tivity. The combination therapy with rosiglitazone is superior for peripheral R2 in separate periods; 28 subjects completed all 3 treatment periods. PK and PD insulin resistance. And the insulin resistance at baseline, the change of BMI (Glucose Infusion Rate, GIR) by euglycemic clamp were assessed up to 12 h. and PPG, the insulin dosage by CSII were key determinants of insulin sensi- Mean concentration and GIR vs. time profi les for T, R1 and R2 were similar. tivity recovery. Exposure to and activity of T, R1 and R2 were similar between treatments, with the 90% CI for the ratios of geometric least squares means contained in the pre-specifi ed bioequivalence limit of 0.80 - 1.25, and insignifi cant differ- ences in time related parameters (Table). Adverse events were similar for T, R1 and R2. No safety concerns were noted in laboratory, vital signs, or ECG data.

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A261 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULINS

In summary, this study demonstrated similar insulin lispro exposure Inclusion of nicotinamide in IAsp formulations containing Zn augmented the profi les and PD activity for SAR342434 to both U.S. and EU Humalog® and trans-endothelial absorption of IAsp, as refl ected by a difference in perme- between both U.S. and EU Humalog®, rendering SAR342434 a biosimilar ation rates (5 x 10-6 cm/s vs. 4 x 10-6 cm/s, respectively; p<0.05) (n≥3). Specifi - candidate. cally, its capacity to confer a higher early exposure in vivo was paralleled by Table. Analysis of the Primary PK and PD Parameters of Rapid-Acting Insu- differences in amount accumulated0-15min [pmol]/amount accumulated0-60min lin Lispro Products, SAR342434 Solution (T), and U.S.- (R1) and EU-approved [pmol] (%) compared to control (31% vs. 25%, respectively; p<0.05). In Zn-free (R2) Humalog®. formulations lacking stable hexamer species, it was observed that permeation Parameter Treatment Point estimate Parameter Treatment Hodges-Lehmann rates of IAsp were higher than that containing Zn - confi rming the infl uence of ratio (90% CI) difference shift multimeric state(s) of IAsp on absorption rate - while inclusion of nicotinamide had no notable effect. Collectively, these data suggest that nicotinamide may INS-Cmax T vs. R1 0.97 (0.89 to 1.05) INS-tmax (h) T - R1 -0.17 (-0.25 to -0.08) T vs. R2 0.96 (0.89 to 1.04) T - R2 -0.17 (-0.25 to 0.09) promote formation of IAsp monomer at the subcutis-endothelial interface R1 vs. R2 0.99 (0.94 to 1.03) R1 - R2 0.08 (-0.00 to 0.17) upon s.c. injection and in this way facilitate a more rapid rate of absorption. These studies reveal that nicotinamide effi ciently augments the rate at INS-AUC T vs. R1 0.95 (0.92 to 0.99) T50%-INS-AUC (h) T - R1 -0.13 (-0.20 to -0.08) 0-12 which IAsp permeates across the endothelium; likely via promotion of the T vs. R2 0.97 (0.94 to 1.00) T - R2 -0.10 (-0.17 to -0.01) R1 vs. R2 1.02 (1.00 to 1.05) R1 - R2 0.05 (-0.01 to 0.08) monomeric state, and supports observations in human subjects that faster aspart elicits a faster onset and higher early exposure compared to IAsp. GIR-AUC0-12h T vs. R1 1.00 (0.94 to 1.07) GIR-tmax (h) T - R1 -0.30 (-0.56 to -0.03) While the absorption process preceding the appearance of insulin in plasma T vs. R2 1.06 (0.97 to 1.15) T - R2 -0.26 (-0.61 to 0.00) R1 vs. R2 1.05 (0.98 to 1.14) R1 - R2 -0.07 (-0.42 to 0.28) is a complex event infl uenced by many factors, these data provide evidence to support one such contributing mechanism via which nicotinamide can GIRmax T vs. R1 1.04 (0.98 to 1.10) T50% GIR-AUC0-12 (h) T - R1 -0.18 (-0.28 to -0.07) confer a faster rate of absorption. T vs. R2 1.07 (0.99 to 1.14) T - R2 -0.12 (-0.23 to -0.00) R1 vs. R2 1.03 (0.95 to 1.10) R1 - R2 0.04 (-0.07 to 0.12) T: SAR342434; R1: U.S. Humalog®; R2: EU Humalog®. 1025-P Point estimate method: Hodges-Lehmann - CI method: Moses (exact). Lymphatic Absorption of Basal Insulin Peglispro (BIL) in Sheep GIR = body weight standardized glucose infusion rate (mg.kg-1.min-1). INS: MARY PAT KNADLER, TRI-HUNG NGUYEN, KRISTINA M. CAMPANALE, MICHAEL Plasma insulin lispro concentration (pmol.L-1). J. DE VEER, JOHN M. BEALS, CHRISTOPHER J.H. PORTER, Indianapolis, IN, Mel-

POSTERS GIRmax and GIR-tmax are based on smoothed GIR profi les (tension 0.06). bourne, Australia, Clayton, Australia Therapeutics Basal insulin peglispro (BIL) is a novel, PEGylated insulin lispro that has a

Clinical Diabetes/ Supported By: Sanofi large hydrodynamic size. It has a prolonged duration of action which is related to a delay in insulin absorption and a reduction in clearance. Human insulin is 1023-P reported to have ~17% lymphatic absorption. Large globular proteins adminis- Utilization of Biosimilar Insulin in Asian Patients with Diabetes— tered subcutaneously are absorbed more via the lymphatic than the vascular The Joint Asia Diabetes Evaluation (JADE) Program system. The objective was to determine the absorption of BIL via the periph- LINSEY U. GANI, ERIC LAU, ANDREA LUK, LEORINO SOBREPENA, QUANG KHANH eral lymphatic system vs. the vascular capillary system in lymph duct cannu- TRAN, JOTHYDEV KESAVADEV, WEIPING JIA, JULIANA C.N. CHAN, Singapore, lated (LDC) vs. non-lymph cannulated (non-LDC) sheep. In a parallel design, a Singapore, Hong Kong, China, San Jose City, Philippines, Ho Chi Minh City, Vietnam, dose of 120 nmol (3 nmol/kg) BIL was administered IV or SC into the interdigital Trivandrum, India, Shanghai, China space of the hind leg (below the cannulated efferent popliteal lymph duct in Biosimilar insulin availability will increase with patent expiry for originator LDC sheep). Non-LDC sheep were administered 20 nmol (0.5 nmol/kg), 40 nmol insulins. While they may reduce treatment costs, there are few comparative (1 nmol/kg), or 120 nmol BIL IV to determine pharmacokinetic (PK) linearity. Pe- safety and effi cacy data. We examined biosimilar insulin use in Asia using data ripheral lymph and/or serum samples were collected from 3-5 sheep/group for from the JADE portal. JADE is a quality improvement initiative incorporating generally 96 hours postdose, and concentrations were determined by ELISA. structured protocols and reports. Between 2007 to 2014, 81,953 diabetic pa- After IV dosing to non-LDC sheep, BIL PK was linear over the 20 nmol-120 nmol tients were enrolled from 11 countries-Hong Kong, India, China, Philippines, In- dose range. The apparent elimination half-life after SC dosing was about twice donesia, Korea, Malaysia, Singapore, Taiwan, Vietnam, Thailand. We extracted as long as that after IV dosing. After IV dosing of 120-nmol BIL, the AUC was records containing insulin-related terms to capture drug usage in the JADE por- similar in LDC and non-LDC sheep. SC bioavailability in a separate non-LDC tal. Amongst 81,953 patients, 23.9% (n=19,600) were on insulin, 6.9% (n=1,359) group was 123%, indicating complete absorption of BIL. In LDC sheep, bio- were on biosimilar insulins, mainly from India (n=811, 59.7%), Philippines (n=297, availability decreased to <2%, indicating that most of the dose was absorbed 21.9%), China (n=149, 11.0%) and Vietnam (n=89, 6.5%). Biosimilar insulin users via the lymphatic system. The mean % (±SD) of BIL recovered in the peripheral were younger (mean±SD: 56.2±11.4 versus 57.9±11.8 years, p<0.001), had higher lymph after SC dosing was 88% (±19%; range: 61%-102%) in contrast to 0.06% HbA1C (9.4±2.3 versus 9.0±2.2% p<0.001) than originator insulin users despite (±0.02%; range: 0.04%-0.08%) after IV dosing. Addition of the 20-kDa PEG to using higher insulin dosage [median (IQR) 0.50 (0.28, 0.73) versus 0.45 (0.27,0.68) 2 insulin lispro, therefore, appears to shift the absorption of BIL to primarily via units/kg, p=0.01] and had higher BMI (26.2±5.0 versus 25.8±4.5 kg/m , p <0.001) the lymphatic system. and waist circumference (male: 92.7±12.8 versus 91.1±11.9 cm, p<0.001, female: Supported By: Eli Lilly and Company 92.1±12.8 versus 88.6±13.1 cm, p<0.001). In Philippines where biosimilar insulin usage was over 10% among insulin users, the respective HbA1C were 9.7±2.7 and 9.2±2.5% (p=0.02) and insulin dosages were 0.52 (0.40, 0.64) and 0.35(0.21, 1026-P 0.57) unit/kg (p<0.001). In a multivariate model, biosimilar insulin use was inde- A Single Dose Euglycemic Clamp Study in Healthy Subjects Dem- pendently associated with higher insulin dose and HbA1C. The association with onstrating Pharmacokinetic and Pharmacodynamic Equivalence lower incidence of hypoglycaemia was attenuated after adjusting for confound- between MK-1293 and Lantus ing variables. Biosimilar insulin use is prevalent in Asia which is associated with JOHN PALCZA, KATE MOSTOLLER, CHANTAL MAHON, APRIL M. BARBOUR, YANG worse glycemic control despite higher insulin dose. Pharmacological vigilance XU, ERIC MANGIN, PAMELA ALGATT-BERGSTROM, LINDA MORROW, MARCUS studies are needed to evaluate their long term effects on clinical outcomes. HOMPESCH, MICHAEL CRUTCHLOW, Whitehouse Station, NJ, Chula Vista, CA Supported By: Asia Diabetes Foundation; Merck & Co., Inc. MK-1293 is a follow-on/biosimilar insulin glargine under development using Lantus™ as the benchmark comparator. This double-blind, randomized, three- period balanced crossover euglycemic clamp study in healthy male subjects 1024-P (age: 18-45 yrs; BMI: 18.5-25.0 kg/m2) was conducted to demonstrate phar- Faster-Acting Insulin Aspart: Towards an Understanding of the macokinetic (PK) and pharmacodynamic (PD) equivalence between MK-1293, Mechanism(s) of Action of Nicotinamide Lantus™ procured in the U.S. (‘U.S.-Lantus™’), and Lantus™ procured in the EU STEPHEN T. BUCKLEY, CLAUS B. JEPPESEN, HELLE B. OLSEN, SUSANNE HOST- (‘EU-Lantus™’). In each treatment period, subjects received single 0.4 units/ RUP, JEPPE STURIS, Måløv, Denmark kg doses of MK-1293, U.S.-Lantus™, or EU-Lantus™ in random sequence fol- Faster-acting insulin aspart (faster aspart) is insulin aspart (IAsp) in a new lowed by a 24-hour assessment period for PK sampling and euglycemic clamp- formulation containing two additional excipients (nicotinamide and arginine), ing (clamp target 80 mg/dL [4.44 mmol/L]). An LC-MS/MS assay was used to which result in a faster initial absorption after s.c. injection. To establish an quantify concentrations of the major circulating active glargine metabolite understanding of the mechanism(s) via which nicotinamide elicits its effect, (M1) as well as parent glargine and the M2 metabolite. Data from a prelimi- we studied the permeation rate of IAsp across human dermal-derived micro- nary analysis of the primary PK and PD endpoints are presented in the table. All vascular capillary endothelial (HDMEC) cell monolayers in Zn-containing and treatments were well tolerated. This study demonstrated PK and PD equiva- Zn-free formulations with and without nicotinamide.

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A262 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULINS lence between MK-1293, U.S.-Lantus™, and EU-Lantus™, thereby supporting 1028-P the potential for MK-1293 as a follow-on/biosimilar insulin-glargine. Particle Size Does Not Impact the Pharmacokinetic Response of a Table. Novel Inhaled Human Insulin ERIC ZIJLSTRA, TIM HEISE, LESZEK NOSEK, HANS-VEIT COESTER, KATHRIN MK-1293 / MK-1293 / EU-Lantus / ™ ™ ™ LÜCKEMEYER, LISA PORTER, SAMANTHA MILLER, ANDY VICK, JAMES B. FINK, U.S.-Lantus EU-Lantus U.S.-Lantus JOHN PATTON, Neuss, Germany, Brisbane, CA, Ashland, OH Primary PK Endpoints Deep lung delivery of inhaled insulin maximizes its systemic absorption.

AUC0-24hr of M1* 0.98 (0.93, 1.04) 0.97 (0.92, 1.02) 1.01 (0.97, 1.05) This fi rst-in-human trial investigated the optimal particle size for absorption C of M1* 1.01 (0.96, 1.07) 1.00 (0.95, 1.05) 1.01 (0.96, 1.06) of Dance 501, an aerosolized liquid human insulin for inhalation (INH). max Twelve subjects with type 1 diabetes received an INH dose (50 IU) using Primary PD Endpoints an inhaler on 4 visits and 6 U insulin lispro (LIS) s.c. on a separate visit to as- GIR AUC0-24hr 1.01 (0.92, 1.10) 0.96 (0.89, 1.04) 1.05 (0.97, 1.14) sess relative bioavailability (FREL) of INH. The inhaler was confi gured to gen- GIR AUC0-12hr 0.96 (0.84, 1.09) 0.91 (0.82, 1.02) 1.05 (0.93, 1.19) erate insulin aerosol particles sized 3.5-4.0 µm (Small), 4.3-4.8 µm (Medium) GIR AUC 1.03 (0.95, 1.12) 0.98 (0.91, 1.05) 1.05 (0.97, 1.14) or 5.0-5.5 µm (Large) during low inspiratory fl ow. To assess within subject 12-24hr variability, Medium was used twice. Pharmacokinetics (PK) were measured GIRmax 0.96 (0.87, 1.06) 0.91 (0.84, 0.99) 1.05 (0.95, 1.17) up to 8 hours after dosing. *M1 metabolite accounts for >90% of the total circulating active glargine Stratifi ed by particle size, the resulting PK parameters for INH were not and was therefore the primary PK analyte. statistically different from each other (Table). FREL was in a range (10-12%) PK endpoint results presented as geometric mean ratios and 90% confi - typical for published inhaled insulin data. Within subject variability was dence intervals. 27.5% for AUC which is similar to published results for s.c. soluble insulin. PD endpoint results presented as arithmetic mean ratios and 90% confi - 0-8h dence intervals. Compared to LIS, onset of appearance of INH was faster, peak concentra- tions were lower and duration of exposure was longer (i.e. higher values for GIR= glucose infusion rate; GIRmax= maximal glucose infusion rate. MRT). INH was well tolerated; no cough and no relevant changes in lung Supported By: Merck & Co., Inc. function were observed. Inhalation of Dance 501 insulin is safe and results in clear and reproduc- 1027-P ible PK responses. Small variations in aerosol particle size do not infl uence POSTERS A Clinically-defi ned Nocturnal Window for Analysis of Hypoglyce- the PK/PD response. Therapeutics mia with New Insulin Glargine 300 U/mL in Type 2 Diabetes (T2DM) Clinical Diabetes/ MATTHEW C. RIDDLE, PHILIP D. HOME, ANGELO AVOGARO, MARGARITA GIMÉ- NEZ ÁLVAREZ, ANA MERINO-TRIGO, MARIE-LISE GRISONI, STANISLAV GLEZER, GEREMIA B. BOLLI, Portland, OR, Newcastle upon Tyne, United Kingdom, Padova, Italy, Barcelona, Spain, Paris, France, Levallois-Perret, France, Perugia, Italy Analysis of 6-month data from EDITION 1, 2 and 3 shows that in T2DM insulin glargine 300 U/mL (Gla-300) causes less nocturnal (0000 to 0559 h) and anytime (24 h) confi rmed or severe hypoglycemia than glargine 100 U/ mL (Gla-100). However, this nocturnal window may not accurately refl ect a real-life overnight fasting period. A sensitivity analysis of these data defi ned nocturnal exposure as 2200 h to pre-breakfast SMPG. Data were available for 2488 participants (randomized population [N=2496], mean age 59 y, dia- 2 1029-P betes duration 13 y, BMI 35 kg/m ). Median breakfast time was 0730 h (IQR Evaluation of High Insulin Antibody Response and Related Clinical 0700-0819). More events occurred in the clinically defi ned window (Gla-300 Outcomes in Patients with T1DM or T2DM Treated with LY2963016 3585 vs. 1235; Gla-100 4730 vs. 1791). The % of individuals with ≥1 event (rel- and Lantus® ative risk) was lower with Gla-300 vs. Gla-100 with both defi nitions (Table). LIZA L. ILAG, ROBYN K. POLLOM, TIMOTHY M. COSTIGAN, JASON S. ZIELONKA, Annualized event rates were also lower with Gla-300 with both defi nitions ROBERT J. KONRAD, MARK A. DEEG, MELVIN J. PRINCE, Indianapolis, IN (rate ratio 31% lower 0000 to 0559 h; 24% in the clinically defi ned window). LY2963016 (LY IGlar) and Lantus® (IGlar) are insulin glargine products with Absolute difference in numbers of events (favoring Gla-300) was greater in similar effi cacy and safety including insulin antibody responses that are low the clinically defi ned window (1145 vs. 556). and similar between treatments. This evaluation assessed maximal anti- Summary: The nocturnal hypoglycemia benefi t of Gla-300 vs. Gla-100 is body responses and relationships to clinical outcomes. confi rmed with both defi nitions. Greater relative reduction of % people af- Data were analyzed from the ELEMENT 1 (T1DM) and ELEMENT 2 (T2DM) fected and event rates is suggested from 0000 to 0559 h, but lower absolute studies. Maximum post-baseline antibody levels and proportion of patients numbers of events with Gla-300 during a clinically defi ned fasting period in the upper quartile of maximum antibody % binding (UQMAPB: patients may be more clinically relevant. with maximum post-baseline % binding in the upper 25% of maximum values observed) were compared for differential treatment effects on outcomes. There were no signifi cant differences in maximum post-baseline antibody levels and no signifi cant differential treatment effects in the relationship between maximum post-baseline % binding and outcomes (ie, changes in HbA1c, basal insulin dose, weight, and total hypoglycemia; all interaction p-values >0.05). Similar proportions of patients and AE frequencies were noted within UQMAPB. No signifi cant differential treatment effect of UQ- MAPB (yes/no) was observed (Table). In conclusion, patients treated with LY IGlar and IGlar had similar maxi- mum antibody responses, with similar proportions having high antibody response. High antibody levels were not associated with effects on clinical outcomes.

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A263 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULINS

Table. POSTERS Therapeutics

Clinical Diabetes/ Supported By: Sanofi (NCT01499082, NCT01499095, NCT01676220)

1031-P Lower Mean Blood Glucose during Short-Term Intensive Insulin Therapy Was Associated with Better Clinical Outcomes in Patients with Newly Diagnosed Type 2 Diabetes LIEHUA LIU, JUAN LIU, HAI LI, WAN XUESI, PENGYUAN ZHANG, WANPING DENG, YANBING LI, Guangzhou, China Supported By: Eli Lilly and Company/Boehringer Ingelheim Short-term near-normoglycemia achieved by intensive insulin therapy (ITT) induced glycemic remission by improving acute insulin response (AIR) in 1030-P patients with newly diagnosed type 2 diabetes (T2DM). However, whether Glycemic Control and Hypoglycemia with Insulin Glargine 300 U/mL stricter glycemic control during the therapy could lead to better outcomes (Gla-300) vs. Glargine 100 U/mL (Gla-100) in Type 2 Diabetes (T2DM) was unknown. in a Patient-Level Meta-analysis of 1-Yr Phase 3a EDITION Studies We retrospectively investigated 74 patients with newly diagnosed T2DM ROBERT RITZEL, RONAN ROUSSEL, ANDREA GIACCARI, JITEN P. VORA, MARIE- treated with short-term ITT. Insulin dose was titrated according to results LISE GRISONI, CLAIRE BRULLE-WOHLHUETER, STANISLAV GLEZER, HANNELE of daily 8-point capillary blood glucose (before and 2 hours after 3 meals, YKI-JÄRVINEN, Munich, Germany, Paris, France, Rome, Italy, Liverpool, United King- 11pm and 3am) to achieve near-normoglycemia (FBG 4.4-6.1mmol/L, PBG dom, Levallois-Perret, France, Helsinki, Finland 4.4-7.8mmol/L) which was maintained for additional 2 weeks. Daily mean EDITION 1, 2 and 3 assessed new Gla-300 vs. Gla-100 in T2DM. A patient- capillary blood glucose (MBG) and glucose coeffi cient of variance (CV) during level meta-analysis of 1-yr data was conducted. Glycemic control was sus- the 2-week maintenance period were calculated. Intravenous glucose toler- tained in both groups, with more sustained HbA1c reduction for Gla-300 at 1 ance tests were performed before and after the therapy for AIR measure- yr (LS mean difference between groups in HbA1c change from baseline −0.10 ments. Patients were followed up for 1 year. Glycemic remission was defi ned [−0.18 to −0.02]; p=0.0174). There was a reduced risk of confi rmed (≤70 mg/ as FPG<7.0mmol/L and 2hPG<10mmol/L without medication. dL) or severe hypoglycemia at any time (24 h) and during the night vs. Gla- Glycemic targets were achieved in 3.9±2.0 days. MBG was 6.1±0.5 100. Weight gain was less with Gla-300 vs. Gla-100. The slight insulin dose mmol/L during the maintenance period, with glucose CV of 0.28±0.05. AIR difference at 6 months remained at 1 yr. In conclusion, Gla-300 allows bet- increased from -10.0±24.5 pmol/L·min to 66.6±59.8 pmol/L·min after the ter up-titration of insulin dose for more sustained glycemic control without therapy (P<0.001). Patients with lower MBG (≤6.0 mmol/L ) had more promi- increasing the risk of any time and nocturnal hypoglycemia or weight gain nent improvement in AIR compared with those with higher MBG (93.0 ±68.0 vs. Gla-100. vs. 60.8± 48.4 pmol/L·min, P=0.02). In a logistic regression model, lower MBG was associated with 1-year glycemic remission (RR 3.4, 95% CI 1.2- 9.9, P=0.02) after adjusted for age, sex and baseline A1c. No association was found between glucose CV and remission. Incidence of hypoglycemia was similar in patients with higher or lower MBG. We concluded that stricter overall glycemic control during maintenance period of ITT, rather than glycemic variation, was associated with better clinical outcomes in patients with newly diagnosed T2DM.

1032-P Analysis of Basal Insulin Peglispro (BIL) Binding Kinetics with the Use of a Harmonic Oscillator Insulin Receptor Binding Model VLADISLAV V. KISELYOV, LIYUN DING, GINGER Y. WU, JULIE S. MOYERS, Indiana- polis, IN Basal insulin peglispro (BIL) is a novel insulin analog that has a large hy- drodynamic size. It consists of insulin lispro and a 20-kDa PEG moiety at- tached to lysine B28 of the insulin lispro backbone. We analyzed mecha- nism of the insulin receptor (IR) activation by BIL with the use of a harmonic oscillator model of the IR binding and compared it to that of biosynthetic

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A264 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULINS human insulin (BHI). IR exists in the cell membrane as a covalent dimer of univariate analysis (p<0.001; totaling 48/39 [naïve/prior]) were included in two identical subunits and possesses two pairs of partial binding sites for stepwise multivariate analyses; those with r2 values ≥0.01 (pre-specifi ed) insulin in each receptor subunit (site 1 and site 2). The IR binding mechanism were considered to explain a useful part of the variation between people. In is complex and is characterized by such phenomena as negative cooperativ- both groups these factors included: global region; and baseline body weight ity and a bell shaped curve for the accelerated receptor dissociation rate and BMI (higher associated with less gain). Specifi c to naïve group were also: as a function of ligand concentration. These complex phenomena can be number of prestudy oral agents; EoT postprandial glucose; to prior group: understood in terms of the harmonic oscillator model, in which insulin bind- changes in systolic blood pressure and total cholesterol. Compared to bi- ing to IR is described by fi ve parameters: association and dissociation rate phasic and meal-time study insulin regimens, insulin detemir was associated constants for site 1 (a1, d1), association and dissociation rate constants for with relative weight advantage of 0.3-0.8 kg, p=0.0125 to <0.001, but with site 2 (a2, d2) and a crosslinking constant describing the IR oscillator proper- low predictive power, r2=0.006/0.008 (naïve/prior). On multivariate analy- ties. Whole cell binding experiments with radio-labeled BIL and BHI were sis only region (r2=0.083/0.055) and baseline body weight (r2=0.103/0.079) performed using human IM9 cells. Our fi ndings show that the values of d1 retained r2≥0.01 in both groups; EoT dose featured in naïve only (r2=0.011) and d2, the accelerated dissociation rate and crosslinking constant were not (all p<0.001). Values for insulin detemir were similar to results of univariate signifi cantly different, whereas the values of a1 and a2 were substantially analysis. In conclusion, body-weight change with insulin analog therapy in reduced for BIL in comparison to BHI. These fi ndings are consistent with a routine care is small (with a small average benefi t to insulin detemir); people process whereby the increased hydrodynamic size of BIL compared to BHI with higher baseline weight tend to gain least. Most other factors are poor reduces the rate of BIL diffusion in solution, resulting in a corresponding predictors of weight change in individuals. decrease in association rate constants for the two partial binding sites on IR for binding of BIL in comparison to BHI. Upon binding to IR, the subsequent 1035-P process of receptor activation by BIL is similar to that of BHI as evidenced by The Study to Estimate the Long-Acting Effect of Insulin Degludec preservation of the crosslinking constant and the receptor dissociation rate in Type 1 Diabetes: Using a Continuous Glucose Monitoring and In- constants for both partial sites. sulin Pump Supported By: Eli Lilly and Company KAYAKO HASHIMURA, TOMOYUKI KAWAMURA, YUKO HOTTA, MEGUMI HATA- NO, YONEO KASHIHARA, TOMOMI HASHIMOTO, MASAKAZU HIROSE, TAKASHI 1033-P HIGASHIDE, MAYUMI AONO, SHIGEO AONO, HARUO SHINTAKU, Osaka, Japan,

The In Vitro Pharmacology of LY IGlar (LY2963016): A New Insulin Fuchu, Japan, Nishinomiya, Japan, Toyonaka, Japan POSTERS Glargine Product Insulin degludec (IDeg) shows fl at and stable action profi le by the single Therapeutics Clinical Diabetes/ REBECCA A. OWENS, STEVEN D. KAHL, XIAOPING RUAN, CHEN ZHANG, MARK dose a day. The pharmacokinetic study showed that the duration of IDeg W. FARMEN, JULIE S. MOYERS, M. DODSON MICHAEL, Indianapolis, IN action was 32-48 hours. Accordingly, overlap of basal insulin dose becomes Basal insulin analogs, with durations of action suffi cient for coverage over the problem when switching to insulin pump therapy in patients using IDeg. the course of 24 hours, are important for the proper management of gly- In this study, we examined the duration of IDeg action in type 1 diabetes mel- cemic control in the diabetic patient. LY IGlar (LY2963016, insulin glargine), litus, using a Continuous Glucose Monitoring (CGM) and insulin pump (CSII). an insulin analog with the same amino acid sequence as LANTUS® (insulin Type 1 diabetes patients who were 16 years or older, using insulin pump glargine [rDNA origin]; Sanofi -Aventis), differs from human insulin by the ad- and whose HbA1c was <7.5%, were selected. At 1st phase, they injected dition of two arginine residues to the C-terminus of the B-chain as well as IDeg once a day for one month, the same dose as daily basal insulin dose by replacement of asparagine at position A21 with a glycine. These changes of CSII, and the basal infusion of pump was stopped. They continued bolus shift the isoelectric point such that the insulin glargine analog is soluble at insulin injections by pump. At the switching phase, we attached CGM (iPro2) an acidic pH but then precipitates after injection at the neutral physiological to patients (day 0). The patients injected last IDeg at night of day 0. We pH. The pharmacological properties of six independent lots of LY IGlar and allocated them to two groups at random. In group A, the subjects restarted LANTUS were compared using a panel of in vitro biological assays. Using the basal insulin infusion by pump in 50% after 24 hours and 100% after 36 competitive receptor binding assays, the affi nity, Ki, of LY IGlar was deter- hours, from last injection of IDeg. In group B, the subjects restarted the basal mined to be 0.41±0.01, 0.45±0.03, and 16.0±0.4 nM for the human insulin insulin in 50 % after 36 hours and 100% after 48 hours, from last injection receptor, isoforms A (hIR-A) and B (hIR-B), and the human IGF-1 receptor of IDeg. The data of CGM was analyzed and the area under the curve (AUC (hIGF-1R), respectively. These affi nities were comparable to the affi nities (mg/dl*3hr)) was calculated. observed for LANTUS, 0.40±0.02, 0.45±0.04, and 15.5±0.6 nM, respectively. Eight patients (3 males and 5 females, age 16-43) were enrolled. Four The half-maximal concentration, EC50, of LY IGlar required to stimulate hIR- patients were allocated for each group. In Group A, the hypoglycemia and A and hIR-B phosphorylation was similar to the EC50 for LANTUS. Both LY the decrease of AUC was not observed, during the time when the effect of IGlar and LANTUS were maximally effi cacious with comparable EC50 con- IDeg and basal insulin of CSII might be overlapped, at day 2 in the switch- centrations for stimulating de novo lipogenesis from glucose. The mitogenic ing phase. On the other hand, in Group B, AUC of the same period showed potential of LY IGlar and LANTUS in the hIGF-1R dominant cell line, Saos- the increasing tendency of blood glucose levels. In results, we suggest that 2, was 0.53±0.03 and 0.53±0.03 nM, respectively. Statistical comparisons when patients with type 1 diabetes switch from IDeg to CSII, they should were determined for the Ki/EC50 responses from each assay using the Sidak start 50% of basal insulin of pump at 24 hours after last IDeg injection. and Holm-Bonferroni multiple comparison adjustment methods with the sig- In conclusion, the duration of IDeg action of type 1 diabetes might attenu- nifi cance level set at α=0.05. Results showed the in vitro pharmacological ate within 36 hours, in the real clinical fi eld. properties of LY IGlar were not signifi cantly different from LANTUS, thus supporting LY IGlar as an alternative therapy for diabetic patients. 1036-P Supported By: Eli Lilly and Company/Boehringer Ingelheim A Large Difference between Bedtime and Prebreakfast Blood Glu- cose (BeAM) Indicates the Need for Initiation and Intensifi cation of 1034-P Prandial Therapy Predictive and Explanatory Factors of Change in Body Weight after THORSTEN SIEGMUND, ANJA BORCK, ARIEL ZISMAN, STEPHAN KRESS, Mu- Starting Insulin Analogs nich, Germany, Berlin, Germany, Aventura, FL, Landau, Germany MOHAMMAD KHAMSEH, JIHAD HADDAD, ANAND JAIN, PHILIP HOME, Tehran, Background: A high BeAM value has been associated with the need for Islamic Republic of Iran, Amman, Jordan, Zürich, Switzerland, Newcastle upon Tyne, initiation and intensifi cation of prandial therapy in patients receiving BOT. United Kingdom We aimed to characterize patients that had a high BeAM value and were Body-weight change with glucose-lowering therapy is important to peo- initiated on a single dose of mealtime insulin glulisine and its impact on the ple with diabetes. In the noninterventional A1chieve study, 66 726 people effi cacy/safety of basal plus insulin regimens. with type 2 diabetes starting or switching to an insulin analog were followed Methods: The BeAM value was retrospectively evaluated in the pooled for 24 weeks; body weight was measured at baseline and end of trial (EoT). OPAL and POC trials (type 2 diabetes, 24 weeks, BOT with added single injec- HbA1c improved by 2.2 (SD 1.7) and 1.8 (SD 1.7) %-units for insulin-naïve peo- tion of mealtime insulin glulisine). ple and prior insulin users, respectively; body-weight change was +0.1 (SD Results: A total of 358 patients had insulin glulisine added to their BOT 3.7) kg in both groups. Basal insulin (insulin detemir) had some weight advan- regimen of which 182 patients had a BeAM value > 50 mg/dL. Patients were tage compared to regimens with meal-time insulin. This study, in naïve and older, had a lesser body weight/BMI and a longer treatment with oral antidi- prior groups, examined predictive (baseline) and explanatory (post-baseline) abetic drugs. Mean HbA1c was higher and FBG values lower at comparable factors associated with individual weight change. Factors of signifi cance on long-acting insulin doses. Furthermore there was a wider fl uctuation of

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A265 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULINS

blood glucose changes throughout the 24-hour day. There were no differ- a fasting plasma glucose of ≤70mg/dL during an offi ce visit. A multivariate ences in the proportion of patients with severe, nocturnal or symptomatic logistic regression model assessed baseline characteristics and 3-month re- hypoglycaemic events. sponse as risk factors for long-term glycemic control and HG. A high BeAM value at baseline was associated with signifi cant reductions Of 2330 patients included, mean patient age was 68 years (SD 11). Mean in HbA1c (7.2 vs. 7.5% at baseline; p<0.0001) and postprandial glucose (143.1 (SD) HbA1c declined from 8.5% (1.7) at baseline to 7.9% (1.3) at 3 months, re- vs. 201.8 mg/dL; p<0.0001) following addition of mealtime glulisine while maining stable to the end of 24 months. Glycemic control was suboptimal; 67% weight (88.6 vs. 87.7 kg; p<0.0001), BMI (31.1 vs. 30.7 kg/m2; p<0.0001) and of patients failed to achieve target HbA1c ≤7.0% after 2 years’ BI treatment. FBG (114.3 vs. 105.6 mg/dL; p<0.0001) were signifi cantly increased. Patients who failed to achieve target HbA1c at 3 months post-BI initiation were Multivariable adjusted analyses found no association of a high BeAM less likely to achieve target at 24 months (odds ratio [OR] 5.02; p<0.001). with HbA1c change, any severity of hypoglycemia, but a reduced likelihood Over 2 years, 8% of patients experienced HG. A greater proportion of patients of having HbA1c <7% at follow-up alone or in combination with no symptom- with HbA1c ≤7% at month 24 had HG than those with HbA1c >7% (11.2% vs. 6.4%). atic hypoglycaemia (<60 mg/dl). Risk of HG during 3–24 months of follow-up was associated with HG during the Conclusions: The BeAM value identifi es patients with increased HbA1c fi rst 3 months of follow-up (OR 7.53; p<0.001), pancreatitis (OR 3.42; p=0.022), values and close to target fasting blood glucose values indicating the need renal disease (OR 1.84; p=0.032), and male gender (OR 1.57; p=0.030). for the initiation of prandial insulin supplementation. Two thirds of patients with T2DM initiating BI in Germany fail to reach gly- Supported By: Sanofi -Aventis Deutschland GmbH cemic targets. Treatment response by 3 months post-BI initiation is clearly associated with long-term treatment experience. Under-reporting of HG by 1037-P patients may lead to reduced numbers of recorded HG events in the medical Comparison of 2 Algorithms for Adding Insulin Glargine (GLA) to records database. Those who achieve glycemic goals experience higher levels Metformin (MET) in Patients (Pts) with T2DM of HG than those with poorer glycemic control, indicating a need for a new BI GEORGE DAILEY, LOUISE TRAYLOR, JASVINDER GILL, La Jolla, CA, Bridgewater, NJ offering sustained glycemic control with less risk of HG in this population. We compared outcomes in T2DM pts initiating insulin using 2 protocol Supported By: Sanofi mandated treat-to-target algorithms: titration once-weekly (QW) or every 2 days. 1039-P Standardized pt-level data were pooled from 4 RCTs (fasting plasma glu- Insulin-derived Amyloidosis Causes Poor Glycemic Control and In-

POSTERS cose [FPG] target < 100 mg/dL) of ≥ 24 weeks. Pts were insulin-naïve adults creased Insulin Dose Requirements Therapeutics adding GLA to MET. Outcomes included A1C at Week 24 and hypoglycemia TERUMASA NAGASE, KEIICHI IWAYA, YOSHIKI IWAKI, TOMOTADA ODAKA, TA- Clinical Diabetes/ (with confi rmed plasma glucose < 70 mg/dL: overall, including severe events; MOTSU ZAKO, MASAYUKI NORITAKE, YOSHIYA KATSURA, Ami, Japan, Tokoro- nocturnal [0:01-5:59 AM]; and daytime [6:00 AM-midnight]). A1C and hypo- zawa, Japan, Wako, Japan glycemia were derived from ANCOVA and generalized linear models, respec- Insulin-derived amyloidosis is a skin-related complication of insulin therapy. tively, considering baseline data. The amyloid fi bril protein is derived from the injected insulin, and usually forms At baseline, compared with pts titrated every 2 days (n = 172), pts titrated QW a hard subcutaneous mass at the injection site. The aim of this study was to (n = 203) were younger (52 vs. 58 years), had shorter T2DM duration (7.2 vs. 9.9 show the effects of insulin-derived amyloidosis on glycemic control and insu- years), and higher body mass index (33.7 vs. 29.3 kg/m2), A1C (9.2% vs. 8.5%), lin therapy. We studied the clinical characteristics and insulin therapy of 14 and FPG (217.5 vs. 185.2 mg/dL); all P < 0.05. When adjusting for baseline data, patients with insulin-derived amyloidosis (6 had type 1 diabetes and 8 had pts titrated QW had a signifi cantly lower Week 24 A1C (7.0% vs. 7.3%; P < 0.05), type 2 diabetes, duration of diabetes 23±8 years, duration of insulin therapy experienced signifi cantly less overall or nocturnal hypoglycemia, and were more 15±6 years). Additionally, we investigated the insulin absorption by comparing likely to reach A1C < 7.0% without overall or nocturnal hypoglycemia (Table). the serum insulin levels after insulin injections into insulin-derived amyloidosis In pts adding GLA to MET, QW titration achieved better glycemic control sites versus injections into normal sites in 5 patients. When the insulin-derived than titration every 2 days, with less hypoglycemia. In this post hoc analysis, amyloidosis was discovered, the mean HbA1c value was 8.9±1.1%, and the biological differences between groups may be greater than those consid- daily insulin dose was 55±26 units. After changing the insulin injection sites ered when normalizing for confounding. to avoid the insulin-derived amyloidosis, the blood glucose concentrations im- Table. Adjusted Hypoglycemia Incidence and Event Rate in Pts Adding GLA proved, and the daily insulin dose could be reduced to 30±19 units (p = 0.001; to MET Titrated QW or Every 2 Days. 45% reduction). The mean HbA1c was 7.3±0.7% (n=13; p < 0.001) after 4±1 months. The insulin absorption at insulin-derived amyloidosis sites was 32% Titration Titration P value QW Every 2 Days of that at normal sites (p = 0.009). In conclusion, the insulin-derived amyloi- (n = 203) (n = 172) dosis causes poor glycemic control and increased insulin dose requirements because of impairments in insulin absorption. Overall hypoglycemia < 70 mg/dL Incidence, % 24.30 37.29 0.019 Rate, events/pt-year 1.39 2.45 0.018 1040-P Daytime hypoglycemia < 70 mg/dL Effi cacy, Patient-Reported Outcomes (PRO), and Safety of Insulin Incidence, % 20.58 28.94 0.104 Degludec U200 vs. Insulin Glargine in Patients with Type 2 Diabetes Rate, events/pt-year 1.05 1.49 0.178 (T2D) Requiring High-Dose Insulin Nocturnal hypoglycemia < 70 mg/dL MARK WARREN, LOUIS B. CHAYKIN, SERGE JABBOUR, MAE SHEIKH-ALI, CHAR- Incidence, % 7.35 17.88 0.008 LOTTE T. HANSEN, SØREN RASMUSSEN, PAUL NORWOOD, Greenville, NC, Bra- Rate, events/pt-year 0.32 0.88 0.009 denton, FL, Philadelphia, PA, Jacksonville, FL, Søborg, Denmark, Fresno, CA Pts achieving A1C < 7.0% without This 32-week, open-label, crossover, treat-to-target trial compared the ef- overall hypoglycemia < 70 mg/dL, % 35.4 25.9 0.0522 fi cacy, PRO and safety of insulin degludec (IDeg) 200 U/mL vs. insulin glargine (IGlar) 100 U/mL, administered once daily (OD) after 16 weeks run-in. Adults 18 Pts achieving A1C < 7.0% without ≥ nocturnal hypoglycemia < 70 mg/dL, % 44.0 35.3 0.0359 years with T2D ≥6 months, receiving IGlar OD (≥65 - ≤100 U/day) + metformin ± 1 other oral antidiabetic drug for ≥3 months, A1C ≥7.5% after a 16 week run-in Supported By: Sanofi U.S. who required ≥81U insulin were randomized 1:1 to IDeg/IGlar or IGlar/IDeg (Figure). After 16 weeks, non-inferiority of IDeg to IGlar with respect to change 1038-P in A1C was confi rmed. Mean fasting plasma glucose was signifi cantly reduced Glycemic Control and Hypoglycemia Burden in Patients Initiating with IDeg vs. IGlar (-14.5 mg/dL vs. -0.5 mg/dL; estimated treatment difference Basal Insulin in Germany [ETD]: -13.9 mg/dL, p<0.05). For IDeg vs. IGlar, the confi rmed hypoglycemia rate LAURA LIAO, HONGWEI WANG, JIYOUNG CHIN, ANNA M.G. CALI, PETER STELLA, was signifi cantly lower (estimated rate ratio [ERR]; 0.59, p<0.05) and noctur- PAULO CARITA, Bridgewater, NJ, Jersey City, NJ, Paris, France, Chilly-Mazarin, France nal hypoglycemia rate was numerically lower (ERR; 0.66, NS). Mean weight A longitudinal analysis of German medical records evaluated glycemic change was 0.4 kg (IDeg) vs. 1.0 kg (IGlar), NS. The IDeg delivery device was control and hypoglycemia (HG) burden in insulin-naïve patients with T2DM rated signifi cantly better for function (ETD 8.40, p<0.05) and less bother (ETD initiating basal insulin (BI) (2008–2012). Patients were aged ≥30 years at 6.01, p<0.05) vs. the IGlar device, and more patients preferred IDeg treatment T2DM diagnosis, had previously used OADs, had ≥1 HbA1c measurement pre- (54.5%) vs. IGlar (20.0%); 15% no preference and 2.8% didn’t know. IDeg U200 and post-BI initiation and data available for ≥1 year pre- and ≥2 years post-BI signifi cantly reduces confi rmed hypoglycaemia vs. IGlar and may be preferred initiation. Occurrence of HG was defi ned as a recorded diagnosis of HG or by patients with T2D requiring high-dose insulin.

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Indicators of GV (standard deviation (SD), J index, mean amplitude of gly- caemic excursion (MAGE)) and glycaemic control (mean glucose, area under glucose-time curve (AUC), HbA1c) were assessed at baseline and 24 weeks post-insulin initiation using parameters obtained from Continuous Glucose Monitoring data (iPro, Medtronic) and HbA1c assays performed by a DCCT aligned laboratory. Multilevel regression analysis examined predictors of change between these time points. 78 subjects participated: 41% female, mean (SD) age 59.2 (10.4) years, mean (SD) diabetes duration 10.8 (5.8) years, median (IQR) HbA1c 9.7 (8.7, 11.0)% [82.5 (71.6, 96.7) mmol/mol]. At baseline, body mass index (BMI) sig- nifi cantly correlated with SD (r=-0.30, p=0.007) and MAGE (r= -0.26, p=0.02), and HbA1c correlated with J-index (r=0.61, p <0.001). HbA1c fell to 7.3 (6.8, 7.7)% [56 (51, 61) mmol/mol; p<0.001) and mean (SD) glucose decreased from 12.0 (3.0) to 8.5 (1.6) mmol/L (p <0.001) during the study. No signifi cant change in MAGE or SD was observed. The temporal profi le of glucose over 24 hours was largely unchanged at 24 weeks from baseline with the most signifi cant glycaemic excursion seen in the morning. The results from this study have major implications for management deci- sions for T2D patients requiring intensifi cation of therapy if GV is a therapeutic consideration. The observation that the greatest postprandial excursion occurs post-breakfast may inform the timing of the rapid acting insulin injection in a basal plus regimen or those GLP-1 analogue injections with a shorter half-life. Supported By: Sanofi

1043-P

Hospital Outcomes with Different Subcutaneous Insulin Regimens POSTERS in Patients with Admission Hyperglycemia Therapeutics Clinical Diabetes/ ARCHANA R. SADHU, HARLAN G. SPARROW, NELDA P. WRAY, WILLA A. HSUEH, Supported By: Novo Nordisk Houston, TX, Columbus, OH Inpatient insulin therapy has evolved from sliding scale alone (SS) to basal 1041-P and bolus regimens (BB). We retrospectively reviewed a total of 1,614 inpa- Perception of Diabetic Patients Regarding Basal Bolus Injections tients age > 18, admit glucose > 200mg/dl, treated with subcutaneous but of Insulin not IV insulin. Three Insulin regimens were observed: BB only (n=230), Mixed MUHAMMAD SHAHID, AQIBA SARFARAZ, SAEED A. MAHAR, SHIRAZ SHAIKH, (M) (hospital days with SS only, BB, or long only N=750), or SS only (N= 634). ALI ASGHAR, MAQSOOD ALAM, Karachi, Pakistan Comparing the 3 groups diabetes was coded least frequently in SS (SS 68%; A basal bolus insulin regimen provides better glycemic control; however the BB 93%; M 91% P <0.01). SS had lower mean admit glucose (SS 249; BB patient has to take frequent injections of insulin. Perceptions, fears and que- 282; M 279, P<0.01) and lower mean daily glucose (SS 177; BB 202; M 196; ries of patients regarding insulin is not known at the time of starting multiple P<0.01). The reduction in mean daily glucose was signifi cantly more in BB injections per day and this can lead to different misconceptions regarding the and M than SS (P<0.01). BB had the lowest LOS (BB 5.4 days; M 8.3; SS 6.6, treatment options. The objective of the study was to assess the perceptions P<0.01) and lowest mortality (BB 0.4%; M 2.1%; SS 2.8 % P 0.10) even though of diabetic patients regarding basal bolus insulin injections regimen presenting rates of CKD (BB 23%; M 24%; SS 14% p<0.01) or CHF (BB 24%; M 25%; SS to a tertiary care hospital. This was a cross sectional study conducted in the 18% p< 0.01) were higher in BB and M patients. Despite higher admit and Department of Endocrinology, Liaquat National Hospital Karachi in November daily mean glucose and presence of comorbidities, the reduction in glucose and December 2014. 220 patients were enrolled in the study. Patients between achieved with BB was associated with the lowest LOS and mortality. BB 18-70 years of age, type 1 and 2 diabetes mellitus (DM) of ≥ 3 months, HbA1c ≥ should be considered the preferential way to manage patients with admit 8.0% and started on basal bolus insulin in the current consultation were included glucose >200. in the study. Patients with complications of DM were excluded. They were asked to answer 17 questions related to their perceptions regarding basal bolus insulin regimen. Fasting Blood Glucose (FBS), Random Blood Glucose (RBS) and HbA1c were also checked. Mean age of the patients was 49±13.9 years and 150 (68.2%) were females. Body mass index of the patients were ≤25 in 98 (44.5%), between 25-30 in 68 (30.9%) and more than 30 in 54 (24.5%). Mean FBS was 261±52.2 mg/dl, RBS was 385.01±41.9 mg/dl and HbA1c was 12.7±1.9. Mean duration of illness was 10.2±4.81 years. 59.5% of the patients believed that basal bolus insulin will improve their blood glucose levels; however only 25% had fear of using needle injections. 66.3% patients thought that they can delay basal bolus insulin despite having such high blood glucose. 48.6% of patients had fear of hypoglycemia. 12.3% patients believed that basal bolus insulin will not be able to control their blood glucose. There were many misconceptions of the patients who were started basal bolus insulin. Proper education and guidance can help these patients to properly manage their blood glucose levels.

1042-P The Impact of Insulin Initiation on Glycaemic Variability and Control in a Primary Health Care Cohort with Type 2 Diabetes Using Con- tinuous Glucose Monitoring: The Initiation Study JO-ANNE E. MANSKI-NANKERVIS, IRENE BLACKBERRY, CHRISTOPHER J. YATES, JOHN FURLER, LOUISE GINNIVAN, NEALE COHEN, ALICIA J. JENKINS, SHERAN VASANTHAKUMAR, ALEXANDRA GORELIK, DORIS YOUNG, JAMES D. BEST, DAVID O’NEAL, Carlton, Australia, Parkville, Australia, Melbourne, Australia, Camperdown, Australia, Clayton, Australia, Singapore, Singapore, Fitzroy, Australia Glycaemic variability (GV) may be an important clinical target for people with type 2 diabetes (T2D). The aim of this study was to examine the effect of glargine +/- glulisine initiation on GV in a primary health care T2D cohort.

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1044-P 1046-P Insulin Mid Mixture Lispro Mix50 (LM50) Showed Better Glycemic Predictive and Explanatory Factors of Change in Health-related Control than Low Mixture Lispro Mix 25 (LM25) as Starter Insulin in Quality of Life after Starting Insulin Analogs Chinese Patients with Type 2 Diabetes Mellitus (T2DM): A Subgroup PHILIP HOME, INES SLIM, VISHAL GUPTA, ANAND JAIN, GUILLERMO DIEUZEIDE, Analysis of CLASSIFY Study Newcastle upon Tyne, United Kingdom, Sousse, Tunisia, Mumbai, India, Zürich, QING SU, LEI QIAN, PENGFEI LI, WENYING YANG, Shanghai, China, Beijing, China Switzerland, Chacabuco, Argentina CLASSIFY study is a Phase 4, parallel-arm, randomized, 26-week trial in Health-related quality of life (HRQoL) is an important outcome of glucose- Asian patients (pts) with T2DM. The data of China subgroup were analyzed lowering therapy. In the noninterventional A1chieve study, people with type 2 to compare the effi cacy and safety of LM25 and LM50 twice-daily as starter diabetes (n=66 726) starting or switching to an insulin analog were followed insulin in Chinese patients. Chinese patients (N=156; age, 57.74 years; A1c, for 24 weeks; HRQoL was measured at baseline and end of trial (EoT). EQ-5D 8.54%) who had inadequate glycemic control with one or more antihypergly- score (scale 0-100) improved in insulin-naïve people (+15.0) and prior insulin us- cemic medications (OAMs) were randomized to either LM25 (N=80) or LM50 ers (+11.1). Here, predictive (baseline) and explanatory (post-baseline) factors (N=76). At Week 26, LM50 showed better glycemic control than LM25 in China associated with individual change in HRQoL were analyzed in naïve and prior subgroup (signifi cant differences including ΔA1c, Δ1,5-AG and % pts with groups. Factors of signifi cance on univariate analysis (p<0.001) were included A1c<7.0% or ≤6.5%). The reductions in fasting blood glucose (FBG) at 26 weeks in stepwise multivariate analyses. Many factors (totaling 43/36 for naïve/ from baseline were not signifi cantly different between LM25 and LM50 in Chi- prior) were signifi cant on univariate analysis but few explained a useful part na level, but signifi cant differences were observed in trial level. Total and noc- of the variation in HRQoL change between people (r2 values ≥0.01, prespeci- turnal hypoglycemic (HYPO) rates (event/patient*year) were not signifi cantly fi ed). In both groups were: global region; baseline HRQoL; EoT glucose control different in LM50 vs. LM25 group for both trial and China level. Moreover, in (HbA1c, postprandial glucose [PPG], fasting glucose [FPG]); and change in PPG. both China and trial level, no signifi cant differences were observed in weight Specifi c to naïve group were also: number of oral agents (prestudy, baseline); gain and insulin dose between these two groups. The results show that LM50 creatinine (baseline, EoT); and change in systolic blood pressure; to prior group: could achieve better glycemic control than LM25 in Chinese patients as insulin changes in HbA and FPG. On multivariate predictive analysis, only region and starter, though there is no signifi cant difference observed in trial level. 1c baseline HRQoL retained r2≥0.01 in both groups. Baseline oral agents (naïve Table. only) and study insulin type (basal, biphasic, meal-time, other) were statisti- 2 China Trial cally signifi cant but of low discriminatory power (p≤0.004; r ≤0.006). With explanatory factors added, region (r2=0.070/0.089 [naïve/prior]) and baseline POSTERS

Therapeutics LM25 LM50 LM25 LM50 HRQoL (r2=0.407/0.514) had r2≥0.01 in both groups (p<0.001). Insulin type was Clinical Diabetes/ ΔA1c, % -1.55(-1.73, -1.36) -2.03(-2.21, -1.84)## -1.52 (-1.66, -1.39) -1.69 (-1.83,-1.55) 2 signifi cant in prior only and of low power (p<0.001; r =0.003). EoT HbA1c fea- Δ1,5-AG, % 5.03 (3.49, 6.57) 7.75 (6.16, 9.34)# 4.24 (3.39, 5.10) 5.62 (4.74, 6.51)# tured in prior only (explaining 2.3% of variation in HRQoL change; r2=0.023). In % pts with A1c<7.0% 45.0 72.4# 45.9 59.7# conclusion, baseline HRQoL accounts for 41-51% of variance in HRQoL change with insulin analog therapy (people with low score see larger improvement); % pts with A1c 6.5% 20.0 52.6## 26.1 42.3# ≤ few other factors have any explanatory effect. ΔFBG, mmol/L -2.50(-2.89,-2.11) -2.12(-2.53,-1.72) -2.37(-2.68, -2.06) -1.99(-2.30, -1.68) # All HYPO rate (event/pts*year) 2.971 3.446 5.661 6.343 1047-P Nocturnal HYPO rates 0.304 0.426 0.828 0.731 Discontinuation and Down-Titration of Sulfonylurea Therapy in (event/pts*year) Type 2 Diabetes Patients Who Initiate Insulin Δweight (kg) 1.60 (0.88, 2.33) 1.53 (0.80, 2.27) 2.31 (1.85, 2.77) 2.32 (1.84, 2.79) KRISTY IGLAY, ALEX Z. FU, PEDRO LAIRES, Kenilworth, NJ, Washington, DC ΔA1c, Δ1,5-AG, ΔFBG and Δweight were least-squares mean change from Patients (pts) with type 2 diabetes (T2DM) are frequently treated with sul- baseline (95% confi dence interval). fonylureas (SUs), but therapy can be discontinued or down-titrated for reasons #p<0.05 or ##p<0.001 indicates statistical signifi cance between LM25 and such as hypoglycemia or weight gain. A retrospective cohort study using Mar- LM50 groups. ketScan was conducted to identify factors associated with SU discontinua- tion (DC) or down-titration (DT) after insulin initiation. Pts ≥21 years with a 1045-P T2DM diagnosis from 2006-2012 were identifi ed. The index date was the fi rst Defi ning Successful Insulin Response with a Composite Measure insulin claim between 2007 and 2011. Pts were treated with SU at the index Beyond HbA1c <7% date and were excluded if they did not have continuous enrollment ≥12 months M. SUE KIRKMAN, IGNACIO CONGET, DACHUANG CAO, MAYME WONG, JESUS before (pre-index) and after the index date, were receiving insulin in the 12 REVIRIEGO, DAVID KENDALL, Chapel Hill, NC, Barcelona, Spain, Indianapolis, IN months prior to the index date, or had type 1 diabetes mellitus, other forms In patients with type 2 diabetes (T2D), intensive glycemic control signifi cant- of secondary or gestational diabetes. DC occurred when the gap between the ly reduces diabetes complications, yet <50% of T2D patients have HbA1c (A1C) end date of current SU claim and the start date of subsequent claim was ≥90 <7%. Patients with a high baseline (BL) A1C may have clinically relevant A1C days apart or there was no subsequent SU. DT occurred when a subsequent reductions with insulin, but not reach the <7% goal suggested by guidelines. SU had a lower dose than the index dose. Logistic regression was performed We used an integrated database of 53 insulin lispro clinical trials to develop a to identify factors associated with SU DC or DT vs. continuation without DT. composite A1C measure to defi ne T2D patients responding to therapy. Of the 76,525 pts selected, 26.5% discontinued and 3.7% down-titrated their The analysis population included 9869 T2D patients (mean age ± SD, 57.9 ± SUs within 1 year. Median time from insulin initiation to SU DC and DT was 9.8 yr; 52% male) treated with any insulin regimen with a BL and ≥1 post-BL A1C 60 and 100 days, respectively. In the logistic regression, factors associated value. Responders were defi ned as patients with endpoint A1C <7% plus those with SU DC included female gender (OR=1.05), age (OR=0.95), pre-index hospi- with either ≥1% absolute (AA) or ≥10% relative (AR) decrease in A1C from BL. talizations (OR=1.21), and presence of pre-index hypoglycemia (OR=1.19), liver Percent of responders was assessed at 12 and 24 weeks, with age, BMI, and BL disease (OR=1.24), microvascular complications (OR=0.95) or chronic renal dis- A1C as subgroups. Concordance between AA and AR was assessed. ease (OR=1.09; all P<.01). Pre-index cardiovascular disease (OR=1.15) and hos- Overall, <41% of patients reached A1C <7%. By AA or AR, >62% were pitalizations (OR=1.22), as well as age (OR=1.06) and female gender (OR=1.26), responders. AR identifi ed a higher percent of responders than AA. Age and were associated with SU DT (all P<.01). In conclusion, over 30% of patients BMI subgroups had similar rates of responders. More responders were pa- discontinued or down-titrated their SU therapy one year after insulin initiation. tients with BL A1C ≥9% than <9%. Concordance between AA and AR was Several factors, including comorbidities and hypoglycemic events, impacted high at 12 (94.4%) and 24 (96.0%) weeks. these treatment changes. Composite A1C measures identifi ed more patients with clinically mean- ingful responses to therapy. High AA and AR concordance suggests adding 1048-P either defi nition to responders with A1C <7% may be useful in population Characteristics and Prescription Patterns of Insulin Glargine Use management and quality measures. among Patients with Diabetes Mellitus in the U.S. Table. ALEX Z. FU, SHENGSHENG YU, JEAN WILLIAMS, Washington, DC, Rahway, NJ To better understand the clinical use of insulin glargine in the U.S., a ret- rospective cohort study using MarketScan data was conducted to identify factors associated with pts initiated insulin glargine. Pts with a T1DM (age ≥6) or T2DM diagnosis (age ≥18) from 2008 to 2013 were identifi ed. The in- Supported By: Eli Lilly and Company dex date was the fi rst insulin claim from 2009 to 2012. Pts were treated with

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A268 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULINS insulin at the index date and were excluded if they did not have continuous of reduced C-peptide clearance. To the best of our knowledge, almost no enrollment ≥12 months before (pre-index) and after the index date, were re- reports have investigated the effect of GFR on β-cell function-related pa- ceiving the index insulin in the 12 months prior to the index date, or had other rameters. Therefore, we examined it in this study. forms of diabetes. Logistic regressions were performed to identify factors In 159 inpatients with type 2 diabetes, we conducted a retrospective case- associated with initiation of insulin glargine vs. other insulin, and changes control study and examined the cut-off values with an over 80% specifi city from the index insulin. Of the 119,170 pts (3,714 T1DM and 115,456 T2DM), and the utility of CPR, CPI, and SUIT for the prediction of insulin requirement 29% and 59% pts with T1DM and T2DM, respectively, initiated their insulin using a receiver operating characteristic (ROC) curve analysis. We measured therapy with glargine, and among them, 66% and 21% changed their index FPG and CPR for each patient during hospitalization and calculated CPI and insulin (switch or add-on) within 1 year. In the logistic regression, factors SUIT. We classifi ed the patients into insulin-requiring group (IR) and non- associated with glargine use among pts with T2DM included male gen- insulin-requiring group (NIR) based on the treatment 12 months after dis- der (OR=1.11), no pre-index hypoglycemia (OR=0.63), chronic renal disease charge. The CPR, CPI, and SUIT in IR were signifi cantly lower than those in (OR=0.93), liver disease (OR=0.90), microvascular complications (OR=0.90), NIR by Mann-Whitney U-test. The Cut-off values of CPR, CPI, and SUIT were cardiovascular disease (OR=0.90), and more recent calendar years. Pre-index 1.5 ng/ml, 1.07, and 28.8, respectively, and the area under the curves of the use of other antidiabetic medications, geographic location, and health insur- ROC analysis of those indices were 0.617, 0.755, and 0.789, respectively. ance are also signifi cantly predictive of glargine use (all P<0.05). Glargine Then to examine the effect of estimated GFR (eGFR) on the cut-off values initiation is positively associated with change of index insulin (switch or add- for insulin requirement, we divided participants into three strata according on) among T1DM (OR=3.52), while such an association is negative among to eGFR at admission. The cut-off values of CPI were 0.97, 1.04, and 1.32 in T2DM (OR=0.55), after adjusting for demographic characteristics and comor- eGFR >90, 60-90, and 30-60 ml/min/1.73m2 groups, respectively. In case of bidities. In conclusion, more pts with T2DM start their insulin therapy with SUIT, those were 23.1, 25.6, 42.0, respectively. glargine and do not tend to switch to others, as compared to pts with T1DM. In conclusion, the cut-off values for CPI and SUIT for predicting insulin Several factors, including comorbidities and other antidiabetic medications, requirement increase, as eGFR decreases. impacted the use of glargine for T2DM. 1051-P 1049-P Effi cacy of Switching from Insulin Glargine to Insulin Degludec in Effi cacy and Safety in Persons with T2DM Treated with Insulin Patients with Type 1 Diabetes: A 52-Week Retrospective Study

Glargine Plus Thrice-Daily Insulin Glulisine: A Meta-analysis of JUN SUZUKI, TADASHI YAMAKAWA, JOE NAGAKURA, Yokohama, Japan POSTERS Four Studies Insulin degludec (IDeg) is an ultralong-acting basal insulin that is in clinical Therapeutics Clinical Diabetes/ DAVID R. OWENS, LOUISE TRAYLOR, WOLFGANG LANDGRAF, FRANCESCA POR- development. The benefi cial effects of IDeg have been confi rmed in several CELLATI, GEREMIA B. BOLLI, Swansea, United Kingdom, Bridgewater, NJ, Frankfurt, clinical trials, but long-term effi cacy of IDeg in routine clinical practice in Germany, Perugia, Italy Japan remains unknown. Thus, we retrospectively investigated the effect of This meta-analysis examined effi cacy and safety outcomes in persons IDeg on glycemic control in Japanese type 1 diabetic patients who switched with T2DM treated with an intensifi ed basal-bolus insulin regimen compris- from insulin glargine (IGlar). ing basal insulin glargine and prandial insulin glulisine. Data were collected during the 4 weeks before and the 52 weeks after Standardized subject-level data were pooled from 4 RCTs of ≥ 24 weeks the insulin-switch. 45 subjects were switched from a predominantly basal- duration. Participants were adults with T2DM, treated with once-daily insu- bolus, IGlar-based regimen (IGlar once-daily: 17, twice daily: 28) to an IDeg- lin glargine before bedtime plus 3 pre-prandial injections of insulin glulisine based, basal-bolus regimen by usual practice. Patients were eligible for the during the day. Outcomes of interest included A1C, fasting plasma glucose study if they were at least 18 years of age, and patients during pregnancy (FPG), weight, insulin dose and hypoglycemia. Hypoglycemia was defi ned as were excluded. any event with confi rmed plasma glucose < 70 mg/dL and reported as overall The results of this study showed that the subjects had signifi cant improve- (including severe), daytime (6:00 AM to midnight), nocturnal (0:01 AM-5:59 ment of HbA1c in a short period of time (baseline: 8.3±1.3% vs. 4 weeks: AM), and severe (requiring third party assistance). Event rates were derived 8.0±1.0%, Mean±SD, p=0.005), without any signifi cant increase in weight from a generalized linear model including baseline characteristics. (57.3±9.5kg vs. 57.3±9.1kg, p=0.86), and this tendency lasted for 52 weeks. Overall, 577 patients were analyzed (45.9% male; mean [SD] age 56 years, Total basal-insulin dose (TBD) showed a signifi cant decrease (Total: 17.8±7.5 duration of T2DM 12.2 years, body mass index 35.3 kg/m2, baseline A1C U/day to 15.3±6.3 U/day, p<0.001, Once: 15.1±5.9 U/day to 14.6±6.1 U/day, 8.3% [0.9], FPG 163.9 mg/dL [61.5]). At Week 24, mean (SD) A1C was 7.0% p=0.47, Twice: 19.4±8.0 U/day to 15.7±6.5 U/day, p<0.001). The number of epi- (0.95) and 53.5% of patients achieved an A1C < 7.0%. Mean (SD) values at sodes of hypoglycemia had a tendency to increase temporarily, but not signifi - Week 24 for FPG and weight were 130.8 mg/dL (50.9) and 3.1 kg (4.4), respec- cant. Blood glucose fl uctuation was evaluated with SMBG by its coeffi cient of tively. Week 24 total insulin dose was 1.54 U/kg (0.77 U/kg each for glargine variation (CV). However, CV did not signifi cantly change. These results implied and glulisine). Adjusted mean (SE) overall, daytime, nocturnal, and severe hy- that it is necessary to reduce TBD when switching from IGlar to IDeg. poglycemia rates were 29.1 (1.6) 24.1 (1.3), 3.4 (0.3), and 0.57 (0.09) events/ In conclusion, IDeg once daily improves glycemic control in patients with patient-year, respectively. The percentages of patients achieving A1C < 7.0% type 1 diabetes to a greater extent than IGlar without increasing the risk of without any, daytime, nocturnal, or severe hypoglycemia were 4.2%, 5.4%, hypoglycemia. When switching from IGlar to IDeg, especially IGlar twice- 24.9%, and 45.7%, respectively. daily, a reduction in the initial IDeg dose is recommended to reduce the risk In conclusion, good glycemic control can be achieved in persons with of hypoglycemia. T2DM treated with a basal-bolus regimen comprising insulins glargine and glulisine. The addition of prandial insulin to basal insulin results in higher 1052-P total insulin doses and rates of hypoglycemia than observed in previous Ease of Use of the New Insulin Glargine 300 U/mL SoloSTAR Pen basal-only meta-analyses. Injector in Insulin-Naïve People with Type 2 Diabetes Supported By: Sanofi HARALD POHLMEIER, DAVID C. KLONOFF, LORI BERARD, CLAIRE BRULLE- WOHLHUETER, JUNLONG WU, RAPHAEL DAHMEN, IRENE NOWOTNY, Muen- 1050-P ster, Germany, San Mateo, CA, Winnipeg, MB, Canada, Paris, France, Beijing, China, The Effect of Renal Function on β-Cell Function Related Parameters Frankfurt, Germany in Japanese Type 2 Diabetic Patients New insulin glargine 300 U/mL (Gla-300) contains the same active ingredient KEISUKE OKABE, MINORU IWATA, ISAO USUI, YUKIKO KOSHIMIZU, KAZUHITO as glargine 100 U/mL (Gla-100). A new disposable (prefi lled) SoloSTAR injector FUKUDA, HISAE HONOKI, TOMONOBU KADO, SATOMI SHINNMURA, AKIKO pen provides accurate delivery of Gla-300. Ease of use/learning, safety, satis- TAKIKAWA, AYUMI NAKASHIMA, MANABU ISHIKI, KAZUYUKI TOBE, Toyama, faction, glycemic control and reliability with the Gla-300 SoloSTAR pen were Japan assessed in 40 insulin- and pen-naïve people with T2DM receiving Gla-300 The accurate evaluation of residual pancreatic β-cell function is impor- once daily in a 4-week, multi-center, open-label, single-arm study. The primary tant for deciding whether insulin is required to control glucose levels in type endpoint was evaluated by the Ease-of-Use/Ease-of-Learning questionnaire 2 diabetes. We previously reported that C-peptide immunoreactivity index (scores range from 1 [excellent] to 5 [very poor]). At week 4, 95.0% of partici- (CPI) calculated by fasting serum C-peptide(CPR)/fasting plasma glucose pants assessed the pen as excellent/good and none as poor/very poor; 97.5% (FPG)×100 and secretory units of islets in transplantation index (SUIT) are would recommend it to others (Figure). Incidences of hypoglycemic events useful parameters to evaluate β-cell function. However, low glomerular fi l- (5.2/participant-year, none severe or serious) and adverse events (AEs) were tration rate (GFR) makes CPR higher than the actual β-cell function, because low. Total Diabetes Treatment Satisfaction Questionnaire scores were stable

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A269 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULIN DELIVERY SYSTEMS

from start of pen use. Mean (SD) FPG levels decreased from 166.1 (35.0) mg/ & 1054-P dL at baseline to 124.2 (41.1) mg/dL at week 4. Regarding reliability, no Product Optimization of CSII Basal Rate Adjustment by Personalized Knowl- Technical Complaints (PTCs) or AEs related to PTCs were reported. edge-based Decision Support In conclusion, over 4 weeks of once-daily dosing with Gla-300, pen-naïve ECKHARD SALZSIEDER, LUTZ VOGT, PETER HEINKE, ANDREAS THOMAS, Karls- and insulin-naïve people with T2DM considered the Gla-300 SoloSTAR pen burg, Germany, Meerbusch, Germany to be easy to use and easy to learn; Gla-300 basal insulin treatment was well Background and Aims: Each patient has his individual changes in daily tolerated and effective; and the pen was reliable. insulin requirements. Therefore physicians have to adjust the basal rates to the individual insulin sensitivity pattern, if a patient has to be subjected to CSII Therapy. It was the aim of our study to develop and to verify a knowl- edge-based decision support system for easy, quick, and save personalized basal rate adjustment procedures. Material and Methods: A special version of the well known Karlsburg Diabetes Management System KADIS® was developed (CSII-KADIS®) and a three step CSII adjustment procedure created. At fi rst the individual meta- bolic situation of a given patient was identifi ed by CSII-KADIS®-supported calculation of the so called “Metabolic Fingerprint.” At second the individual basal rate requirement was estimated by interactive, CSII-KADIS®-based simulation strategy and fi nally the CSII-KADIS®-supported individual basal rate adjustment was performed whereas the basal rate profi le was divided into 24 one hour segments and each segment was adjusted to the individual one hour insulin requirement of the given patient. To verify and to evaluate the practicability and the effectiveness of the CSII-KADIS®-supported basal rate adjustment procedure, a feasibility study with 12 type 1 diabetic pa- tients (age: 31.3±11.1 years, diabetes duration: 15.7±6.7 years, BMI 25.2±2.7 kg/m2, A1c: 8.2±0.8%) was performed in Germany.

POSTERS Results: The effort needed by the physician for a suffi cient individual Therapeutics basal rate adjustment was remarkably reduced from commonly one to two Clinical Diabetes/ weeks to less than 30 minutes if CSII-KADIS®-supported basal rate adjust- Supported By: Sanofi (NCT02227212) ment procedure is applied. Using CSII-KADIS® the A1c declined after three months from 8.2±0.8% to 7.6±0.5% and remains stable up to six months. In addition, the glucose variability was signifi cantly reduced. CLINICAL THERAPEUTICS/NEW TECHNOLOGY— Conclusion: Individually related basal rate adjustment becomes easier, INSULIN DELIVERY SYSTEMS safer, and is less time consuming by applying CSII-KADIS®-based decision support. Supported By: Medtronic GmbH Guided Audio Tour: Continued Progress with Insulin Pump Therapy (Post- ers: 1053-P to 1059-P), see page 13. & 1055-P Effi cacy and Safety of Insulin Pump Therapy in Type 2 Diabetes: The & 1053-P OpT2mise Study Glycemic Control Post Suspension of Insulin Using the Threshold RONNIE ARONSON, YVES REZNIK, IGNACIO CONGET, SARAH RUNZIS, JAVIER Suspend Feature CASTANEDA, SIMONE DE PORTU, SCOTT LEE, OHAD COHEN, Toronto, ON, Can- JOHN SHIN, SCOTT W. LEE, FRANCINE R. KAUFMAN, ASPIRE IN-HOME STUDY ada, Caen, France, Barcelona, Spain, Tolochenaz, Switzerland, Maastricht, Nether- GROUP, Northridge, CA lands, Ramat Gan, Israel The ASPIRE In-Home study evaluated the Threshold Suspend (TS) fea- The OpT2mise study was a multicenter, randomized, controlled trial com- ture of sensor-augmented pump (SAP) therapy, which automatically sus- paring effi cacy and safety of CSII vs. MDI in insulin-using patients with pends insulin delivery at a programmed sensor glucose (SG) value. During T2D. the 3-month study period, 247 type 1 subjects (mean age 43.4 yrs., mean Subjects using MDI with persistent hyperglycemia (A1c ≥8%) after a diabetes duration 26.9 yrs., mean baseline A1C 7.2%) were randomized to 9-week optimization period were randomly assigned to CSII or to continue SAP+TS (n=121) or SAP alone (n=126). The primary fi ndings of the ASPIRE In- MDI in a “study phase” (SP) of 6 months. In a 6-month “continuation phase” Home study were a 32% reduction in rate and a 38% reduction in area under (CP), CSII patients continued while MDI subjects crossed to CSII. the curve of nocturnal hypoglycemic events (p<0.001 for each). As shown in Of 331 randomized (45.6% women, age 56.0±9.6 yr, BMI 33.4±7.3 kg/m2, Panel A, SG profi les were ~4 mg/dL higher overall in the SAP+TS group than diabetes duration 15.1±8.0 yr, A1c 9.0±0.8%), 291 completed the study. in the SAP group (95% CI [0.14, 7.93]). Mean SG values were 158±20 and At 6 months, CSII subjects had achieved signifi cantly greater A1c reduc- 154±25 mg/dL in the SAP+TS and SAP groups, respectively, with no differ- tion (-1.1±1.2% vs. -0.4±1.1%, p<0.001) (1) - maintained at 12 months. MDI ences in the A1C change for either group. In order to characterize the glucose subjects crossing to CSII showed -0.8% A1c reduction, with fi nal A1c identi- profi le following 1873 2-h TS activations (mean of 1.4 per patient-week), SG cal in both arms. SP response rate (A1c <8.0%) was higher in the CSII arm values were assessed from time 0 (onset of automatic TS) to 8 h. As shown (CSII 55% vs. MDI 28%) but by end of the CP, both groups had achieved in Panel B, by 1 h after activation of TS, the mean SG value had begun to similar response rates of 57%. increase and was greater than the threshold value, reached a peak by 4-5 CSII Total Daily Dose (TDD) was 20.4% lower in the SP; in the CP, MDI h (2-3 h after resumption of basal insulin), and was 161 ± 69.5 mg/dL at 8 h subjects crossing to CSII showed a 19.0% TDD reduction; fi nal TDD was (6 h after resumption). The data suggest that the reduction in hypoglycemia equivalent in both groups. There was no difference between groups in seen with the TS feature was not associated with a signifi cant increase in weight gain nor ketoacidosis. In each group, 1 patient experienced severe hyperglycemia, including after maximum insulin suspensions lasting 2 h. hypoglycemia. The OPT2MISE study demonstrates that CSII provides a signifi cant ad- vantage in glycemic control over MDI with a safe and consistent effect in long-term treatment. 1 Reznik Y et al. Lancet 2014; 384:1265.

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A270 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULIN DELIVERY SYSTEMS

quency of hypoglycemia and hyperglycemia decreased in parallel (-44% and -35%, respectively, both p<0.001). Participants reported lower prandial and basal insulin dose requirements (-12% and - 8%, respectively; both p<0.001) at the end of the observation period. There were 14 reports about skin reac- tions during device use (4.1%). 12.1% of the participants reported less occur- rence of lipodystrophy (86.5% unchanged). Use of the InsuPad device was associated with substantial improvements in glycemic control and treatment effi cacy and safety in previous controlled clinical studies. The results from this post-marketing surveillance study confi rm that these trial results also translate into similar benefi ts when the device is used in daily routine treatment practice. Supported By: InsuLine Medical Ltd.

& 1058-P Preprandial Oral Insulin (ORMD-0801) Reduces Rapid-Acting Insu- lin Requirements and Fasting Glucose Levels in T1DM Patients MIRIAM KIDRON, JOEL M. NEUTEL, EHUD ARBIT, Jerusalem, Israel, Tustin, CA Supported By: Medtronic Europe Sàrl Systemically administered insulin is the mainstay of antidiabetes regi- mens but is associated with risk of hypoglycemia and weight gain. Portally & 1056-P infused insulin brings to a more rapid and pronounced suppression of hepatic Long-Term Glycemic Remission in Patients with Type 2 Diabetes glucose production and to reduced circulating peripheral insulin levels. Simi- Mellitus Treated with Insulin Pump Therapy larly, oral insulin (ORMD-0801), deposited directly into the portal vein follow- SOO BONG CHOI, EUN SHIL HONG, EUN KYOUNG JEON, KYUNG JIN KIM, HYUN ing its release from enteric-coated capsules in the gastrointestinal tract, has JU AN, YUN HEE NOH, Seoul, Republic of Korea, Cheongju, Republic of Korea been shown to reduce fasting and prandial glucose excursions in diabetes patients and to minimize glucose instability when provided as an adjunct to Intensive insulin therapy (IIT) is known to improve β-cell function and in-

subcutaneous insulin regimens in T1DM patients. This prospective, random- POSTERS duce glycemic remission in newly diagnosed T2DM patients. However, it is Therapeutics ized, placebo-controlled Phase 2a study aimed to evaluate the impact of pre- not known whether IIT can induce long-term remission in patients with long Clinical Diabetes/ T2DM duration. prandial ORMD-0801 on exogenous insulin requirements in T1DM patients We reviewed retrospectively the medical records of the T2DM remission monitored with a continuous glucose monitor over a 7-day double-blind cases achieved by insulin pumps who visited for routine check-ups from treatment period. A single ORMD-0801 capsule (8 mg insulin) was adminis- March to June in 2014. Remission is defi ned as maintaining normal fast- tered three times daily, 45 min before meals to 15 patients, while 10 received ing and postprandial glucose levels for 6 months after discontinuation of placebo. Patient insulin requirements were documented and glucose levels all anti-diabetic medications. Blood samplings were performed at fasting were recorded with a blinded continuous glucose monitor. Fasting plasma and 120 minutes after ingestion of a mixed meal (500 kcal), at baseline and glucose (FPG) levels were consistently lower than baseline on all treatment 6 month intervals during the treatment and follow-up periods. Values are days among ORMD-0801-treated patients, peaking at -60.2±63.3 mg/dL on presented as median (minimum-maximum) or mean ± SD. Eighteen patients day 7, while a mere -10.2±55.7 mg/dL change was measured for the placebo (8 males, 10 females) were enrolled during the 4 months [age at diagnosis, cohort at the same time point. Reduced FPG levels directly correlated with 51 (32-57) years; duration of T2DM, 0.9 (0.0 - 23.0) years]. Two patients had reduced rapid-acting insulin requirements, reaching a mean difference of been newly diagnosed (11.1%) and 16 patients (88.9%) on oral anti-diabetic -5.9 mIU/mL insulin intake between active versus placebo-treated patients medications before insulin pump therapy. Baseline HbA1c level was 7.4 ± on day 7. On day 7 of treatment, an equal number of hypoglycemic events 2.1%, and total daily insulin dose at the initiation of insulin pump therapy (<60 mg/dL) requiring clinical intervention was reported for each cohort. In was 55 (22-344) IU. The time to remission was 23 (5-108) months and the summary, preprandial ORMD-0801 reduced the exogenous insulin demands duration of remission was 25 (7-108) months. During the follow-up of 4.5 (1.7- required to maintain euglycemia in T1DM patients and proved safe and well 10.0) years, 4 subjects had T2DM relapse and restarted insulin pump therapy tolerated at the tested regimen. [duration of remission, 16 (7-36) months]. In the 14 patients with sustained remission, the latest HbA1c level was signifi cantly lower than the initial level & 1059-P (6.1 ± 0.4 vs. 7.7 ± 2.1%, p=0.009) and their latest BMI decreased (24.4 ± The Effi cacy of Single- and Dual-Hormone Artifi cial Pancreas Sys- 3.7 vs. 25.2 ± 3.4, p=0.033). Their disposition index increased from 0.14 ± tems at Regulating Glucose Levels during Continuous and Interval 0.09 (initial) to 0.35 ± 0.15 (maximum) (p=0.002). In conclusion, insulin pump Exercise in Type 1 Diabetes therapy improved β-cell function and induced long-term glycemic remission NADINE TALEB, AHMAD HAIDAR, CORINNE SUPPERE, ALI EMAMI, VIRGINIE regardless of T2DM duration. MESSIER, LAURENT LEGAULT, JEAN-LOUISE CHIASSON, RÉMI RABASA-LHO- RET, Montreal, QC, Canada & 1057-P The artifi cial pancreas (AP) in its two versions, single-hormone AP (insulin Use of InsuPad in Daily Routine Practice—Results from a Post- only; SAP) and dual-hormone AP (insulin and glucagon; DAP), is a promising Marketing Observation Study in Germany modality for the treatment of type 1 diabetes (T1D). Head-to-head compari- ANKE H. PFÜTZNER, FILIZ DEMIRCIK, JAN SPATZ, SELINA KNÜFER, GABRIEL BIT- sons of the two versions in different settings are needed to weigh the added TON, ANDREAS PFÜTZNER, Mainz, Germany, Petah Tikva, Israel clinical benefi ts against the increased complexity of DCL. We conducted Improvement of blood fl ow at the insulin injection site as induced by the an open-label, randomized, crossover study comparing SAP and DAP in 12 InsuPad device leads to a more effi cient and consistent uptake of prandial adults (age 39.25±15.4 yrs, HBA1c 8.0±0.7%) during two types of exercises insulin, resulting in better glycemic control, less hypoglycemic events and reported to have different hypoglycemic risks: moderate-intensity continu- lower prandial insulin dose requirements in a previous controlled clinical ous exercise (60% VO2peak for 60 min) and high-intensity interval exercise study. The purpose of this observational study was to investigate the device (2 min alternating intervals at 85% and 50% VO2peak for 40 min, with 2 x 10 effects, when used in daily routine. min at 45% VO2peak at the start and the end of the sessions), both exercises A post-marketing observation study was conducted in Germany in 2014 matched for overall energy expenditure. SAP and DAP were applied from and all reported cases until end of December with patients using short- 15:30 till 19:30, exercise started at 18:00 and announced 20 minutes earlier acting insulin analogs for prandial insulin treatment were included into this to the AP systems. During SAP as compared to DAP: exercise-induced hypo- analysis. Observation parameters included HbA1c, body weight, frequency glycemia (plasma glucose ≤3.3 mmol/l with symptoms or <3 regardless of of hypoglycemia ( 250 mg/dL) and adverse events. Student’s t-test was used symptoms) was observed in 27% (6/22) vs. 9% (2/22) of interventions (p=0.12); for parameter comparison between baseline and endpoint. percentage of time with glucose < 4.0 mmol/l was 19.9±26% vs. 2.4±7.6% A total of 340 people with diabetes were included into this analysis (157 (p=0.006); time with glucose between 4 and 10 mmol/l was 74.5±24.6% vs. female, 295 type 2, HbA1c: 8.6±1.4%, body weight: 109±22 kg, daily insulin 90.2±23.5% (p=0.037). This effect was conserved after adjustment for type dose: 144±76 IU). Mean observation time was 11.2±3.9 weeks (range: 1-32 of exercise, glucose level at AP initiation, and order of interventions. A trend weeks). During the observation period, there was a signifi cant reduction in of higher time spent below 4 mmol/l was observed in continuous exercise HbA1c (-0.56±0.98%, p<0.001) and in body weight (-1.0±4.0 kg, p<0.001). Fre- compared to interval exercise (15.9±24.1% vs. 6.1±16.0%; p=0.12); however,

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A271 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULIN DELIVERY SYSTEMS

the type of exercise did not affect the number of hypoglycemia events (21% (5/24) vs. 15% (3/20) of interventions; p=0.63) or time spent between 4 and Table. Pump Alert Settings in the ASPIRE In-Home Study. 10 mmol/L (80.5±23.9% vs. 84.5±26.8%; p=0.6). In summary, DAP is offering SAP + TS (N = 121) SAP (N = 126) a tighter control and a better potential to prevent hypoglycemia during two Parameter Mean parameter value Mean parameter value types of exercise in adults with T1D. (number using feature) (number using feature) Supported By: Société Francophone du Diabète and Diabète Québec HI_ALERT (mg/dL) 226.4 (121) 234.8 (121) HI_SNOOZE (min) 75.4 (121) 81.9 (126) 1060-P HI_PREDICTIVE (min) 18.4 (51) 17.9 (49) Glucagon Nasal Powder: An Effective Alternative to Intramuscular Glucagon in Youth with Type 1 Diabetes LO_ALERT (mg/dL) 71.4 (121) 70.3 (120) JENNIFER L. SHERR, KATRINA J. RUEDY, NICOLE C. FOSTER, CLAUDE A. PICHÉ, LO_SNOOZE (min) 28.1 (121) 29.9 (126) HÉLÈNE DULUDE, MICHAEL R. RICKELS, WILLIAM V. TAMBORLANE, KATHLEEN LO_PREDICTIVE(min) 18.6 (58) 17.4 (55) E. BETHIN, LINDA A. DIMEGLIO, PAUL WADWA, LARRY A. FOX, DESMOND A. SCHATZ, BRANDON M. NATHAN, SANTICA M. MARCONVIA, ROY W. BECK, New Supported By: Medtronic, Inc. Haven, CT, Tampa, FL, Montreal, QC, Canada, Philadelphia, PA, Buffalo, NY, Indianap- olis, IN, Denver, CO, Jacksonville, FL, Gainesville, FL, Minneapolis, MN, Seattle, WA 1062-P Intramuscular glucagon (IM) is the only currently available treatment A Study to Assess the Performance of PaQ®, a Simple 3-Day Basal for severe hypoglycemia outside of the hospital setting. Unlike current IM Bolus Insulin Delivery Device, after 12 Weeks of Treatment in Peo- emergency kits, needle-free dry-powder intranasal glucagon (IN) does not ple with Type 2 Diabetes require reconstitution prior to administration. In this study, the effi cacy and JULIA K. MADER, LESLIE C. LILLY, FELIX ABERER, TINA PÖTTLER, MICHAEL safety of a novel IN product in 45 youth with T1D was evaluated at 7 centers TRAUTMANN, THOMAS R. PIEBER, Graz, Austria, Marlborough, MA, Hamburg, participating in the T1D Exchange (Table). The two youngest cohorts (4-<8; Germany 8-<12 yrs) were randomized to one IM or two IN administrations, which were PaQ® (CeQur SA) is a simple continuous subcutaneous insulin infusion de- double-blinded (with random order of 2mg IN during one and 3mg IN during vice that provides set basal rates and bolus insulin on demand. This single- the other); those 12-<17 yrs received in a randomly assigned order, 1mg IM arm study evaluated the performance of PaQ to deliver basal bolus insulin

POSTERS at one session and 3mg IN at another session. Glucagon was administered 5 after 12 weeks of use in people with type 2 diabetes (T2D) who were on an Therapeutics min after blood glucose was lowered to <80 mg/dL. A sharp rise in glucose established regimen of insulin therapy (at least 2 injections per day). PaQ Clinical Diabetes/ was observed in all age groups following either IM or IN dosing (Table). An performance was measured by HbA1c, venous fasting blood glucose (VFBG), increase in glucose ≥25 mg/dL within 20 min of treatment was observed self-monitored BG (SMBG), total daily dose of insulin (TDD) and body weight in all but one IN participant (who immediately blew his nose following his (BW). Safety was assessed by examination of the application site, surveil- 2-mg dosage). Nausea (with or without vomiting) occurred with 67% of IM lance of adverse device effects (ADE) and hypoglycemic episodes (SMBG ≤ sessions vs. 42% of IN sessions (P=0.06). These data support the effi cacy 70 mg/dL). The study was comprised of three periods; screening/baseline (1 and safety of a novel glucagon nasal powder delivery system for treatment week on current insulin therapy), transition to PaQ (up to 2 weeks), and PaQ of hypoglycemia in youth with T1D. therapy (12 weeks). Eight patients (age 63 ± 5.6 y, 87% male, BMI 32.4± 5.9 2 Table. kg/m , diabetes duration 22.3 ±9 y, HbA1C 8.6 ± 1.0 %) were enrolled and 7 completed the study (1 completed early due to false alerts). A mean reduc- tion in HbA1c and VFBG of 1.67±0.85% (P=0.0020) and 46.29±82.67 (P=0.19), respectively was seen after 12 weeks of PaQ insulin delivery. Change in SMBG values (mean ± SD mg/dL) compared to baseline were: pre- and post-breakfast -19.5±75.0 (P=0.52), -79.1±66.3 (P =0.02), pre-and post-lunch -19.9±46.5 (P =0.30), - 6.5±38.5 (P =0.67), pre- and post-dinner -48.4±47.9 (P=0.04), -12.8±96.3 (P =0.76) and bedtime 5.9±65.8 (P=0.83). TDD and body weight did not change signifi cantly from baseline. No SADEs or cannula site infections occurred and the device was well tolerated. People with T2D were easily and safely transitioned from injectable insulin to PaQ. PaQ deliv- Supported By: The Leona M. and Harry B. Helmsley Charitable Trust ered insulin as intended as evidenced by signifi cant reductions in HbA1c and SMBG values post breakfast and pre dinner. A simple insulin infusion device like PaQ may facilitate intensive insulin treatment in patients with T2D. 1061-P Supported By: CeQur Utilization of Pump Alert Settings by Intervention vs. Control Sub- jects in the ASPIRE In-Home Study Evaluating Automatic Threshold Suspend 1063-P JOHN SHIN, FRANCINE R. KAUFMAN, ASPIRE IN-HOME STUDY GROUP, North- A Randomized Trial of Training Type 1 Diabetes in Advanced Carbo- ridge, CA hydrate Counting With or Without an Automated Bolus Calculator The ASPIRE In-Home Study evaluated the Threshold Suspend (TS) feature EVA E. HOMMEL, SIGNE SCHMIDT, MARIA GRIBHILD, KIRSTEN NEERGAARD, of sensor-augmented pump (SAP) therapy, which stops insulin delivery at ANNETE G. SKOUBOE, THOMAS ALMDAL, KIRSTEN NØRGAARD, Gentofte, Den- a programmed sensor glucose (SG) value, in 247 type 1 subjects who were mark, Hvidovre, Denmark randomized to SAP+TS or SAP alone. The SAP+TS group had a 32% reduction Use of advanced carbohydrate counting (ACC) in patients with type 1 in rate and a 38% reduction in area under the curve of nocturnal hypoglyce- diabetes (T1D) improves HbA1c signifi cantly. Whether there is an additional mic events (p<0.001 for each), with no change in A1C. To test whether these benefi cial effect of concurrent use of an automated bolus calculator (ABC) benefi ts were attributable to between-group differences in alert settings remains to be determined. related to SG values, we compared mean values for several parameters in The present study was a 12-month, randomized, parallel group study com- the two groups (Table). Almost all subjects used alerts to indicate hypo- and paring the effects of training carbohydrate counting-naïve MDI-treated T1D hyperglycemia and mean triggering values were comparable, as were the patients in ACC with or without the support of an ABC. In a 1:1-ratio patients alert dismissal (“snooze”) intervals. Fewer subjects used predictive alerts, were randomized to ACC using mental calculations (ACC-group) or ACC using but usage rates and parameter settings were similar between the groups. the ABC (Accu Chek Aviva Expert, Roche), (ABC-group). ACC or ACC+ABC Rate-of-change alerts for both increasing and decreasing SG values were training was provided during a 4-hour group teaching session. used at similar frequencies and had similar settings in the two groups. Sub- We recruited 177 T1D patients with HbA1c 8.0-11.3%. In total, 131 com- jects in the SAP+TS and SAP groups had the low alert setting at values <70 pleted the study (71 males, 60 females), (65 ACC-group/66 ABC-group). Base- mg/dL 66% vs. 60% of the time, respectively. It appears the TS feature helps line characteristics were: Age 50.2±13.8 yrs, diabetes duration 22.6±13.9 2 to reduce hypoglycemia as a result of the automatic suspension of insulin yrs, HbA1c 8.8±0.7%, and BMI 25.7±3.8 kg/m . Drop-out rate was similar in and not as the result of using pump alerts alone. the ACC- and ABC-groups. HbA1c declined signifi cantly within both groups; ACC-group 0.3% (p=0.006) and ABC-group 0.6% (p<0.001). The decline in HbA1c was signifi -

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A272 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULIN DELIVERY SYSTEMS cantly greater in the ABC-group (p=0.024). No patients reported having had U/kg in a 1 cm2 patch was associated with a Cmax of 16.7 microU/mL at a severe hypoglycemic event during the study. 2 h post-treatment, t1/2 ~2 h, and AUC0-6 of 82.7 mU.h/mL. A euglycemic A baseline 6 days blinded CGM recording revealed the following distribu- response (BG 100-160 mg/dL) was achieved in ~3.5 h post administration. tion of glucose values: 5.9% lower than 70 mg/dl, 45.7% in target 70-180 The relative bioavailability of the 20 U/kg/cm2 glargine patch was calculated mg/dl and 48.5% above 180 mg/dl. In a 6 days recording after 12 moths none to be 15.3%. A separate group of 15 STZ-induced male diabetic hairless rats of the groups experienced a signifi cant change in time below target, but were randomized to detemir injection-only (9 U/kg, s.c., twice a day) vs. de- the ABC-group experienced 8.8 % more of the time in target glucose range temir patch (10 U/kg/cm2 patch + 6 U/kg, sc twice a day). While the average (p<0.001) and above target was reduced with 8.3% of the time compared to BG readings decreased signifi cantly in both groups, each animal in the patch the ACC-group (p<0.01). group exhibited a BG lowering effect into the normal range (100-160 mg/dL) In conclusion, 12 months after training adult T1D patients in ACC, HbA1c within 24 h. In contrast, the BG response varied signifi cantly in the injection- improved but signifi cantly more in the group using the ABC. Further, the time only group. 24 h post-treatment, three animals had no BG lowering effect in target glucose assessed by CGM increased and the time above target from baseline, two exhibited BG lowering to the sub-optimal range of 200- decreased in the group using automated bolus calculation. 225 mg/dL, and two became hypoglycemic. These in vivo studies support the feasibility of developing an effective insulin Topicon™ patch that can achieve 1064-P more consistent BG lowering than sc injection. Validation studies in a swine Does Glucose Control Differ with Insulin Pump Infusion Set Wear model with are underway. Time in Adults with Type 1 Diabetes? VIRAL N. SHAH, TONYA D. RIDDLESWORTH, DAVID M. MAAHS, KELLEE M. 1066-P MILLER, ROY W. BECK, SATISH K. GARG, Aurora, CO, Tampa, FL Impact of Overnight Home Closed Loop (CL) Insulin Delivery on In real-life, many patients with type 1 diabetes (T1D) on insulin pumps use Glycemia and Counterregulatory Hormones Compared with Sensor infusion sets (IS) longer than recommended (≤3 days). This study evaluated Augmented Pump Therapy with Low Glucose Suspend (SAP-LGS) characteristics and glycemic outcomes by duration of IS use from the T1D AMIN SHARIFI, MARTIN DE BOCK, MARGARET LOH, JODIE C. HORSBURGH, Exchange registry data. ALICIA J. JENKINS, KAVITA KUMARESWARAN, JANE SPEIGHT, CHRISTEL HEN- The cohort included 3,813 registry participants ≥18 years who have been DRIECKX, RICHARD J. MACISAAC, GLEN M. WARD, PETER G. COLMAN, LEON using a pump for >1 year. Of these, 926 (24%) reported changing IS ≥4 days BACH, ANDREW KYOONG, NATALIE KURTZ, BENYAMIN GROSMAN, ANIRBAN

and 2,887 (76%) changed IS <3 days. HbA1c data were obtained from clinic ROY, TIMOTHY W. JONES, DAVID N. O’NEAL, Melbourne, Australia, Perth, Austra- POSTERS records at a visit closest to questionnaire completion. lia, Northridge, CA Therapeutics There were no differences in age, gender, ethnicity, duration, education, Overnight CL insulin delivery improves glycemic control although related Clinical Diabetes/ income, employment status, insurance category or CGM use between two changes in counter-regulatory hormones have not been studied. We con- groups. The longer use of IS group had longer duration of pump use (11.0 vs. ducted a randomised controlled cross-over study to evaluate the perfor- 10.1 years, P<0.001) and lower frequency of daily blood glucose monitoring mance of a uni-hormonal artifi cial pancreas (proportional integral deriva- (5 vs. 6, P<0.001). Mean HbA1c was 7.8% and 7.7% for the longer and shorter tive with insulin feedback algorithm). Eleven type 1 diabetes participants (8 IS groups, respectively. There were no differences between the groups for adults; 3 adolescents; HbA1c 7.4±0.5%) were assigned in random order to CL HbA1c, DKA and severe hypoglycemia (Figure) or by type of insulin used (lis- and control (SAP-LGS) for 1 night in clinic followed by 4 nights at home. On pro or aspart). night 4 at 3 AM an orange juice challenge was performed. In these cross-sectional, self-reported, observational, non-randomized The primary outcome, (sensor time in target range overnight at home: data, longer duration of IS use was not associated with optimal glucose con- 4.0-8.0 mmol/L) in CL vs. control, was not different (p=0.23). Sensor time trol in adults with T1D on insulin pumps. Further large randomized trials are between 4.0 and 10.0 mmol/L, area under the curve of sensor glucose above needed to investigate longer-term use of infusion sets. and below target were all signifi cantly better with CL. The number of symp- tomatic hypoglycemic episodes overnight at home confi rmed by capillary glucose readings (<4.0mmol/L) was signifi cantly lower with CL vs. control (6 vs. 19; p=0.0093). There were no changes observed in counter-regulatory hormones. In conclusion, CL at home improved nocturnal glycemia and reduced symp- tomatic hypoglycaemia compared to SAP-LGS. The absence of changes ob- served in counter-regulatory hormones may relate to the small participant numbers and short study duration.

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1065-P PK/PD Studies of Topicon™-mediated Patch Delivery of Insulin Ana- logs in a STZ-induced Hairless Rat Model STEPHEN I. HSU, CARL MANGLEBURG, HUA YAO, Alachua, FL The Topicon™ patch is a needle-free novel platform technology developed to achieve truly passive transdermal delivery of insulin. We report PK/PD studies comparing needle injection (sc) vs. patch delivery of long-acting insulin analogs glargine (LANTUS®) and detemir (Levemir®) in STZ-induced hairless rats. All PK studies of sc glargine were performed with a dose of 10 U/kg, which is the smallest dose that can be injected accurately without dilution of LANTUS®. A single sc injection of 10 U/kg of glargine in adult rats resulted in a rapid rise in plasma glargine concentration with a Cmax Supported By: JDRF ~120 microU/mL at 1 h, rapid elimination with t1/2 ~2 h, and return to base- line level by 5 h. A blood glucose (BG) lowering effect was observed from a baseline mean BG of ~375 mg/dL to a nadir of ~70-80 mg/dL for 0.5-5 h, representing asymptomatic hypoglycemia (BG<100 mg/dL). Therapy with 20

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A273 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULIN DELIVERY SYSTEMS

1067-P A post-marketing observation study was conducted in Germany in 2014 Use of eGlycemic Management System Safely Achieves Optimal and all reported cases until end of December with patients using regular Subcutaneous Glycemic Control with Low Hypoglycemia in Pa- human insulin for prandial insulin treatment were included into this analysis. tients without Diabetes Observation parameters included HbA1c, body weight, frequency of hypo- MELANIE MABREY, JOSEPH ALOI, RAYMIE MCFARLAND, ROBBY BOOTH, JAG- glycemia and hyperglycemia, and adverse events. Student’s t-test was used DEESH ULLAL, Greenville, SC, Winston-Salem, NC, Rocky Mount, NC, Norfolk, VA for parameter comparison between baseline and endpoint. Hyperglycemia, regardless of its cause, is clearly associated with adverse Meeting the inclusion criteria were 55 participants (25 female, 51 type outcomes in hospitalized patients. Hyperglycemia in patients with no known 2, HbA1c: 8.8±1.7%, body weight: 113±26 kg, daily insulin dose: 141±70 IU). history of diabetes and having an A1c < 6.5%, are typically defi ned as having Mean observation time was 12±4 weeks (range: 2 - 24 weeks). During the illness-related or stress-induced hyperglycemia. observation period, reductions in HbA1c by 0.6±0.9% (p<0.001) and in body A retrospective, observational study was conducted comparing Glucom- weight by 1.4±4.2 kg (p<0.05) were observed. In parallel, monthly hypogly- mander TM (GM) SubQ treated patients to standard order (SO) sets at a com- cemia rate (-44%, from 2.9±4.6/month to 1.6±4.8/month, p<0.05) and hy- munity-based hospital involving 186 adult, ICU NPO patients, having an A1c perglycemia rate (-35%, from 48±39/month to 31±31/month, p<0.001) were < 6% and no confi rmed diabetes diagnosis on admission or post discharge. reduced. Prandial and basal insulin doses were reduced by -16% and - 8%, Glucommander SubQ™, an FDA-cleared, computerized, predictive dosing respectively (both p<0.001). Device use was well tolerated with only two algorithm was used to calculate daily basal and correctional insulin require- reports of skin reactions to the device adhesive. A lower incidence of lip- ments and Basal Correction was used in the control group through CPOE odystrophy was reported by 24% of the patients (no change: 76%). orders and titrated by clinicians. Many patients had been transitioned from Use of InsuPad device in daily treatment routine in people with diabetes IV insulin treatment with Glucommander IV to SubQ™ transition module in on intensive insulin treatment using regular human insulin as prandial insulin the GM arm. The SO group were transitioned by clinicians. component resulted in improvement in glycemic control (better HbA1c, less The average A1c was 5.6±0.4% for GM and 5.5 ± for SO. The average initial hypoglycemia, lower insulin dose requirements) as was demonstrated with blood glucose concentration was 156 ±58 mg/dL for GM and 143 ±62 mg/dL for diabetic patients using short-acting insulin analogs in a previously conduct- SO. Using Glucommander SubQ™, patients were able to reach an average fasting ed randomized controlled clinical study. BG of 128 mg/dL and 127 for SO. The average BG of 144 mg/dL was seen for GM Supported By: InsuLine Medical Ltd. and 134 mg/dL for SO. The average number of point of care glucose tests per patient was 17±24. There were no incidents of severe hypoglycemia < 40 mg/dL, POSTERS 1070-P Therapeutics and 2% < 70 mg/dL for GM and 0.37% <40 mg/dL, 3.15% < 70 mg/dL for SO. Effi cacy of Insulin Pump in DM2 beyond HbA1c Reduction Clinical Diabetes/ In conclusion, patients who either transitioned from IV to SubQ or those RUDOLF CHLUP, SARAH RUNZIS, JAVIER CASTANEDA, SCOTT LEE, OHAD CO- started on SubQ who do not have confi rmed diabetes on admission were able HEN, Moravský Beroun, Czech Republic, Tolochenaz, Switzerland, Northridge, CA, to achieve target glucose with no severe hypoglycemia and lower incidence of Ramat Gan, Israel mild hypoglycemia with Glucommander TM compared to Standard Order sets. CSII therapy has previously been proven to lead to reduced insulin re- quirements, potentially allowing for body mass loss in obese DM2. This pro- 1068-P spective single-center study recruited insulin-resistant CSII-naive patients Prevalence of Insulin Pump Therapy and Its Association with Glyce- with type 2DM, uncontrolled, using insulin analogues-based MDI therapy mic Control in Longstanding T1DM: Results from the Canadian Study (+ metformin). Insulin dosing was optimized over a 9-week run-in period and of Longevity in Diabetes Cohort subjects with persistent HbA1c ≥8% were randomly assigned to the CSII arm GENEVIEVE BOULET, LEIF ERIK LOVBLOM, ELISE M. HALPERN, ALANNA WEIS- or to MDI continuation arm to explore global metabolic improvement: glu- MAN, DEVRIM ELDELEKLI, HILLARY A. KEENAN, MICHAEL BRENT, NARINDER cose control, weight loss, reduction of insulin and insulin resistance. After 6 PAUL, VERA BRIL, DAVID CHERNEY, BRUCE A. PERKINS, Toronto, ON, Canada, months, the MDI arm crossed over to CSII therapy as well. A total of 23 DM2 Boston, MA (16 men) were randomized (mean±SD, age 57.6±7.94 y, BMI 35.4±6.54 kg/m2, Estimates of the prevalence of insulin pump use in those with longstanding diabetes duration 14.3±5.93 y, HbA1c 10.0±1.05%). At 6 months, subjects, T1DM have not been extensively studied. We aimed to determine in a national assigned to the CSII arm, achieved a signifi cant mean HbA1c reduction of cohort the prevalence of insulin pump use, factors associated with use, and -0.9% (95% CI=-1.6, -0.1) while reducing their total daily insulin dose (TDD) its independent association with glycemic control. The prevalence of current by -29.8±28.41 U/d (33% of baseline 92.1±20.35U/d) and achieving weight re- pump use was 44% (133/303). Pump users were younger (64 vs. 66 years, duction of -0.8±5.61 kg (0.98% of baseline 104.8±16.15 kg). Subjects on MDI p=0.04), more educated (84 vs. 74% greater than high school, p=0.03), more demonstrated a non-signifi cant HbA1c reduction of -0.3% (95% CI=-0.8, 0.1) physically active (78 vs. 65% reporting daily activity; p=0.01), and had less with TDD reduction of 5% from baseline 99.0± 25.25 U/d to 94.3±21.25 U/d, chronic kidney disease (28 vs. 42%, p=0.03). Despite a non-signifi cantly lower and body mass reduction of -1.0±2.03 kg (0.99% of baseline 108.9±20.55 kg). A1c (7.4 vs. 7.6%; p=0.12), pump users had lower insulin requirement (0.47 vs. At 12 months, patients continuing on CSII demonstrated an additional mean 0.56 u/kg/d, p=0.01). Daily glucose tests (6.0 vs. 4.0), use of carbohydrate ratios 0.7% HbA1c reduction with 54.6% achieving HbA1c<8%. TDD and weight (84 vs. 34%), use of insulin sensitivity factor (95 vs. 85%), use of computer data increased during the perusing 6 months, the fi nal reduction achieved in TDD uploads (37 vs. 12%), and use of continuous glucose monitors (22 vs. 7%) were was -9.7 U/d in comparison to baseline; body weight increased by 1.1 kg signifi cantly greater among pump users (p<0.005 for each comparison). In mul- from baseline. MDI patients crossed to CSII showed a HbA1c reduction of tivariable analysis, male gender (p=0.01), greater daily glucose tests (p=0.001), -0.5±1.04%, HbA1c response rate 27.3%, TDD reduction of -17.4±21.06 U/d and greater minor hypoglycemia (p=0.01) - but not insulin pump therapy - were and weight reduction of -0.3±3.39 kg. No ketoacidosis or severe hypoglyce- independently associated with lower A1c. In pump users, among these vari- mia occurred in either group. Hence, in insulin resistant DM2 patients, CSII ables and pump parameters only male gender was associated with lower A1c signifi catively and safely improved metabolic control with less insulin and (p=0.03). In conclusion, insulin pump use is very frequent among patients with with no sustainable reduction of body weight. longstanding T1D, approaching half. Despite a trend toward lower A1c among Supported By: Medtronic International Trading Sàrl pump users that is comparable in magnitude to that observed in clinical trials, the only modifi able factor independently associated with better glycemia was 1071-P greater frequency of daily glucose tests. Continuous Subcutaneous Insulin Infusion (CSII) Sets: Reduced Supported By: JDRF Flow Interruptions with a Novel Catheter Set LAURENCE HIRSCH, MICHAEL GIBNEY, MONICA SWINNEY, ZHENYI XUE, 1069-P THOMAS KLUCK, Franklin Lakes, NJ, Billerica, MA, Baltimore, MD Impact of InsuPad on Glycemic Control in Patients Using Regular Effective CSII requires consistent insulin delivery via infusion set. An in- Human Insulin as Mealtime Insulin in Daily Routine—Results from vestigational, side-ported 28G polymer infusion set has been designed to a German Observation Study reduce fl ow interruptions including sub-alarm threshold “silent” occlusions FILIZ DEMIRCIK, JAN SPATZ, SELINA KNÜFER, ANKE H. PFÜTZNER, GABRIEL BIT- (below pump pressure settings). With an in-line pressure measuring method TON, ANDREAS PFÜTZNER, Mainz, Germany, Petah Tikva, Israel that reliably refl ects fl uid fl ow, we compared the new set with a marketed The InsuPad device enhances prandial insulin absorption by injection site set (Quick-set, Medtronic). modulation with a standardized warming protocol. The purpose of this anal- Each of 60 healthy subjects received 4 diluent basal/bolus infusions (2 ysis was to explore the impact of using the device in intensive insulin treat- with each set, inserted manually by study staff in randomized abdominal ment with regular human insulin on glycemic control in a real-world setting. sites). Diluent was infused at 0.01 mL/hr (1.0U/hr) via insulin pump for 3 hrs,

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A274 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULIN DELIVERY SYSTEMS followed by a 10U bolus and another hr of basal delivery. The set was then 25 pregnant women who started CSII > 3 months before conception (group clamped (positive control) and remained in place for 30 mins. A fl ow inter- A) and 15 women who started CSII within the 1st trimester of pregnancy ruption/silent occlusion was defi ned as continuous pressure rise ≥30 mins. (group B). All the women underwent to a careful re-training (group A; before Based on a prior study, the trial was designed to show ≥ 50% reduction in and soon after conception) or training (group B; before and soon after pump pressure rise events with the investigational set. Pump alarms and leakage commencement) to the CSII use, with emphasis on pregnancy management. after set removal were also assessed. Main outcomes were: mean of glycosylated hemoglobin (HbA1c) values ob- Subjects were 45% female, mean (SD) age 42.6 (14.4) years, BMI 27.0 (3.5) tained throughout the pregnancy during the use of insulin pumps (MHbA1c); kg/m2, with 235 infusions evaluable. Pressure rise events occurred in 3/117 complications rate (fetal + neonatal + maternal complications). The groups (2.6%) vs. 12/118 (10.2%) infusions for new sets vs. Quick-sets (RR 0.25 [95% A and B showed similar age, duration of diabetes and prevalence of pre- CI 0.08, 0.8], p=0.03 by Fisher’s test). The new set had signifi cantly less time pregnancy complications, but group A had lower pre-conception HBA1c than interrupted than Quick-set (p=0.002, Wilcoxon Rank Sum). Using a Poisson group B (pre-conception HbA1c: group A = 8.36 ± 1.39% versus group B = model, the new set had signifi cantly fewer fl ow interruptions per unit of time 9.06 ± 2.64%; p < 0.05). On the contrary, both MHbA1c and complications vs. the marketed set, p=0.0001. Leakage at insertion site, occlusion alarms, rate were not different between the groups (MHbA1c: group A = 7.17 ± 1.08% and catheter kinking observed on removal were infrequent and NS between versus group B = 7.04 ± 1.21%; p = n.s.) (complications rate: group A = 9/25 sets. versus group B = 4/15; p = n.s.). In conclusion, despite the higher pre-con- In this study, compared to a commonly used infusion set, the investiga- ception HbA1c values, the women with T1D who commenced insulin pumps tional set had fewer fl ow interruptions/silent occlusions and less time with within the 1st trimester of pregnancy achieved the same mean HbA1c values interrupted fl ow. Decreasing fl ow interruptions may benefi t CSII patients by and rate of complications of women who started insulin pumps before con- providing more consistent insulin delivery and reducing hyperglycemic epi- ception. However, these results were obtained with a careful training pro- sodes caused by infusion set failures and/or temporary blockage. gram, and further studies are needed to defi ne the predictors of pregnancy Supported By: JDRF outcomes in women with T1D on insulin pumps.

1072-P 1074-P Preliminary Comparative Study on Beta-Cell Function, Insulin Sen- Clinical Comparison of MPC and PID Artifi cial Pancreas Control- sitivity, and Disposition Function between Continuous Subcutane- lers: A Randomized Crossover Trial

ous Insulin Infusion and Other Treatment Modalities in Type 2 Dia- JOON BOK LEE, JORDAN E. PINSKER, EYAL DASSAU, DALE E. SEBORG, KRIS- POSTERS betic Patients TIN CASTORINO, RAVI GONDHALEKAR, WENDY C. BEVIER, PAIGE K. BRADLEY, Therapeutics Clinical Diabetes/ SOO BONG CHOI, EUN SHIL HONG, EUN KYOUNG JEON, KYUNG JIN KIM, HYUN HOWARD C. ZISSER, FRANCIS J. DOYLE III, Santa Barbara, CA, Billerica, MA JU AN, YUN H. NOH, Cheongju, Republic of Korea, Seoul, Republic of Korea Numerous control algorithms have successfully been implemented in To see if there is any difference in beta cell function, insulin sensitivity, clinical trials of an artifi cial pancreas (AP) in people with type 1 diabetes and disposition function between the patients with T2DM treated by con- mellitus (T1DM), but equitable comparisons of algorithm performance have tinuous subcutaneous insulin infusion (CSII) or the other treatments (oral not been reported. We present the results of a randomized crossover clinical agents, conventional insulin therapy; OTHER), we examined changes in trial of ten adults with T1DM, comparing the two most widely-used AP con- HBA1C, serum C-peptidogenic Index (CI), Matsuda Index (MI), and disposi- trol approaches: Model Predictive Control (MPC) and Proportional-Integral- tion Index (DI) for 6 months. Derivative (PID) control. Blood samplings were performed at fasting and 120 minutes after inges- To ensure equivalence, basic versions of both controllers were designed tion of a mixed meal (500 kcal), at baseline and 6 months after treatments. based on an identical insulin-glucose model and personalized based on indi- And CSII group (n = 53; age 55.5 ± 12.2 years; duration of diabetes 7.8 ± vidual basal profi les (glucose target 110 mg/dL). Insulin-on-board and insulin 4.9 years) and OTHER group (n = 33: 21 oral agents, 12 conventional insulin feedback strategies were used to prevent insulin stacking for MPC and PID, therapy; age 52.8 ± 12.1 years; duration of diabetes 5.8 ± 6.2 years) were respectively. Subjects were randomly assigned to 27.5 h sessions with two compared. announced and one unannounced meals of 65/50/65 g carbohydrates (CHO) Baseline characteristics were similar between the two groups (including and an overnight period. Subjects crossed over to the other controller for a age, sex, BMI, duration of diabetes, and HbA1C level). second visit using an identical protocol. The baseline for each AP controller As shown in Table 1, the mean HBA1C levels decreased signifi cantly in was sensor-augmented pump (SAP) control for a 24 h period prior to the both groups. In CSII group, the CI, MI, and DI increased signifi cantly. In OTH- clinical visit. ER group, the CI increased signifi cantly but the MI and DI did not increase Both controllers produced statistically signifi cant reductions in percent signifi cantly. time <70 mg/dL compared to SAP, with median and interquartile range of These fi ndings suggest that compared to the other therapies, CSII therapy 0.46% [0-1.42] (MPC) and 0.15% [0-2.15] (PID) vs. 7.68% [1.51-11.5] (SAP) may exert more favorable effects on insulin sensitivity and disposition func- (p<0.05), without concomitant increases in hyperglycemia. Overnight con- tion in T2DM patients. trol also improved, with increased median percent time in the 70-180 mg/dL Table 1. range (MPC and PID >90%, SAP 61%; p<0.05 for MPC vs. SAP). Both control- lers successfully overcame the challenge of a large unannounced meal (65 g Changes of HBA1C. CI, MI, DI for 6 Months (Mean ± SD). CHO) with similar insulin delivery profi les. CSII OTHER This fi rst prospective study comparing MPC and PID control demonstrated Baseline at 6 months P value Baseline at 6 months P value that both methods provided safe and effective glucose management and HBA1C (%) 9.353 ± 2.049 6.975 ± 1.094 .000 9.858 ± 2.169 7.330 ± 1.309 .000 showed statistically superior performance compared to conventional SAP. Both controllers appear well suited for future artifi cial pancreas applica- CI 0.025 ± 0.028 0.035 ± 0.032 .050 0.036 ± 0.041 0.053 ± 0.044 .015 tions. MI 2.268 ± 0.915 2.694 ± 1.662 .010 3.261 ± 2.368 3.523 ± 2.414 .713 Supported By: JDRF (22-2011-237); National Institutes of Health (DP3DK094331, DI 0.054 ± 0.069 0.083 ± 0.071 .013 0.084 ± 0.074 0.138 ± 0.110 .079 R01DK085628)

1073-P 1075-P Insulin Pump Commencement Before and After Conception in Wom- Effect of Injection Site Treatment on Regular and Analog Insulin en with Type 1 Diabetes: A Pilot Study Pharmacodynamics ANNA DI NOTO, GABRIELLA SAURA, DAVIDE BRANCATO, MATTIA FLERES, ALES- GABRIEL BITTON, DMITRY FELDMAN, ESTER VEINBERG, TAL ALON, ANDREAS SANDRO SCORSONE, VITO AIELLO, LIDIA FERRARA, FRANCESCA PROVENZANO, PFÜTZNER, ITAMAR RAZ, Jerusalem, Israel, Holon, Israel, Petah Tikva, Israel, Mainz, LUCIA SPANO, VINCENZO PROVENZANO, Partinico, Italy, Palermo, Italy Germany In women with type 1 diabetes (T1D) it is recommended to optimize mul- The InsuPad device is intended for use by diabetic subjects using short act- tiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII) ing insulin. The device applies local controlled heat to the skin at the injec- before conception is attempted. When the pregnancy is unplanned and the tion site resulting in increased and consistent local blood perfusion. About glycemic goals are not achieved with MDI, some women start insulin pumps third of the world’s MDI diabetic patients, mainly in developing countries, after conception, but the effectiveness of CSII commenced after conception are still using regular insulin although analog insulin is considered better. In is unclear. Aim of the present study is to compare the effectiveness of insu- this study we compared the effect of injection site heating on post prandial lin pumps commenced before and after conception. Therefore, we assessed glucose (PPG) levels of regular human insulin (RHI) and analog insulin.

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8 Type 2 diabetic patients (aged 62.5 ± 7.4 years, HbA1c of 8.1 ± 1.2%, croneedles (Nanopass MicronJet) vs. subcutaneous (SC) delivery through a BMI of 30.6 ± 4.1 kg/m^2) on basal bolus insulin therapy were admitted after 6 mm, 31G needle (BD Ultra-Fine). overnight fast for a meal tolerance test. The test was conducted four times Subjects were injected at t=0 with 5 units of insulin ID or SC on separate with and without the use of the InsuPad device with injection of 0.2 U/kg of visits. During both visits 50 mcg of glucagon was injected at t=5 and t=125 analog or regular insulin. min ID and SC in random order. Bleb formation/leakage were documented. PPG levels were lower when the InsuPad device was used when analog or Plasma insulin and glucagon levels were measured at 5-15 min intervals. regular insulin’s were injected. Use of the InsuPad device with regular insulin After correction for baseline, as-observed Tmax, Cmax, and AUC were cal- injection resulted in lower PPG levels compared to analog insulin injection culated. without the use of the device as can be seen in the fi gure below. Mean insulin Tmax was reduced after ID vs. SC injection (35.6 vs. 41.7 min, The results from this feasibility study shows that RHI injection site treat- p=0.004). AUC trended lower (p=0.086) and Cmax was lower after ID vs. SC ment can improve PPG levels even compared to analog insulin injection with- injection (p=0.033). AUC and Cmax were reduced by leakage or absence of out site treatment. bleb after ID injection (p=0.011), while Tmax was not (p=0.65), by Wilcoxon Figure 1. PPG Levels With (Test = RHI Insulin) and Without (Control=Analog rank sum test. Mean glucagon Tmax was not different after ID vs. SC (15.6 Insulin) the Use of the InsuPad Device. vs. 16.6 min p=0.63). AUC and Cmax were higher for SC (p<0.000) vs. ID and were reduced by absence of bleb formation after ID (p=0.002, 0.003), while Tmax was not (p=0.06). Nonlinear mixed effects modeling was consistent with the as-observed results. Subjects with slower insulin absorption after SC delivery had a greater reduction in Tmax with ID delivery. This relationship was not as strong for glucagon. ID injection appeared to be sensitive to technique. POSTERS Therapeutics Clinical Diabetes/

1076-P Early Detection of Infusion Set Failure during Insulin Pump Therapy in Type 1 Diabetes MARZIA CESCON, EYAL DASSAU, DANIEL J. DESALVO, TRANG T. LY, DAVID M. MAAHS, LAUREL H. MESSER, BRUCE A. BUCKINGHAM, FRANCIS J. DOYLE III, Santa Barbara, CA, Stanford, CA, Aurora, CO, Denver, CO Infusion set failures resulting in prolonged hyperglycemia or diabetic ketoacidosis (DKA) can occur with insulin pump therapy in type 1 diabetes (T1D). Set failures are frequently characterized by variable and unpredict- able patterns of increasing glucose levels despite increased insulin infusion. Early detection of such failures may minimize the risk of prolonged hyper- glycemia and ketone formation, an important consideration for automated insulin delivery and closed-loop applications. A novel algorithm for early detection of the onset of a set failure was evaluated retrospectively using only CGM and insulin data without any infor- mation on meal intake or the timing or cause of infusion set failures. Twenty-three T1D subjects recruited at 2 clinical sites wore a Dexcom G4 Platinum glucose sensor and a Tefl on infusion set for 7 days or until there was a failure (defi ned as a glucose >250 mg/dL that failed to decrease at least 50 mg/dL in 1 hour, and/or serum ketones >0.5 mmol/L in the absence of infection, or an infection at the infusion site). Twelve weeks without set Supported By: The Leona M. and Harry B. Helmsley Charitable Trust failures from 4 patients were used to calibrate this algorithm and an addi- tional 18 weeks (13 with verifi ed set failures and 5 without) from 9 patients were used for validation. The algorithm identifi ed a failure 2.52 ± 1.91 days 1078-P ahead of the actual event as recorded by the clinical team, with 6 TP, 2 FP, Effect of an Insulin Infusion Site Warming Device on Insulin Phar- 6 FN, 4 TN corresponding to 50% sensitivity, 66% specifi city and 55% ac- macokinetics in a Closed-Loop System curacy. If set failure alarm had been activated in real time, the average time NEHA S. PATEL, STUART A. WEINZIMER, GABBY BITTON, BENYAMIN GROS- >180 mg/dL would be reduced from 82.7 ± 40.9 hours/week (without alarm) MAN, JENNIFER L. SHERR, CAMILLE MICHAUD, EILEEN TICHY, LORI CARRIA, to 58.8 ± 31.1 hours/week (with alarm), corresponding to a potential 29% WILLIAM V. TAMBORLANE, EDA CENGIZ, New Haven, CT, Jerusalem, Israel, Min- reduction in time spent >180mg/dL. neapolis, MN A novel method for early detection of infusion set failure based on glucose The effectiveness of closed-loop (CL) systems in mitigating post-prandial sensor and insulin data alone demonstrated favorable results on retrospective hyperglycemia is limited by slow absorption of subcutaneously delivered data. This method may be implemented as an additional safeguard in a future insulin and prolongation of the “meal bolus” over several hours by the con- fully automated closed-loop system without requiring meal information. troller algorithm. We have shown that an insulin infusion site warming de- vice (InsuPatch, IP) accelerates insulin absorption when given as a standard subcutaneous bolus in an open-loop setting. However, the effect of IP on the 1077-P kinetics of insulin in CL setting has not been studied. Comparison of the Intradermal vs. Subcutaneous Delivery of Insulin Nine T1D subjects (age 20±7y, duration 11±9y, A1c 7.4±0.7%) underwent and Glucagon in T1DM two 24 hour periods of CL control using Medtronic ePID+IFB controller: with- MANASI SINHA, TIAN YU, CATHERINE M.T. SHERWIN, MALLORY A. HILLARD, out (CL-NoIP) and with insulin infusion site skin warming (CL+IP) to 400C. MICHAEL G. SPIGARELLI, STEVEN J. RUSSELL, Boston, MA, Salt Lake City, UT Meals were identical for both conditions and were accompanied by small The objective of this study is to compare insulin and glucagon pharma- manual insulin boluses (0.08 units/kg). Insulin levels were measured every cokinetics after intradermal (ID) injection with an array of three 0.6 mm mi- 30-60 minutes.

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Peak insulin levels, time to peak, AUC, time to ½ peak rising and falling were were as follows: age, 31±17.7, [9, 65] yr; diabetes duration, 17±13.1, [2, 51] similar in both conditions (Table). Mean blood glucose was lower with vs. yr; pump use, 6±3, [0.7, 14] yr; A1C, 7.6±0.84, [5.5, 9.7]%, and BMI, 23.5±3.9, without IP (123±13 vs. 129±13 mg/dL, p=0.01), but prandial glycemic excursions [16.7, 32.6] kg/m2; 46% were female. Provisional data from 38 subjects were similar under both conditions. Total insulin delivered per meal was similar using the system for 30 days is given in the Table. The mean programmed under both conditions (10.2 CL+IP vs. 10.0 NoIP). Skin warming with IP did not threshold value was 57.3±4.3 mg/dL, the mean pump stoppage time was result in faster insulin kinetics in a CL setting. Larger manual prandial insulin 58.1 min (range, 0.32 to 120 min), and the mean SG nadir following pump doses may be necessary for optimal effect of infusion site warming. stoppages was 69.4 mg/dL. A total of 61% of SG values were in the 70-180 Table. mg/dL range. SG values avoided the low programmed threshold following 87% of the pump stoppages. Patient questionnaire results suggested that Peak Insulin Time to Peak AUC – 5h Time to ½ Time to ½ the subjects found the system useful and unobtrusive. There were four mild (uU/mL) Insulin (hrs) (uUxhr/mL) Peak rising (hr) Peak falling (hr) adverse events (2 skin reactions, 1 cold, and 1 urinary tract infection). The CL-NoIP 60.2 2.1 95.4 0.6 4.7 PLGM feature as implemented in the MiniMed 640G system helped to pre- CL+IP 64.3 2.3 99.0 0.7 4.5 vent hypoglycemia in patients with T1DM. P-value 0.15 0.32 0.71 0.30 0.38 Table. MiniMed 640G System Performance. Supported By: National Institutes of Health; JDRF Subjects N = 38 PLGM subject-days (PLGM events) 965 (2066) 1079-P Self-monitored blood glucose (SMBG) per subject-day 3.5 ® The Clinical Impact with V-Go Based on Baseline Basal Insulin Calibration SMBG per subject-day 1.2 Doses DIANNE FETCHICK, ROSEMARIE LAJARA, CARLA NIKKEL, San Antonio, TX, Plano, Paired SMBG/SG values 4519 TX, Bridgewater, NJ Mean Absolute Relative Difference (ARD) (%) 9.8 Optimal insulin therapies for the treatment of diabetes mimic the body’s Median ARD (%) 5.9 physiologic release of insulin providing fasting and prandial coverage. Ad- Supported By: Medtronic, Inc. ministering basal-bolus (BB) therapy can be complex and inconvenient, which can delay insulin intensifi cation resulting in poor glycemic control. POSTERS To date, no data has been published for patients (pts) with diabetes receiv- 1081-P Therapeutics ing basal insulin (BI) injections (+ non-insulin glucose lowering agents) and Direct and Reliable Tuning of Bolus Calculators Using CGM, Meal Clinical Diabetes/ evaluating if the BI dose at baseline impacts clinical results when switched and Insulin Data to a fi xed basal rate and titrating bolus dosing with the V-Go Disposable FLORIAN REITERER, HARALD KIRCHSTEIGER, GUIDO FRECKMANN, LUIGI DEL Insulin Delivery Device (V-Go). An analysis was conducted comparing clinical RE, Linz, Austria, Ulm, Germany results in 40 pts with elevated A1c’s switched from BI therapy to BB delivery Introduction: T1DM patients determine insulin needs using patient and with V-Go. Two analyses from a large EMR database were conducted, with daytime specifi c values for insulin to carbohydrate ratio (CIR) and insulin sen- stratifi cation by BI <50 or >50 U/day and BI <0.5 U/kg or >0.5 U/kg. sitivity (ISF). They are determined by skilled diabetologists using high quality Following a mean of 94 days on V-Go all pts achieved signifi cant improve- data and need to be modifi ed until good glucose control is achieved. We ment in A1c regardless of BI dose at baseline. Pts on lower baseline BI doses propose a method to automatically estimate CIR and ISF values. experienced the most weight gain and greatest increase in total daily dose Methods: Patient and daytime specifi c CIR and ISF are obtained directly (TDD) on V-Go. Pts on higher baseline BI doses had robust A1c reductions from continuous glucose measurement, insulin, and meal carbohydrate data despite less total insulin when the TDD was redistributed with V-Go. Provid- by an identifi cation procedure based on a model of the glucose insulin me- ing fasting and prandial coverage with V-Go was simple and effi cacious for tabolism. Clinical data (40 patients) were used to test the method. Validation pts on lower and higher doses of BI dose at baseline. was done by comparing estim. to patient/meal specifi c values used by pa- Table. tients which provided a reasonable control (HbA1C 7.8 +/- 1.2%). Results: CIR, ISF estimates are in very good agreement with patient val- ues. The fi gure shows the distribution of estim. vs. clinical values. The 25% quantile, median, 75% quantile are 0.94, 1.06, 1.21 (CIR) and 0.74, 0.87, 1.01 (ISF). Underestim. ISF could be explained by intentional overestim. of patient ISF to reduce hypoglycemic risk. The plot shows results using 5 days of data, for 70% (19%) of patients, good agreement is achieved after 3 (1) days. Conclusions: The method potentially eases determination of reliable pa- tient and daytime specifi c CIRs and ISFs, can assist health care professionals and can automatically analyze recorded data.

1080-P Performance of the Predictive Low Glucose Management Feature of the MiniMed 640G System in a User Evaluation Study PRATIK CHOUDHARY, BIRTHE S. OLSEN, IGNACIO CONGET, LINDA VORRINK, JOHN J. SHIN, SCOTT W. LEE, FRANCINE R. KAUFMAN, London, United Kingdom, Herlev, Denmark, Barcelona, Spain, Tolochenaz, Switzerland, Northridge, CA The predictive low glucose management (PLGM) feature is intended to reduce the risk of hypoglycemia by stopping insulin delivery before sensor glucose (SG) values reach a programmed threshold. It was evaluated on a new pump platform, the MiniMed 640G system, with second-generation En- lite sensors (Medtronic, Northridge, CA, U.S.) for usability and hypoglycemia avoidance. Three study sites in Europe enrolled subjects with T1DM. The mean±SD and [minimum, maximum] values for various baseline parameters

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1082-P Table. Continuous Subcutaneous Insulin Infusion: Better Metabolic Con- trol than Multi-dose Insulin, but Similar Obstetrics Outcomes in Pregestational Diabetes Mellitus Type 1 DOMINGO ACOSTA-DELGADO, ANTONIO JESÚS MARTÍNEZ ORTEGA, EDUARDO MORENO REINA, LUCAS CERRILLOS GONZÁLEZ, MARIA ASUNCIÓN MARTÍNEZ BROCCA, RAQUEL GUERRERO VÁZQUEZ, MIGUEL ANGEL MANGAS CRUZ, AL- FONSO PUMAR LÓPEZ, FERNANDO LOSADA VIÑAU, FEDERICO RELIMPIO AS- TOLFI, ALFONSO MANUEL SOTO MORENO, Seville, Spain Pregestational Diabetes Mellitus type 1 (PGDM1) requires tight glucose control before and during pregnancy. To achieve this, Continuous Subcuta- neous Insulin Infusion (CSII) is often needed. Nevertheless, several studies have reported not global differences between CSII and Multi-Dose Insulin (MDI). To compare clinical outcomes between CSII and MDI, we analized our results in PGDM1 women between 1990-2014. Table 1 records clinical results with signifi cant differences between CSI and MDI Groups. There weren’t signifi cant difference between groups in: Hba1c at 2nd-3rd trimes- ter (6% vs. 6,1% - 6,2% vs. 6,05%) ; Body Mass Index: 24.23 vs. 25.01, 26.16 vs. 27.29, and 29.56 vs. 30.11 in 1st-2nd-3rd trimester respectively; weight gain during pregnancy (Kg) +12.3 vs. +12.9. Miscarriage: 9 vs. 23 (11.7% vs. 4.8%); stillbirth: 0 vs. 1 (0% vs. 0.2%); Caesarean section: 39 (50.64%) vs. 207 (43.57%); Newborn weight: 3515 vs. 3582 grams; macrosomia: 9 (17.3%) vs. 23 (4.8%); low birth weight: 4 (5.2%) vs. 9 (1.9%); and fetal malforma- tions: 0 vs. 4 (0,83%). In conclusion, in our series, CSII allows better glucose control in the preconceptional period and in the fi rst trimester of pregnancy and lower insulin requirements prior and during pregnancy in PGDM1 wom- POSTERS Therapeutics en, despite more age and diabetes duration. We observed similar pregnancy Clinical Diabetes/ outcomes between CSII and MDI. Table 1. CSII vs. MDI in DMPG Type 1. Total sample n= 556 CSII MDI p 13.8% (77) 86.2% (479) Age at pregnancy (Years) 33 31 <0.05 1084-P Diabetes evolution time from onset to pregnancy (Months) 245 181 <0.05 Gender Differences in the Association of Continuous Subcutaneous HbA1c (%) Pregestational 6.7 7 <0.05 Insulin Infusion (CSII) with Severe Hypoglycemia (SH) in Type 1 Dia- Week 8-12 6.5 ] 6.6 <0.05 betes (T1D) Participants in the Pittsburgh Epidemiology of Diabetes Complication (EDC) Study Insulin requirements (IU/Kg) per trimester fi rst 0.55 0.66 GEORGIA PAMBIANCO, TREVOR J. ORCHARD, Pittsburgh, PA second 0.58 0.78 <0.05 Severe Hypoglycemia is a feared complication of type 1 diabetes and a major third 0.75 0.94 obstacle to achieving optimal glycaemic control. The DCCT trial confi rmed the importance of maintaining strict glycaemic control to prevent complications, but also demonstrated a three-fold increased risk of SH in the intensive group. 1083-P As there is some evidence that CSII can reduce SH in comparison with multiple Glycemic Effect with V-Go® Based on Baseline A1c daily injections (MDI), we examined data collected over the 22 yr follow up ROSEMARIE LAJARA, DIANNE FETCHICK, CARLA NIKKEL, Plano, TX, San Antonio, of the Epidemiology of Diabetes Complications study of childhood onset T1D TX, Bridgewater, NJ (mean age 28 and duration 19 years, n=658 at baseline (1986-88)) to determine The purpose of this analysis was to evaluate the change in A1c based if CSII was associated with a lower proportion of self-reported history of SH on baseline A1c across different background treatment regimens [multiple in the past two years. Insulin regimen was categorized as: <=2 injections daily, daily insulin injections (MDI), basal insulin therapy (Basal), or naïve to insulin MDI >=3 insulin injections daily, or CSII. SH was defi ned as unconsciousness, (Naïve)] for patients (pts) with diabetes mellitus (DM) switched to V-Go Dis- requiring assistance and/or having a low blood sugar (<50 mg/dl) without rec- posable Insulin Delivery Device (V-Go). ognition. The number of participants reporting SH varied with insulin regimen Data was collected using an electronic medical records database from a over 5,758 person years of follow up. There were 115.4 SH events per 1000 large specialized diabetes system in 151 pts (mean age, 52y; duration of DM, person years (PY) for participants on <=2 insulin injections daily, 115.6 per 1000 13.8y). Age and duration were similar between groups with the exception of PY for those on MDI, and 95.6 per 1000 PY for those on CSII. These differences the Naive group which was younger than the Basal group (p=0.0090) and had were not statistically signifi cant (p=.26). However, in men (34% of whom ever a shorter duration of DM compared to the MDI group (p=0.0046). used CSII), SH was less frequent in CSII users (51.1 per 1000 PY) than MDI Change in A1c and insulin dosing at 1st follow-up and 2nd follow-up, mean (114.3 per 1000 PY) and <=2 injections (107.9 per 1000 PY). These differences exposure 99, 180 days, respectively, were evaluated in groups by baseline were signifi cant (p=0.0001). SH rates for female participants (50% of whom A1c range (7.2%-8.9%, 9.0-10.4%, 10.5-13.9%). ever used a pump), however, did not differ by treatment regimen (CSII: 119 per All pts on V-Go therapy demonstrated progressively greater reductions in 1000 PY, MDI: 117 per 1000 PY, <=2 injections: 124 per 1000 PY p=0.88). These A1c as baseline A1c increased. Insulin dosing was similar between groups data suggest a gender difference in the potential impact of CSII on SH, which at 1st and 2nd follow-up for all A1c ranges. Pts on basal insulin or naïve to merits further investigation. insulin at baseline switched to V-Go demonstrated the greatest reduction Supported By: R01DK034818 in A1c. V-Go was effi cacious across all A1c ranges and mean insulin dosing was 1085-P similar regardless of baseline A1c. Based on insulin fi ndings, further studies In Vivo Flow Evaluation and Correlation to Insulin Pharmacokinet- are warranted to determine if A1c improvement is related to better insulin ics of Continuous Subcutaneous Insulin Infusion Sets adherence, coverage and/or delivery by continuous infusion. NATASHA G. BOLICK, DIDIER R. MOREL, JAVIER ALARCON, WENDY D. WOOD- LEY, LUWANDA C. CHANDLER, SUVADRA S. GERTH, B. WAYNE BEQUETTE, RON- ALD J. PETTIS, Research Triangle Park, NC, Pont-de-Claix, France, Troy, NY Continuous subcutaneous insulin infusion (CSII) sets exhibit “silent” occlu- sions characterized by in-line infusion pressure excursions that may indicate fl ow interruptions, but are below insulin pump alarm thresholds. A novel in- fusion set is in development to stabilize fl ow. This study correlates in vivo set

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A278 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULIN DELIVERY SYSTEMS

fl ow performance with insulin pharmacokinetics (PK) to establish predictive The percentage of time in range pre-V-Go was 45.1% vs. 56.2% with V-Go. models of insulin delivery and uptake. No patient had a BG below 50 mg/dl. The 9 PM BG value showed marked Infusion pressure and insulin PK were simultaneously monitored up to 6 improvements without resultant morning hypoglycemia. Additional studies hours during insulin lispro infusion at clinically relevant rates (1U/hr basal for are needed to evaluate V-Go in LTC patients. 4 hours; 4U/bolus) in 11 nondiabetic Yorkshire swine using investigational 28G, 6mm, side-ported polymer catheter and commercial CSII sets. Insulin levels were analyzed via a lispro-specifi c radioimmunoassay from standardized, timed blood draws. In-line infusion pressure was analyzed with a proprietary algorithm to identify fl ow interruptions and then used as input functions to a multi-compartmental PK model. The investigational set showed reductions of 88-95% (depending on al- gorithm sensitivity settings) in mean percent time of fl ow interruption com- pared to the commercial polymer catheter set (p ≤ 0.01 per non-parametric testing). Incorporating fl ow performance data into PK models led to improve- ment of PK prediction relative to measured lispro levels for devices inten- tionally occluded as a positive control (p < 0.05 per non-parametric testing). Subcutaneous insulin infusion is affected by multiple parameters includ- ing sub-optimal CSII set delivery. The investigational set showed improved insulin fl ow reliability relative to the commercial polymer set based on de- tectable silent occlusion reduction. Incorporating pressure information to indicate fl ow interruption improved PK modeling. Stabilizing infusion pres- sure and reducing fl ow faults may enable more predictable and consistent insulin delivery.

1086-P

A Continuous Insulin Infusion (CSII) Program Focused on Active Pa- POSTERS tient Involvement: Clinical Outcomes Therapeutics Clinical Diabetes/ GLORIA CÁNOVAS MOLINA, AZUCENA RODRIGUEZ ROBLES, EVA M. DELGADO OLIVENCIA, SORALLA CIVANTOS MODINO, EMILIA CANCER MINCHOT, ROSA VILLAR VICENTE, Madrid, Spain There is extensive evidence of glycemic improvement with CSII. However, there is a great variability in the outcomes of different CSII programs, and limited information on the reason for the differences. We hypothesized that a CSII program focused on active patient involve- ment will result in better clinical outcomes. We started a CSII program in our hospital whose major aim was to empower patients to self-manage their diabetes by an exhaustive training. Training is conducted in two steps. The fi rst phase is carried out in group sessions by a diabetes nurse educator. Patients attend 2 hours training Supported By: Valeritas sessions weekly or biweekly for 2-3 months. Issues discussed are pump mechanics, pump site care, basal and bolus insulin concept, carbohydrate 1088-P counting, insulin to carbohydrate ratios, insulin sensibility and prevention Performance Qualifi cation of a Novel Continuous Subcutaneous and management of ketoacidosis and hypoglycaemia. We focus on applied Insulin Infusion Set Using Medical Imaging knowledge and encourage patients to actively adjust all pump parameters. NATASHA G. BOLICK, DIANE E. SUTTER, BRIAN PFLUG, LAURENCE HIRSCH, The second phase is driven by an endocrine MD in individual interactive ses- BRUCE W. BODE, RONALD J. PETTIS, Research Triangle Park, NC, Franklin Lakes, sions, weekly at the beginning and ad-hoc later for 2-3 months. NJ, Atlanta, GA A retrospective analysis was performed to evaluate clinical outcome. Imaging of CSII sets and fl uid deposition has not been previously per- Data from 22 patients (6M, 16 F; mean age 38.4 y, range 27-60), who had formed. An investigational fl ow-stabilizing ported set for reducing infusion completed at least one year on CSII program, was collected. We used three pressure and other marketed sets were evaluated using multiple medical indicators: A1c, severe hypoglycaemia and ketoacidosis. imaging modalities to assess system performance in animal and human A1c was measured at baseline, 6 and 12 months after entering the pro- studies. gram. The results are: Baseline A1c: 8.39% (SD 0.86). 6 months A1c 6.96% In vivo swine fl uoroscopy of contrast media infusion provided visualiza- (SD 0.59). 12 months A1c 7.19 (SD 0.69). The mean reduction of A1c from tion of device placement, bolus depot patterning, and delivery faults such baseline was -1.43% at 6 months and -1.20% at 12 months, improving other as incomplete insertion and leakage. Contrast-fi lled polymer catheters were previously published (Mean reduction HbA1c 0,3-0,56%). visible in situ. The novel 28G, 6mm, ported polymer catheter with 30G intro- None of the patients suffered severe hypoglycaemia or ketoacidosis. ducer needle exhibited diffuse subcutaneous (SC) depot patterns. Despite having introduced recently the CSII program in our hospital the A corollary human MRI study of the investigational set in 8 non-diabetic observed outcomes are very favorable. We think that the major improve- adults demonstrated effective SC placement and placebo delivery across ment factor is likely to be an exhaustive training program focused on CSII multiple bolus volumes (2-20U) and various routine insulin infusion sites self-managing. (arm, thigh, abdomen, and gluteus). Depots were similar to preclinical obser- vations and indicated side-port fl ow with increased diffusivity in contrast to 1087-P denser depots observed from marketed sets (Figure 1). Initial Experience with the V-Go® Disposable Insulin Delivery De- Both fl uoroscopic and MR imaging techniques provide effective CSII char- vice in Long-Term Care acterization at relevant anatomical sites and may enable better comparative ALAN BOONIN, JOE MARTINEZ, SCOTT ABBOTT, NEELAM DAVIS, BRENDA BAL- device performance assessment. Catheter porting creates an auxiliary tis- INSKI, JERRY SAUTER, Dallas, PA, Bridgewater, NJ sue fl ow pathway that may reduce occlusion and stabilize fl ow. Glycemic variability and insulin dosing present a challenge in long-term care (LTC). V-Go provides a basal rate and on-demand bolus that simplifi es insulin administration. The objective of this analysis was to assess V-Go in LTC patients. A review of the fi rst 4 patients 31 days pre- and post- V-Go ini- tiation was done. Daily blood glucose (BG) readings were obtained at 4 time points at the same time each day. Effi cacy variables included time in range (100-200mg/dl) and change in daily BG. Patients, mean age 79 yrs, demon- strated improved BG control when switched to V-Go from insulin injections.

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A279 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULIN DELIVERY SYSTEMS

1089-P Sixty-one pts, 32 on multiple daily injections (MDI), 21 on basal insulin Insulin Administered by Needle-Free Jet Injection Advances Cor- (BI) therapy and 8 pts on non-insulin glucose lowering agents were evalu- rection of Substantial Hyperglycemia in Patients with Diabetes ated. Mean age was 52 yrs, weight 93 kg, duration of DM 14.8 yrs, and A1c HELENA M. DE WIT, ELSEMIEK E. ENGWERDA, CEES J. TACK, BASTIAAN E. DE 9.8%. Signifi cant and sustained A1c reductions were observed for all time GALAN, Nijmegen, Netherlands points on V-Go with pts previously on BI and non-insulin agents demonstrat- Rapid correction of hyperglycemia in patients with diabetes is important ing the greatest reductions (-2.0, -3.6 from baseline, respectively). For the to reduce the hyperglycemic burden and prevent overcorrection resulting in 53 pts previously on insulin injections, switching to V-Go resulted in a 21% hypoglycemia and glucose fl uctuations. Insulin administered by jet injection decrease in TDD. Distribution of insulin was approximately 60% basal: 40% is more rapidly absorbed than when injected by a conventional pen, which bolus at initiation and was maintained across time. Pts switched to V-Go may be advantageous for the correction of substantial, potentially hazard- had improved glycemic control and the majority of pts reduced their TDD. ous, hyperglycemia. We compared the effi cacy of jet and conventional pen Glycemic improvement was sustained without the need to increase insulin injection for the correction of substantial hyperglycemia. Adult patients over time. with type 1 diabetes (n=10) or insulin-treated type 2 diabetes (n=10) were enrolled in a randomized, controlled, cross-over study. On two separate occasions, patients were instructed to reduce their insulin dose to achieve substantial hyperglycemia (18-23 mmol/l). Subsequently, insulin aspart was administered by jet injector or conventional pen, in a dose based on estimated individual insulin sensitivity. Pharmacologic profi les were derived from plasma glucose and insulin levels, measured for six hours after injec- tion. Jet injection advanced the absorption of insulin as refl ected by shorter time to peak insulin levels compared to conventional injection (40.5±3.2 vs. 76.8±7.7 minutes, P<0.001). Consequently, the time needed to achieve plasma glucose values to drop ≥10 mmol/l was shorter (147.9±14.4 vs. 192.5± 13.6 minutes; difference 44.6 minutes [95% CI 4.3 to 84.8]; P=0.03) and the hyperglycemic burden during the fi rst two hours was reduced (2042±37.2 vs. 2168±26.1 mmol·min·l-1; P=0.01) when insulin was administered by jet rather POSTERS Therapeutics than by conventional injection. The risk for hypoglycemia was not altered. Clinical Diabetes/ Factors associated with greater benefi t of jet injection were higher insulin dose, higher BMI and type 2 diabetes. We conclude that using jet injection for administration of rapid-acting insulin accelerates the correction of sub- 1092-P stantial hyperglycemia in patients with insulin-requiring diabetes, especially eGlycemic Management System Safely Achieves Rapid and Sus- when obese. tained Glycemic Control in Kidney Transplant Patients and Reduces Supported By: European Pharma Group BV Risk of Hypoglycemia Compared with Standard Insulin Infusion JOSEPH ALOI, JAGDEESH ULLAL, ROBBY BOOTH, HARRY HEBBLEWHITE, RAY- 1090-P MIE MCFARLAND, MELANIE MABREY, Winston-Salem, NC, Norfolk, VA, Green- Comparison of Inpatient Glycemic Control with Detemir vs. Glargine ville, SC, Rocky Mount, NC as Basal Insulins in Non-critically Ill Patients with Type 2 Diabetes Management of patients with steroid-induced hyperglycemia can be dif- Mellitus fi cult. Intravenous insulin infusions are generally recommended inpatient NITIN TRIVEDI, BASIM BARAGABA, ABDULMAJEED ALBARRAK, Worcester, MA, for fl exibility with dynamic insulin requirements. Blood glucose control in Baltimore, MD patients undergoing renal transplant is particularly diffi cult as high-dose The objective was to compare the glycemic control with two long acting steroids, immunosuppression and renal function each play an important but insulin analogues, glargine and detemir, as basal insulins to treat hypergly- varying contribution to insulin resistance. cemia in hospitalized patients with type 2 diabetes mellitus. This study was We analyzed records of 22 patients treated with Glucommander IV™ (GM), a retrospective analysis of non-critically ill patients hospitalized to the medi- a computerized IV insulin dosing algorithm, to examine the ability of GM to cal fl oor with the primary or secondary diagnosis of type 2 diabetes mellitus. safely achieve glycemic targets versus standard insulin infusions (SII). Pa- We randomly selected patients admitted during the years 2011 and 2012. tients included had 1 blood glucose (BG) > 200 mg/dL or 2 BGs > 180 mg/dL Following hospitalization, glargine was used as the preferred basal insulin in after renal transplant and were treated with GM at some time during the post- 2011 (glargine group), which was replaced by detemir in 2012 in our hospital operative period. Glucose results were collected for the patient’s entire IV (detemir group). Patients in both groups were treated with glargine before insulin treatment. Prior to treatment with GM, SII patients’ mean BG was 200 hospitalization. The mean blood glucose levels by point of care blood glucose mg/dL ± 87; during treatment with GM patients’ mean BG of 163 mg/dL ± 57. testing at 4 different points, glycemic excursions, and hypoglycemic events Patients continuing IV insulin with SII after GM discontinuation had a mean compared between groups. The mean length of hospital stay, total basal BG of 178 mg/dL ± 60. Hypoglycemia <70 mg/dL was 2% prior to treatment insulin dose, and insulin dose adjustments were also compared between with GM, 0.7% during treatment with GM, and 1% after discontinuation of the two groups. Fifty four and 56 patients were included in the glargine and GM. Percentage of glucose results in goal was 68% with GM versus 45% the detemir groups respectively. Baseline characteristics are similar in both before and 55% after. groups. The mean blood glucose levels at 4 point of care glucose testing Renal transplant patients treated with Glucommander™ achieved a higher were signifi cantly higher in the detemir group compared with the glargine percentage of BG results in goal, lower mean glucose levels, less hypoglyce- group at all time points (p 0.03). The length of stay and hypoglycemic events mia, and lower glucose variability compared to patients on SII. were similar in both groups. The study showed that insulin glargine provided better glycemic control compared to detemir insulin in non-critically ill pa- 1093-P tients with type 2 diabetes mellitus admitted to the general medical fl oor. The Site Rotation Is a Major Factor for the Good Control in CSII of Type 1 Diabetes, Not Related to Which Rapid-Acting Insulin—From 1091-P the Switching Study of Rapid-Acting Insulins Improved Glycemic Control and Reduced Insulin Requirements over TOMOYUKI KAWAMURA, MASAKAZU HIROSE, KAYAKO HASHIMURA, YUKO Time with V-Go® in Patients with Diabetes HOTTA, YONEO KASHIHARA, SHIGEO AONO, MAYUMI AOMO, TAKASHI HI- DIANNE FETCHICK, ROSEMARIE LAJARA, DONNA DOHERTY, CARLA NIKKEL, GASHIDE, TOMOMI HASHIMOTO, Osaka, Japan, Nishinomiya, Japan, Toyonaka, San Antonio, TX, Plano, TX, Bridgewater, NJ Japan The purpose of this retrospective analysis was to evaluate the change Now three rapid acting insulins (RAs) are available. Their action times in glycemic control and insulin dosing for patients (pts) not at glycemic tar- were reported to be different. However, the major difference among them gets on previous therapies, switched to the V-Go Disposable Insulin Deliv- on clinical fi eld was not observed. So far, no study focusing on the relation- ery Device (V-Go). Data was collected using an electronic medical records ship with the site rotation of infusion set and three RAs in CSII was reported. database from a large specialized diabetes system. Pts with at least three The objective of this study was to identify the effect of site rotation of infu- A1c follow-up results (FR) post V-Go initiation were included to evaluate sus- sion set in CSII and three RAs on blood glucose control in type 1 diabetes tained effectiveness. with CSII. Subjects were 35 type 1 diabetes patients with CSII in our hospi-

For author disclosure information, see page A810. & Guided Audio Tour poster ADA-Funded Research

A280 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—NON-INSULIN INJECTABLES tal. We provided them a diary which contains a body map and asked them A total 325 patients in 387 admissions were treated on the CII protocol to record the frequency and the site number in a body map of site rotation. (age 49.9+/-16.5 years; male/female 166/159), 38.5% were treated with cor- Then the RA switching study was carried out. Fourteen patients used glulisin ticosteroids and 21.9% had a history of diabetes. There were a total of 5,674 (G), 8 used aspart (A), and 13 used lyspro (L). After 1 months of the running BG values while on the infusion protocol and mean length of time on CII was periods, insulin was switched to another; from G to L, from A to L, and from 28.9 hours. Mean BG while on CII 182 mg/dL. Based on patient-day analysis, L to G. After 4 month, RA was switched again to an original insulin. Fur- hypoglycemia (BG < 70 mg/dL) and severe hypoglycemia (BG < 40mg/dL) oc- ther 4 months later, data were collected. The main end-point is HbA1c, the curred in 5.3% and 0.68% of patient-days, respectively. Total ICU utilization second end-points were site rotation, severe hypoglycemia, DKA frequency, has been reduced by 466 days among these patients. ITR-QOLc, and the patient preferable insulin. The mean of HbA1c among the Analysis of the UTSW Medical Center noncritical care continuous insu- subject was 8.2+/-1.1 at the beginning. There was no difference of HbA1c re- lin infusion protocol reveals very low rates of hypoglycemia, decrease ICU lated to which RA used. The switching of RAs have not affected on the blood utilization, and rapid correction of hyperglycemia once started on infusion. glucose, site rotation, hypoglycemia, DKA, and QOL. The mean frequency of Utilizing a dextrose infusion to prevent hypoglycemia in combination with site rotation was 8.8 +/- 1.2 times per month and the mean number of sites continuous insulin infusion is an innovative approach to treating hyperglyce- for the infusion set in the body map were 12+/-2.2 among all subjects. mia in the inpatient setting in a safe and effective manner. The frequency of site rotation and the number of sites were signifi cantly related to HbA1c (P< 0.05). Favorite insulin of the patient varied, and the defl ection in particular RA was not observed. In conclusion, the site rotation CLINICAL THERAPEUTICS/NEW TECHNOLOGY— of infusion set was not affected by which used RAs but signifi cantly affected NON-INSULIN INJECTABLES on blood glucose control. The education of site rotation is a major subject for type 1 diabetes patients with CSII. Guided Audio Tour: New Injectable Therapies Other Than Insulin (Posters: 1094-P 1096-P to 1103-P), see page 15. Blood Glucose Control Using Computer Guided Glucose Management System in Allogeneic Hematopoietic Cell Transplant Recipients & 1096-P LENISE TAYLOR, CORA ESPINA, RAFIC FARAH, EUNPI CHO, KEVIN COLEMAN, International Differences in the Use of Non-insulin Medications as

JUAN PINELLI, SHELLY MENTZER, JOSHUA EPWORTH, LORI JARRET, TED GOOLEY, Adjunctive Therapy in Type 1 Diabetes POSTERS PAUL O’DONNELL, IRL B. HIRSCH, MERAV BAR, Seattle, WA, Pittsburgh, PA KELLEE M. MILLER, JULIA M. HERMANN, DAVID M. MAAHS, MICHAELA RIEDL, Therapeutics Clinical Diabetes/ Allogeneic hematopoietic cell transplantation (HCT) is the only potential LINDA A. DIMEGLIO, ROY W. BECK, REINHARD W. HOLL, Tampa, FL, Ulm, Ger- curative treatment for patients with high-risk hematological malignancies. many, Aurora, CO, Vienna, Austria, Indianapolis, IN However, HCT is associated with up to 20-30% non-relapse mortality (NRM). We examined the use of non-insulin medications (meds) for blood glucose We have previously shown that malglycemia is associated with increased (BG) control in type 1 diabetes (T1D) patients in the U.S. T1D Exchange (T1DX) NRM (Hammer et al. Biology of Blood and Marrow Transplantation 2009). and German/Austrian DPV registries. Therefore, improving glycemic control may improve transplant outcome. The analysis included 30,325 DPV (mean age 19.8 yrs) and 16,893 T1DX In this prospective study we evaluated the feasibility of using Glucom- patients (mean age 25.5 yrs) with T1D duration ≥ 1 yr (mean duration 8.6 mander (an FDA approved Computer-Guided Glucose-Management System; and 13.6, respectively) who had data available between 9/1/2013 and CGGM) in order to achieve improved glucose control in hospitalized HCT pa- 12/1/2014. tients. Inclusion criteria were adult patients after allogeneic HCT with either Non-insulin meds were rarely used in children < 13 yrs (0.4% in T1DX and 2 episodes of blood glucose (BG) >180 mg/dL or 1 episode of BG >250 mg/dL. 0.2% in DPV). Use of any non-insulin med was higher in T1DX vs. DPV in 20 patients have been treated. 19 patients had active graft versus host dis- patients 13-<18, 18-<26 and 26-<50 yrs (P<0.001 for all) but not in patients ≥ ease (GVHD) at time of study enrollment, treated with prednisone at median 50 years (P=0.12). Metformin was the most commonly prescribed med with daily dose of 100 mg (range, 10-200), and 9 patients received total parenteral higher use in T1DX among 13-<18 and 18-<26 year olds (P<0.001) but higher nutrition (TPN). Patients were on study for a median of 44.1 hours (range, use in DPV for adults ≥ 50 years (P=0.001). In adults, GLP-1 use was higher 11.9 to 196.5 hours). Median BG at enrollment was 240 mg/dL. All patients in T1DX (P<0.001) but DPP-4 use was higher in DPV (P<0.001). Non-insulin reached the target BG of 100-140 mg/dL, which was achieved after a median med use was associated with age, T1D duration, and BMI z-score in both of 7.5 hours. The median percent of BG values in this range per patient was registries, female gender in T1DX, and total daily insulin dose per kg and 47%, and was 84% for range of 100-180 mg/dL. After BG reached the target migration history in DPV. range, median BG level per patient was 133 mg/dL (range of 116 to 139) com- The use of non-insulin meds for BG control in T1D patients is uncommon pared to 187 mg/dL (range 122 to 383) for historic controls. 5 patients had 1-3 in T1DX and DPV registries. Metformin is the most common non-insulin med events of BG < 70 mg/dL, and no patients experience BG level < 40 mg/dL. prescribed in both registries. International comparison of current practice In conclusion, our study demonstrates that despite high-doses of steroids, for prescribing non-insulin meds allows for subsequent discussions of evi- TPN, and unpredictable oral intake, tight control of BG in HCT patients using dence-based care from the perspective of both registries. CGGM is feasible. Given the previously identifi ed association between mal- Table. glycemia and increased NRM, it is of interest to conduct prospective studies to evaluate if improved glycemic control can reduce NRM in HCT patients. 13- 18- 26- ≥ 50 years DPV/T1DX DPV/T1DX DPV/T1DX DPV/T1DX 1095-P N 11405/5006 3030/2935 2411/2991 2630 / 2328 Analysis of the Safety and Effi cacy of the University of Texas South- Any non-insulin med 1.1% / 2.6% 1.4% / 4.4% 5.1% / 10% 8.4% / 9.7% western Medical Center Insulin Infusion in the Noncritical Care Metformin 1.1% / 2.5% 1.4% / 3.5% 4.6% / 6.1% 6.9% / 5.0% Setting DPP-4 0 / 0 0.3% / 0.3% 1.3% / 0.1% AMY DEGUEME, XILONG LI, BEVERLEY HUET, CHANHAENG RHEE, Dallas, TX GLP-1 0 / <0.1% 0 / 0.7% 0.1% / 1.5% While many studies on inpatient diabetes management have focused on the critically ill population treated with insulin infusions, there is a lack of SGLT2 0.1% / 0.3% data published regarding the use of continuous insulin infusions (CII) in the Other 0 / 0.5% 0.3% / 3.1% 0.8% / 4.0% noncritical care population. Our University Hospital CII protocol combines Supported By: The Leona M. and Harry B. Helmsley Charitable Trust; German insulin and dextrose infusions as well as requiring consultation to the inpa- Federal Ministry of Education and Research tient diabetes service, allowing for decreased nurse to patient ratios, and having no time limit for running CII. This is a retrospective analysis of 325 patients in the noncritical care in- patient setting at the University of Texas Southwestern (UTSW) Medical Center who were treated with CII for at least one hour, from January 1, 2012 to December 31, 2013. Clinical outcomes evaluated include rates of blood glucose (BG) values between 70-180 mg/dL, hypoglycemic (BG < 70 mg/dL) and severe hypoglycemic (BG < 40 mg/dL) events while on infusion using patient-day analysis.

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A281 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—NON-INSULIN INJECTABLES

& 1097-P & 1099-P Short-Term Safety, Pharmacokinetic (PK) and Pharmacodynamic Effect of Cell-Free Mesenchymal Stem Cells Microvesicles (MVs) (PD) of AZP-531, an Unacylated Ghrelin (UAG) Analog in Healthy and and Exosomes Therapy on β-Cell Mass in Type 1 Diabetes Mellitus Overweight/Obese Subjects (T1DM) SORAYA ALLAS, THOMAS DELALE, BETTY NGO, MICHEL JULIEN, PIERRE SA- WAEL F. NASSAR, MERVAT EL-ANSARY, TAMER SHEHAB, MOSAAD ABDEL- HAKIAN, JAMES RITTER, AART JAN VAN DER LELY, THIERRY ABRIBAT, Écully, HAMEED, ABDELNASER SAAD, WAEL ESA, SAMEH SHAWKI, MARWA MO- France, Overland Park, KS, London, United Kingdom, Rotterdam, Netherlands HAMAD, MAHMOUD TEMRAZ, HEBA ADEL, Cairo, Egypt UAG and analog AZP-531 have been previously shown to favorably mod- Type 1 diabetes (T1D) is an immunological mediated disease. The clini- ulate glucose and fat metabolism in models of obesity and diabetes. We cal applications of cord blood stem cells and their microvesicles have been investigated the safety, PK and PD of AZP-531 after single and repeated sc regarded as a crucial means of intercellular communication and their abil- administration to humans. In a randomized, double-blind study, healthy sub- ity to ameliorate autoimmunity have increased enormously in recent years. jects (n=44, mean BMI=24 kg/m2) received a single ascending dose of 0.3, Twenty nine T1DM patients were enrolled into two groups; (group A) 20 pa- 3, 15, 30, 60 or 120 g/kg AZP-531 or placebo. Overweight/obese subjects tients, were treated with 2 doses of cell-free cord-blood mesenchymal stem otherwise healthy (n=32, mean BMI=31 kg/m2) received a multiple ascend- cells derived microvesicles and (group B) 9 patients, as matching placebo ing dose of 3, 15, 30 or 60 g/kg AZP-531 or placebo once daily for 14 days. In group. Participants in Group A exhibited improved HbA1c (6.67 ± 0.321 at 12 these subjects, blood glucose and insulin profi les were assessed on Day-1 weeks vs. 8.245 ± 0.72 at baseline with P ≤ 0.034), fasting C-peptide levels (baseline), Day 1 and Day 14 in addition to 24h interstitial glucose levels. (1.095 ± 0.215 at 12 weeks vs. 0.245 ± 0.069 at baseline with P ≤ 0.003) In both study populations, AZP-531 was well tolerated with no clinically and C-peptide response following a 75-g oral glucose tolerance test (1.817 ± signifi cant fi ndings with respect to laboratory evaluations, blood pressure, 0.27 at 12 weeks vs. 0.504 ± 0.065 at baseline with P ≤ 0.004). Patients of and cardiac assessments. PK parameters were overall comparable. Maximal treatment group A, exhibited signifi cant increases in plasma level of TGF-β1 AZP-531 concentrations were typically reached at 1h post-dose. Cmax and (26.18 ± 4.39 at 12 weeks vs. 3.68 ± 0.55 at baseline with P ≤ 0.001). Patients AUC were dose-proportional. Mean t1/2 ranged from 2 to 3h. At doses above of group A, had also exhibited signifi cant increase in plasma levels of IL-10 30 g/kg, quantifi able levels were measured up to 24h post-dose. Signifi cant from baseline of (3.8535 ± 0.662) to (13.33 ± 1.516) at 12 weeks (P ≤ 0.009). reductions vs. baseline (p<0.05) were observed over time in daily mean blood Participants of the control group B did not show signifi cant improvement in glucose levels in overweight/obese subjects at 15 and 60 g/kg and changes any of the previously mentioned parameters at any time point of the study POSTERS Therapeutics were signifi cant vs. placebo (p<0.05) on Day 14. Comparable fi ndings were period. Administration of (CF-CB-MSCs) microvesicles is safe and can ame-

Clinical Diabetes/ noted in mean 24h interstitial glucose with signifi cant reductions at 15, 30 liorate autoimmunity and regenerate β cell mass in T1DM patients. and 60 g/kg. Individuals with elevated post-prandial glucose at baseline ap- peared to be better responders. Mean insulin levels remained unchanged. & 1100-P A signifi cant reduction vs. baseline was noted in mean body weight in AZP- A Randomized, Double-Blinded, Placebo-Controlled, Phase I Trial 531 treated groups on Day 14 (p<0.0001) while changes in placebo were not to Determine the Safety and Induction of Antibody Response of an signifi cant. Data support a differentiated glucose-lowering product profi le Interleukin-1beta Vaccine in Type 2 Diabetic Patients associating improved insulin sensitivity and weight loss. Trial is underway in CLAUDIA CAVELTI-WEDER, KATHARINA TIMPER, ELEONORA SEELIG, CORNELIA patients with type 2 diabetes. KELLER, MARTIN OSRANEK, UTE LAESSING, GUNTHER SPOHN, PATRIK MAUR- Supported By: Alizé Pharma ER, PHILIPP MUELLER, GARY T. JENNINGS, JOERG WILLERS, PHILIPPE SAUDAN, MARC Y. DONATH, MARTIN BACHMANN, Basel, Switzerland, Zürich, Switzerland & 1098-P Interleukin-1beta (IL-1beta) is a key cytokine involved in infl ammatory ill- The Dual Amylin- and Calcitonin Receptor Agonist KBP-042 Acts nesses including type 2 diabetes. We developed and evaluated the safety Synergistically with Metformin on Glucose Control while Reducing and induction of antibody response (ELISA and neutralizing antibody assay) Weight and Improving Insulin Action of a novel vaccine against IL-1beta (CYT013-IL1bQb) in animal models and in SARA T. HJULER, SOFIE GYDESEN, KIM VIETZ ANDREASSEN, MORTEN A. KARS- a randomized, double-blinded, placebo-controlled Phase I trial in patients DAL, KIM HENRIKSEN, Herlev, Denmark with type 2 diabetes. Insulin sensitizers with a positive effect on weight that act synergistically Murine and simian preclinical trials showed prompt induction of IL-1beta with the fi rst line therapy Metformin are needed. KBP-042 is a dual amy- antibodies upon vaccination. In the clinical study involving 48 type 2 diabetic lin- and calcitonin receptor agonist, based on structure-activity analysis of patients, 6 staggered cohorts of 8 patients each (6 patients IL1bQb, 2 Place- the peptide back-bone of amylin and calcitonin. We evaluated KBP-042 as a bo) were treated with stepwise increasing doses and number of injections at treatment for T2D as monotherapy and in combination with metformin. Post- predetermined time points. CYT013-IL1bQb was safe and well-tolerated. IL- hoc, the effect of salmon calcitonin (sCT) on blood glucose levels in patients 1beta-specifi c antibody responses could be observed in most patients after with elevated FPG was evaluated. immunization with the vaccine. IL-1beta-neutralizing antibodies indicating 6 weeks old ZDF rats treated with: Vehicle, Metformin (400 mg/kg p.o.), the clinical relevance of the immune response, however, were only evident in KBP-042 (5.0 µg/kg s.c.) or combination for 9 weeks. Insulin tolerance test the highest dose group. There was preliminary indication of in vivo activity in (ITT) and oral glucose tolerance test (OGTT) were performed. Analysis of patients with neutralizing antibodies as apparent from decreased HbA1c and patients with diabetic FPG levels (>7.0mM) in a phase III study (n=180) for glucose levels. In summary, IL-1beta-vaccine may represent a novel treat- osteoarthritis exposed to sCT over a two-year period was performed. ment modality for the IL-1beta-dependent diseases such as type 2 diabetes. At two weeks, metformin reduced FPG by ~34% compared to vehicle Supported By: Cytos Biotechnology AG (p=0.17). Treatment with KBP-042 resulted a reduction of FPG ~58% com- pared to vehicle (p<0.01) with combination treatment at -68% reduction & 1101-P (p<0.001). After 9 weeks, metformin did not sustain effi cacy, while KBP-042 Inhibitors of Insulin-degrading Enzyme Improve Glucose Tolerance alone showed a ~28% reduction in FPG (p<0.05), a ~30% reduction in HbA1c in Rodents Primarily through Amylin Rather than Insulin (p<0.01) and the combination treatment a ~36% reduction in FPG (p<0.01), TIMOTHY B. DURHAM, JAMES TOTH, VALENTINE J. KLIMKOWSKI, ANGELA 53% reduction in HbA1c (p<0.001). The combination treatment was superior M. SIESKY, JULIA X.C. CAO, MICHAEL CHRISTE, DANA K. SINDELAR, JESLINE to monotherapy in both ITT and OGTT. In high fat diet rats, KBP-042 treat- T. ALEXANDER-CHACKO, VLADISLAV KISELYOV, GINGER Y. WU, YONG WANG, ment resulted in a 25% weight reduction over 8 weeks. In patients with el- SHERRY GUO, JEFFREY DIXON, JAMES MCGEE, RACHEL CAVITT, JOHN SCHIN- evated FPG, sCT reduced FPG by ~1mM when compared to placebo, p<0.01. DLER, STEFAN THIBODEAUX, NATHAN CALVERT, MICHAEL COGHLAN, M. DOD- In conclusion, KBP-042 treatment as adjunct to metformin was effi cient in SON MICHAEL, KYLE W. SLOOP, Indianapolis, IN reducing hyperglycemia, improving glucose tolerance and insulin action. The A cyclic peptide insulin-degrading enzyme (IDE) inhibitor has been shown synergistic action of KBP-042 and metformin suggests this mode of action to affect the plasma levels of insulin, amylin, and glucagon in mice at high to be of particular relevance for patients on metformin. KBP-042, improves doses (80 mg/kg ip). However, the relative importance of IDE catabolism to insulin action, while causing weight reduction, in contrast to other insulin the overall clearance and/or action of each hormone has yet to be fully es- sensitizers. tablished. Our goal was to explore the relative contribution of IDE mediated Supported By: Danish Agency for Science, Technology and Innovation catabolism on the in vivo clearance and action of insulin and amylin since these hormones have clear value for the treatment of diabetes in humans. Using X- ray crystallography, we developed small molecule inhibitors of IDE that act via

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A282 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—NON-INSULIN INJECTABLES a unique mechanism of action relative to previously published inhibitors. Our term safety (including hypoglycemia) and glycemic control by XMetA admin- compounds are all potent inhibitors of IDE action against insulin (IC50=4 nM) istered SC once weekly for up to 6 weeks. On average, weekly reductions in yet display a range of inhibitor activity for IDE mediated glucagon degrada- fasting hyperglycemia of approximately 30% were observed throughout the tion (IC50=3-150 nM) depending on inhibitor structure. In OGTT experiments study and a signifi cant reduction in HbA1c of 1.2% from the vehicle control with DIO mice, low doses of our IDE inhibitors (15 mg/kg SC) improve glucose baseline was observed. The therapy appeared well-tolerated, did not pro- tolerance (p <0.05), increase plasma amylin (p <0.05), and provide modest en- duce any injection site reactions, and safety fi ndings also included stable hancement of insulin levels (p=0.07). However, no signifi cant effects on insulin body weights and lack of clinical hypoglycemia. Not unexpectedly for a fully clearance or action were observed in rodent ITT experiments. In a defi nitive human mAb administered to monkeys, two out of nine monkeys developed euglycemic clamp experiment in somatostatin treated lean rats, we observed anti-human antibodies, the timing of which coincided with a loss of glycemic that our IDE inhibitors did not affect glucose infusion rates or hepatic glucose regulation. The combined outcomes of the rodent and monkey monotherapy production. Further, using our inhibitors we were able to show that in cell ex- studies, support further development of XMetA as a novel pharmacotherapy periments in vitro insulin clearance is mediated primarily by insulin receptor with broad utility in type 2 diabetes. mediated processes that are independent of IDE action. We believe our studies support the following conclusions: 1. IDE medi- ated catabolism of insulin is not the major mechanism of insulin clearance in Guided Audio Tour: GLP-1 Receptor Agonists—Delivery and Actions (Post- vivo; 2. IDE mediated clearance of amylin in vivo appears to be a signifi cant ers: 1104-P to 1111-P), see page 15. mechanism of amylin degradation; 3. Enhanced glucose tolerance in rodents due to IDE inhibition is mediated primarily through amylin action. & 1104-P Effect of the GLP-1 Receptor Agonist Lixisenatide on Glucagon & 1102-P Counterregulation to Hypoglycemia in Subjects with Insulin-Treat- Immune Modulation of Stem Cell Educator Therapy in Caucasian ed Type 2 Diabetes Type 1 Diabetic Subjects BO AHRÉN, JOHAN FARNGREN, MARGARETHA PERSSON, Lund, Sweden, Malmö, JESUS OTERO, ELIAS DELGADO, MARCOS PEREZ-BASTERRECHEA, JOSE MARIA Sweden GARCÍA-GALA, BEATRIZ SUÁREZ-ÁLVAREZ, EVA MARTINEZ REVUELTA, SILVIA Glucagon counter-regulation is critical for responding to hypoglycemia PEREZ-LÓPEZ, MARIA ALVAREZ-VIEJO, CARLOS LÓPEZ-LARREA, EDWARD GUIN- during glucose-lowering therapy in subjects with type 2 diabetes (T2D).

DI, YONG ZHAO, Oviedo, Spain, Madrid, Spain, Orlando, FL, Hackensack, NJ Recently, the GLP-1 receptor agonist lixisenatide (LIXI) was introduced for POSTERS Over the past 25 years, the failure of conventional immune therapies treatment of T2D, including as add-on therapy to basal insulin. In this study Therapeutics highlights the challenges we face in conquering the autoimmunity of type 1 we have explored the effect of LIXI on the glucagon response to insulin- Clinical Diabetes/ diabetes (T1D). The innovative approaches are needed. We established the induced hypoglycemia in subjects with T2D treated with basal insulin and Stem Cell Educator (SCE) therapy by using human cord blood-derived mul- metformin. The study was a single-center, double-blind, randomized, place- tipotent stem cells (CB-SCs). A closed-loop system that circulates patient’s bo (PBO)-controlled crossover study involving 18 subjects with T2D (11M, 7F) blood through a blood cell separator, briefl y co-cultures the patient’s lym- with mean age 55 yrs, diabetes duration 12 yrs, duration of insulin therapy phocytes with adherent CB-SCs in vitro, and returns the educated cells (but 7 yrs, HbA1c 7.7%, fasting blood glucose (FBG) 9.7 mmol/l and BMI 33 kg/m2 not the CB-SCs) to the patient’s circulation. Our clinical trial reveals that SCE who were treated with basal insulin (mean 39U/day) and metformin (mean provides lasting reversal of autoimmunity that allows regeneration of islet β 2.1g/day). Subjects received LIXI or PBO as add-on therapy for six weeks cells and improvement of metabolic control in Chinese and Caucasian subjects in random order with a four week washout in-between. After the six week with long-standing T1D. Notably, the percentage of naïve CD4+ T cells was periods, subjects underwent a two-step hyperinsulinemic hypoglycemic signifi cantly increased at 26 weeks after SCE treatment (P = 0.0042). The clamp at 3.5 mmol/l for 60 min followed by clamp at 2.8 mmol/l for 60 min. improvement was maintained through the fi nal follow-up at 56 weeks (P = HbA1c (7.3±0.2 vs. 7.5±0.3%; P=0.020) and FBG (8.3±0.6 vs. 9.3±0.7 mmol/l; + 0.0021). The percentage of CD4 central memory T cells (TCM) was markedly P=0.023) were lower after LIXI than after PBO. Fasting glucagon and the and constantly increased at 18 weeks (P = 0.018). In contrast, the percent- glucagon response to lowering glucose to 3.5 mmol/l did not differ signifi - + age of CD8 TCM cells was only temporarily improved at 18 weeks (P = 0.034). cantly between the treatments. However, the marked glucagon response by + + Both CD4 effector memory T cells (TEM) and CD8 TEM cells were considerably reducing glucose from 3.5 to 2.8 mmol/l was signifi cantly enhanced by LIXI decreased at 18 weeks (P = 0.03) and 26 weeks (P = 0.0024) respectively. Flow compared to placebo (10.5±2.3 and 4.9±2.3 pmol/l; P=0.042). We conclude cytometry revealed that SCE treatment acted very quickly on T cells via the that the glucagon response to mild hypoglycemia is preserved and the glu- phosphorylation of ZAP-70, a critical tyrosine kinase in the signal transduction cagon response to deep hypoglycemia is augmented during treatment with from T-cell receptor (TCR). Mechanistic studies confi rmed that co-culture with LIXI as add-on to basal insulin and metformin. This shows that the glucagon CB-SC can up-regulate the expression of co-inhibitory molecules the B- and counter-regulatory response to hypoglycemia is fully operative during treat- T-lymphocyte attenuator (BTLA) and programmed death receptor 1 (PD1) on ment with this combination, which could potentially explain its low risk of CD8β+NKG2D+ effector T cells and suppress their proliferation via CD270 and hypoglycemia. (NCT02020629). PD-L1 ligands on CB-SCs. Thus, Stem Cell Educator therapy functions as “an Supported By: Sanofi artifi cial thymus” that induces the immune tolerance through the action of au- toimmune regulator (Aire) and restores the immune balance and homeostasis. & 1105-P Supported By: American Diabetes Association (1-10-IN-33 to Y.Z.) Hyperglycemia Potentiates the Slowing of Gastric Emptying In- duced by Exogenous GLP-1 & 1103-P MARK P. PLUMMER, KAREN L. JONES, CAROLINE E. COUSINS, LAURENCE G. XMetA, a Novel Allosteric Antibody to the Insulin Receptor, Reduc- TRAHAIR, JURIS J. MEIER, MARIANNE J. CHAPMAN, MICHAEL HOROWITZ, es Hyperglycemia and Improves HbA1c in Type 2 Diabetic Cynomol- ADAM M. DEANE, Adelaide, Australia, Bochum, Germany gus Monkeys Acute hyperglycemia markedly slows gastric emptying. Exogenous GLP-1 PADMA BEZWADA, JINGSONG ZHAO, PAUL RUBIN, KIRK JOHNSON, Berkeley, CA also slows gastric emptying leading to diminished glycemic excursions. The XMetA is a fully human IgG2 monoclonal antibody (mAb) which acts as a primary objective was to determine whether hyperglycemia potentiates the partial agonist of the insulin receptor. In vitro, we have reported that XMetA slowing of gastric emptying induced by GLP-1 administration. Ten healthy stimulates metabolic vs. mitogenic pathways. In vivo, we have reported that participants were studied on 4 separate days. Blood glucose was clamped XMetA lowers glucose levels in diabetic rodents. We have now studied the at hyperglycemia using a 25% dextrose infusion (~12mmol/L; hyper; on 2 effi cacy and safety/tolerability of XMetA as a monotherapy following both days), or maintained at euglycemia (~6mmol/L; eu; on 2 days), between T=-15 acute and chronic dosing of nine obese, type 2 diabetic cynomolgus monkeys to 240min. During hyperglycemic and euglycemic days participants received who had diabetic profi les ranging from mild to advanced, and who were not intravenous GLP-1 (1.2pmol/kg/min) and placebo in a randomized double-blind dependent upon exogenous insulin therapy. Single subcutaneous (SC) admin- fashion. At T=0min subjects ingested 100g of beef mince labeled with 20MBq istration of XMetA at dose levels ranging from 1.5 to 10 mg/kg substantially 99mTechnetium-sulfur-colloid. Gastric emptying was measured scintigraphi- reduced fasting hyperglycemia, even at the lowest dose, with a peak effect cally from T=0 to 240min. The areas under the curve for gastric emptying were 1-2 days post-administration and with a duration of approximately one week. analysed using one-way RM-ANOVA with Bonferroni-Holm adjusted posthoc Postprandial hyperglycemia and serum C-peptide levels trended lower over tests. Hyperglycemia slowed gastric emptying (eu/placebo vs. hyper/placebo; the same time course. Although 1.5 mg/kg substantially reduced fasting hy- P<0.001) as did GLP-1 (eu/placebo vs. eu/GLP-1; P <0.001) [Fig. 1]. There was an perglycemia, a higher dose, 10 mg/kg, was selected for testing the longer- additive effect of GLP-1 and hyperglycemia, such that gastric emptying was

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markedly slower when compared to GLP-1 administration during euglycemia pts discontinued for AEs. At BL, A1C was 10.8%, age 51.9 yrs, BMI 32.0 kg/m2, (eu/GLP-1 vs. hyper/GLP-1; P<0.01). These data imply that GLP-1 agonists may diabetes duration 9 yrs, OAD use 69%. At Week 39, mean reduction of A1C further slow gastric emptying in the setting of pre-prandial hyperglycemia. from BL to Week 39 (LOCF) was -2.8% (p<0.001) and 22% achieved A1C <7%. Signifi cant A1C reductions were seen by Wk 6 (Figure). The most common AEs were nausea, vomiting, diarrhea, headache, and UTI. Nausea, vomiting, and diarrhea rapidly decreased after Week 1. There were no reports of pancreati- tis or major hypoglycemic events; 6.7% reported minor hypoglycemia, and all SAEs were considered unrelated to ITCA 650. In conclusion, ITCA 650 for 39 weeks produced signifi cant reductions in A1C, BW, improved goal attainment and was well tolerated in these poorly controlled T2DM pts with high A1C.

Supported By: Australia National Health and Medical Research Council (1025648)

& 1106-P

POSTERS Exenatide Increases Heart Rate by Augmenting Sympathetic Ner- Therapeutics vous Activity in Healthy Overweight Men Clinical Diabetes/ MARK M. SMITS, MARCEL H.A. MUSKIET, LENNART TONNEIJCK, MARK H.H. KRAMER, MICHAELA DIAMANT, DANIËL H. VAN RAALTE, Amsterdam, Netherlands Supported By: Intarcia Therapeutics, Inc. Glucagon-like peptide 1 receptor agonists (GLP-1RA) consistently increase heart rate (HR) with approximately 2 beats per minute (bpm), both during acute & 1108-P and prolonged intervention. Mechanisms underlying this safety concern remain Delivery of Exenatide by Subdermal Placement of ITCA 650 in a hitherto unexplored. We assessed the acute effect of the GLP-1RA exenatide Nonclinical Model Demonstrates 1 Year of Continuous Exposure on HR, while unraveling potential mechanisms by concurrently measuring and Tolerability vascular resistance and cardiac sympathetic nervous system (SNS) activity. DORIS T. ZANE, LAUREN THORNER, MICHELLE BARON, MANISHA CHARAN, We included ten healthy overweight males (aged 20−27 years) in a single-day, TRACEY ZOETIS, ROBERT M. FIELDING, CHRIS N. PAPAGIANNIS, TOM ALESSI, open-label, cross-over study. Measurements were performed throughout in- Hayward, CA, Boston, MA, Herndon, VA, Boulder, CO, Mattawan, MI travenous placebo (saline 0.9%) and subsequent exenatide-infusion. Systolic ITCA 650 is a mini osmotic pump designed to deliver exenatide as a con- (SBP) and diastolic (DBP) blood pressure and HR were measured using an tinuous zero-order subdermal infusion. In an ongoing 2-year carcinogenicity automated oscillometric blood pressure measuring device (Dinamap®). Digi- study, rats received ITCA 650 at exenatide doses of 0, 3, 10 (females), 20 tal fi nger photoplethysmography (Nexfi n®) was used to derive stroke volume (males) and 40 mcg/d. The low and high doses were selected to provide (SV), cardiac output (CO) and total peripheral resistance (TPR). Beat-to-beat approximately 4-fold and 25-fold exposure multiples of the anticipated intervals were analyzed using spectral analysis to calculate sympathova- clinical dose (60 mcg/d). On Day 1, an ITCA 650 osmotic minipump or pla- gal balance (LF/HF-ratio) using Kubios software. Plasma glucose and insulin cebo was placed subdermally in each rat. At 6-month intervals, devices levels were measured. Mixed models were applied for statistical analyses. were removed and replaced with another of the same dose at the same site Compared to placebo, exenatide increased HR by 4.4±1.1 bpm (p<0.001), and to provide continuous exposure during the 2-year study. Plasma exenatide CO by 0.8±0.2 L/min (p<0.001), without affecting SV. No signifi cant effects was measured by a validated ECL assay in toxicokinetic group animals on on SBP, DBP and TPR were observed during exenatide-infusion. LF/HF-ratio Day 365/366. There was no evidence of systemic toxicity and survival was increased by 1.5±1.2 (p=0.049). Exenatide lowered glucose levels by 0.5±0.1 not adversely affected by treatment. As expected from the pharmacology of mmol/L (p<0.001) while no changes in insulin levels were observed. Exenatide exenatide, a decrease in body weight gain (up to 40% vs. control) was noted infusion acutely increases HR in healthy overweight males. This fi nding was in ITCA 650-treated groups. Macroscopic evaluation of tissues local to the paralleled by increased cardiac SNS activity, whereas TPR was not affected. placement site revealed a minimal tissue response to the device. Despite Unchanged blood pressure and TPR argue against the suggestion that the HR repeated removal and replacement of devices during the study, microscopic acceleration associated with GLP-1RA therapy is a compensatory mechanism observations were minimal to mild in all groups, with minimal infl ammation for systemic vasodilation. Our data rather suggest a direct augmenting effect in some animals. Exenatide exposures increased as the dose increased from through increased SNS activity. 3 mcg/d to 40 mcg/d. Comparing Day 365 AUC24h with human AUCs at the Supported By: European Union (HEALTH-282521) clinical dose (60 mcg/d) showed that this study achieved exposure multiples of at least 7.3-fold at the mid dose and 18.1-fold at the high dose. These & 1107-P results are relevant to the human experience as prolonged exposure and re- Effi cacy and Tolerability of 39 Wks of ITCA 650 (Continuous Subcu- peat minipump placements did not result in any local or systemic toxicologic taneous Exenatide) in Poorly Controlled T2DM with High Baseline differences between the active and control groups. A1c (>10%) ROBERT R. HENRY, JULIO ROSENSTOCK, DOUGLAS S. DENHAM, PRAKASH & 1109-P PRABHAKAR, LISE KJEMS, MICHELLE BARON, San Diego, CA, Dallas, TX, San Glucagon-Like Peptide 1 Receptor Agonist or Rapid-Acting Insu- Antonio, TX, Boston, MA lin as Add-on to Basal Insulin Therapy in T2DM Patients: A Meta- ITCA 650 is an injection-free GLP-1 agonist that provides continuous SC analysis exenatide for up to 12 months from a single sub-dermal placement. Open- LOUIS KURITZKY, JAY LIN, CAROL H. WYSHAM, Gainesville, FL, Flemington, NJ, label Tx with ITCA 650 was offered to T2DM pts ineligible for a double-blind, Spokane, WA placebo-controlled trial because of A1C >10%. Pts were 18-80 yrs with A1C This meta-analysis was conducted to compare add-on glucagon-like pep- >10% to ≤12%, BMI 25-45 kg/m2, on stable (≥3 months) diet and exercise or tide 1 receptor agonists (GLP-1 RA) with add-on rapid-acting insulin (RAI) oral antidiabetics (OADs). ITCA 650 was initiated at 20 mcg/d for 13 wks, then in patients with T2DM whose glycemic control remained unoptimized with 60 mcg/d for 26 wks. Baseline (BL) OADs were continued; SUs were adjusted basal insulin therapy alone. if medically necessary. Endpoints were change from BL in A1C, weight (BW), Endpoints were A1C levels and symptomatic hypoglycemia (blood glucose and % achieving A1C <7% at 39 wks. Sixty patients were enrolled. Six (10.0%) level < 56 mg/dL); and change in body weight, and fasting plasma glucose (FPG).

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Three randomized clinical trials (duration 26-44 weeks) in 1,370 T2DM & 1111-P patients (28.4-54.0% female) were included. Patients were aged 54.8-61.1 Effi cacy and Safety of Once-Weekly Dulaglutide vs. Once-Daily years, had A1C levels of 7.7-8.5%, and a BMI of 32.0-32.7 kg/m2. Liraglutide in Japanese Patients with Type 2 Diabetes Compared with RAI-treated patients, GLP-1 RA-treated patients had TOSHINARI TAKAMURA, JUN-ICHIRO MIYAGAWA, MASATO ODAWARA, YASU- signifi cantly greater reductions in A1C and body weight, and a signifi cantly SHI TAKITA, NORIYUKI IWAMOTO, TAKESHI IMAOKA, Kanazawa, Japan, Nishi- lower risk of symptomatic hypoglycemia. Furthermore, these patients had nomiya, Japan, Tokyo, Japan, Kobe, Japan numerically greater FPG reductions and higher odds of achieving A1C < 7.0% This phase 3, randomized, parallel-arm, placebo-controlled 52-week (wk) compared with RAI-treated patients (Table). Therefore, GLP-1 RAs are a vi- study assessed the effi cacy and safety of once-weekly 0.75 mg dulaglutide able option to optimize insulin therapy because T2DM patients may achieve (DU), a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, in Japa- better glycemic control without increased hypoglycemia or weight gain as nese patients with type 2 diabetes (T2DM) compared to once-daily 0.9 mg compared with the addition of RAI to basal insulin therapy. liraglutide (LIRA). Patients who initially received placebo were switched to Table. DU at 26 wks. The primary objective of superiority of DU to placebo for A1C reduction from baseline at 26 wks was met. Here we report on the 52-wk comparison of DU with LIRA. Baseline characteristics were similar between groups (N=487): age, 57 years; A1C, 8.1%; body weight 70.7 kg; and T2DM duration, 6.6 years. At 52 wks, DU demonstrated signifi cant A1C reduction from baseline com- pared with LIRA; least-squares mean (SE) changes were DU, -1.39% (0.06) and LIRA, -1.19% (0.08) (p=0.04). Fasting blood glucose was decreased in both groups (DU -38.9 mg/dL, LIRA -37.2 mg/dL). Mean total of 7-point self- monitoring blood glucose levels were signifi cantly decreased from baseline with DU compared with LIRA (DU -53.1 mg/dL, LIRA -46.8 mg/dL; p=0.033). Supported By: Sanofi U.S. DU signifi cantly lowered mean of all postprandial blood glucose levels from & 1110-P baseline compared with LIRA (DU -63.7 mg/dL, LIRA -55.4 mg/dL; p=0.036). Mean body weight did not change in either group. Continuous Glucose Monitoring in Patients Treated with Once-

The most common treatment-emergent gastrointestinal adverse events POSTERS

Weekly Dulaglutide or Glargine, both Combined with Prandial Insu- Therapeutics (DU, LIRA) were constipation (7.9%, 8.0%), diarrhea (7.1%, 4.4%), nausea lin Lispro (AWARD-4 Trial Substudy) Clinical Diabetes/ (6.1%, 8.0%), abdominal distension (4.3%, 5.1%) and decreased appetite JOHAN JENDLE, SHERRY MARTIN, HONGHUA JIANG, ZVONKO MILICEVIC, Öre- (0.7%, 5.8%). Hypoglycemia incidence through 52 wks was 2.9% in each bro, Sweden, Indianapolis, IN, Vienna, Austria group. No severe hypoglycemia or pancreatitis was reported. AWARD-4 compared dulaglutide (DU) vs. glargine (GLA), both with pran- dial lispro (±metformin), over 52 weeks (wk) in patients (pt) with type 2 dia- In conclusion, once-weekly DU 0.75 mg was safe and effective in Japa- betes (T2D) uncontrolled on conventional insulin regimens. A subset of pts nese patients with T2DM, with better glycemic control compared with once- (n=144 [884 total randomized]; mean baseline [BL] characteristics: age 59.9 daily LIRA 0.9 mg. y; A1C 8.57%; BMI 32.9) participated in a continuous glucose monitoring Supported By: Eli Lilly Japan KK (CGM) substudy (Medtronic CGMS iPro recorder). The primary measure was % of glucose values in the range defi ned as 71 to 140 mg/dL at wk 26. 1112-P At baseline, mean % of glucose values in the 71-140 mg/dL range was CPR-AUC Is Useful to Predict the Clinical Effects of GLP-1 Receptor 22.0%, 26.0% and 29.9% for DU 1.5 mg, DU 0.75 mg and GLA, respectively. Agonist At wk 26, least squares mean (LSM) % of glucose values in this range was AZUSA OHBATAKE, YUUKI SHIMA, HIROYUKI ASAKA, YUKIKO MORI, SATOKO 58.8%, 47.7%, and 50.1% (change from BL [33.9%, 22.8%, and 25.2%] for DU OKAZAKI, YOSHIYU TAKEDA, MASAKAZU YAMAGISHI, KUNIMASA YAGI, 1.5 mg, 0.75 mg, and GLA, respectively; p ≥0.084, both doses vs. GLA) (Table). DAISUKE CHUJO, Kanazawa, Japan For a 71-180 mg/dL range, the LSM % of values was 83.1%, 72.5%, and 73.0% In our previous studies, the daily insulin dose before starting GLP-1 re- (change from BL [34.9%, 24.3%, and 24.7%] for DU 1.5 mg, 0.75 mg, and GLA, ceptor agonist (GLP-1ra) therapy was an effi cient parameter to predict the respectively; p=0.014 and p=0.91 for DU 1.5 mg and 0.75 mg vs. GLA). The clinical effects of the agent and requirement of additional medications. We groups were similar for other outcomes, including hypoglycemia indices. herein determined whether the parameters related to pancreatic beta cell In this substudy, treatment with DU 1.5 mg compared to GLA resulted in a function could predict the long-term clinical effects of GLP-1ra. similar effect on % of glucose values in the 71 to 140 mg/dL range at 26 wk, Sixty-seven insulin independent diabetics (M/F: 47/20, age: 62.5±13.8 but greater proportion in the 71 to 180 mg/dL, with no difference for other years, disease duration: 17.9±10.5 years, BMI: 26.6±5.7 kg/m2, and HbA1c: CGM outcomes. 7.8±1.5%) participated in this study. Then, we obtained several parameters Table. related to endogenous insulin secretion, such as fasting CPR (F-CPR), ΔCPR and the area under the curve of CPR (CPR-AUC) from glucagon stimulation test (GST), and investigated the relationship between these parameters and changes in HbA1c, body weight (BW), blood pressure (BP), eGFR, and uri- nary albumin excretion (UAE) at 6, 12, and 24 months after the initiation of GLP-1ra therapy. CPR-AUC was inversely correlated with changes in HbA1c at 6 and 24 months (p=0.036 and p=0.044, respectively) and changes in BW at 6 and 12 months (p=0.005 and p=0.037, respectively) after starting GLP-1ra. In the high CPR-AUC (ə15 ng/mL·min) group, HbA1c reduction at 6 months (-0.91±0.26% vs. -0.01±0.31%, p=0.027), 12 months (-0.66±0.22% vs. +0.18±0.24%, p=0.012), and 24 months (-1.24±0.38% vs. -0.05±0.38%, p=0.036) as well as BW reduction at 12 months (-5.5±1.1 kg vs. -2.1±1.2 kg, p=0.045) were greater than those in the low CPR-AUC (< 15 ng/mL·min) group. F-CPR and ΔCPR were not correlated with changes in HbA1c and BW. No other metabolic parameters, including BP, eGFR, and UAE, were observed to signifi cantly correlate with any CPR indices from the GST. In conclusion, CPR-AUC from the GST is an effi cient parameter to predict the long-term clinical effects of GLP-1ra therapy, suggesting that the assess- ment of whole pancreatic beta cell function, including basal and stimulated insulin secretion, is required to predict the effects of GLP-1ra.

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A285 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—NON-INSULIN INJECTABLES

1113-P 1115-P Analysis of the Signaling Response of Lixisenatide and Insulin Short-Acting GLP-1 Receptor Agonists Leading to Improvement of Glargine in Human Cell Lines Coexpressing IR and GLP-1R Whole-Body Insulin-mediated Glucose Utilization in Type 2 Dia- NORBERT TENNAGELS, THORSTEN SCHMIDT, UWE SCHWAHN, SIEGFRIED betic Patients STENGELIN, ULRICH WERNER, Frankfurt, Germany MARI C. FERREIRA, MARIA ELIZABETH ROSSI SILVA, MARIA DO CARMO ARRU- Studies in the rat C-cell line RTC6-23 have shown that the functional DA-MARQUES, ROSA TSENUSHIRO FUKUI, ROSA FERREIRA SANTOS, São Paulo, activation of the glucagon-like peptide 1 receptor (GLP-1R) and the insulin Brazil receptor (IR) by either specifi c GLP-1R agonism or insulin stimulation resulted Both short and long acting GLP-1 receptor agonists (GLP-1 RAs) can affect in a strong downstream signaling response. However, in the human medul- fasting and post-prandial blood glucose levels by different ways. After mixed lary thyroid carcinoma C-cell line TT, which also contains both receptors, the meal ingestion, usually acute iv exenatide administration in T2DM markedly re- cAMP response to GLP-1R agonist stimulation was very weak. duces the postmeal plasma glucose excursion by inhibiting the hepatic glucose We therefore screened for human cell lines that express functionally active production (EGP) and delaying gastric emptying. However, the background of GLP-1Rs as well as IRs, to evaluate possible costimulatory responses. Receptor the resulting heterogeneity of the GLP-1 RAs responses is unclear at present. downstream signaling was characterized by GLP-1-stimulated cAMP production This study was performed with detailed metabolic characterization of adults using lixisenatide (LIXI) and IR-stimulated Akt phosphorylation (pAKT) using in- with T2DM after use of exenatide for 8 wk. We investigated 4h profi les of se- sulin glargine (GLA), respectively. From 11 human cell lines that were evaluated, rum glucose, insulin, proinsulin, C-peptide, glucagon and FFA during a mix meal three cell lines that showed high expression of both GLP-1R and IR were detect- test. We selected 162 individuals with T2DM not using insulin, DPP-4 inhibitors ed. However, after confi rmation of expression of the individual receptors by RT- and GLP-1 RAs (57.4±7.1 yr, BMI 30.5±5.2 kg/m2, HbA1c 7.6±1.79%, T2DM du- PCR and assessment of receptor functionality, only the pancreatic cell line 1.1B4 ration 5.6±3.5 yr) underwent basal peripheral blood collection for biochemical remained for further characterization. In this cell line LIXI was highly potent on and hormonal analises. A subgroup of 56 patients with more similar duration of GLP-1R downstream signaling with an EC50 of ~10 pM, while GLA had an EC50 T2DM, BMI and age was chosen for meal test before and after treatment. We of ~10 nM for stimulated pAKT via the IR. By contrast, LIXI did not activate the verifi ed that after treatment weight, HbA1C and HOMA IR reduced, p<0,001; IR and no effect of GLA on the GLP-1R was detected. Furthermore, costimulation HOMA B and S were increased, p<0,001. During the meal test after exenatide with either a fi xed concentration of LIXI or GLA to the other ligand did not result for 8 wk, serum glucose decreased after 15 min, peak and integrated insulin in different signaling responses at the GLP-1R and IR, respectively. and proinsulin excursions were lower after 30 min, C-peptide was reduced In summary, it could be shown that the human pancreatic -cell line 1.1B4 ex- between 90 and 180 min, glucagon decreased after 15 min, p<0,005. FFA POSTERS β Therapeutics presses GLP-1R and IR that are both functionally active. LIXI is not active at the IR increased after 60 min, p<0,05. Basal TNFα was reduced after treatment, Clinical Diabetes/ and GLA is not active at the GLP-1R. LIXI’s activity at the GLP-1R is not altered by p<0,001. Therefore, our fi ndings suggest the notion that exenatide properties costimulation with GLA and LIXI does not alter GLA’s activity at the IR. In conclu- lead to improvement of whole-body insulin-mediated glucose utilization, that sion, the fi xed-ratio combination of LIXI and GLA does not alter the response on has previously been shown in some studies, but the exact mechanism in hu- receptor downstream signaling observed with either single component. mans remain unclear. Thus exenatide holds promise, for its benefi cial effects on insulin sensitivity, beyond postprandial glucose lowering. 1114-P The Effects of Once-Weekly Dulaglutide on Kidney Function in 1116-P Clinical Trials Superagonistic Mechanism of Increased Glucodynamic and Weight KATHERINE R. TUTTLE, T. DWIGHT MCKINNEY, JAIME A. DAVIDSON, GREG Loss Effects of LAPSCA-Exendin-4 (HM11260C) ANGLIN, KRISTINE D. HARPER, FADY T. BOTROS, Spokane, WA, Indianapolis, IN, IN YOUNG CHOI, SUNG HEE PARK, MICHAEL TRAUTMANN, SANG YOUN Dallas, TX, Toronto, ON, Canada HWANG, JIN YOUNG KIM, YOUNG MI LEE, SE CHANG KWON, Hwaseong, Re- Dulaglutide (DU) is a once-weekly glucagon-like peptide 1 receptor agonist public of Korea, Chula Vista, CA approved for the treatment of type 2 diabetes (T2D). Postmarketing cases of The novel long-acting GLP-1 receptor agonist, HM11260C, was developed acute decreases in kidney function related to other incretin-based therapies for the treatment of type 2 diabetes and is currently in phase II clinical tri- have been reported. However, experimental models of diabetes suggest no re- als as a weekly or monthly GLP-1 receptor agonist (GLP-1R). It consists of nal harm from these therapies. The aim of this study was to determine effects an exendin-4 analog (CA-Exendin-4) conjugated via non-peptidyl linker to a of DU (1.5 mg and 0.75 mg) on kidney function and adverse events (AEs) in post non-glycosylated human Fc fragment. Previously, we demonstrated that the hoc analyses of clinical trials with placebo (PBO) and active comparators (ACs). fast dissociation rate of the non-conjugated CA-Exendin-4 from the GLP-1 Serum creatinine (sCr), estimated glomerular fi ltration rate (eGFR), and urine receptor (GLP-1R) reduced GLP-1R internalization compared to exendin-4. In albumin-to-creatinine ratio (UACR) were evaluated using integrated data from this study, we investigated further the mechanism using CA-Exendin-4 and 9 completed Phase 2 and 3 trials. No differences in sCr or eGFR were observed HM11260C. The in vitro insulinotropic effect revealed 1.7 fold greater maxi- at baseline or during treatment between DU and AC (treatment median, 51 mal effect of CA-Exendin-4 compared to exendin-4. This could be confi rmed weeks [interquartile range, 25-54]). UACR values were slightly but signifi cantly in vivo by ipGTT in normal mice resulting in 5 fold greater glucose lowering. lower for DU than for AC during the treatment period. No signifi cant differ- Previously, it was identifi ed that after conjugation to Fc the fast dissocia- -3 -1 -3 -1 ences in sCr or eGFR were observed between DU and PBO (3 studies) or DU tion kinetics were maintained in HM11260C (kd 4.2x10 s vs. 1.0x10 s for and glargine (2 studies). AE terms refl ecting potential acute kidney injury LAPSExendin-4). Therefore, GLP-1R internalization and in vitro / in vivo effects were reported at rates of 3.4, 1.7, and 7.0 events per 1,000 patient years of of HM11260C were compared with other GLP-1R agonists. HM11260C lead to exposure for DU (n=12; N=4006), AC (n=3; N=1541), and PBO (n=2; N=703), less GLP-1R internalization by 50% or less than liraglutide, exenatide and du- respectively. Overall, treatment of T2D patients with DU in clinical trials did laglutide in human GLP-1R transformed U2OS cells. This translated to more not alter kidney function or increase rates of AEs related to kidney disease. potent glucose lowering in db/db mice and greater body weight loss in DIO Table. mice in comparison to liraglutide and dulaglutide. Taken together, CA-Exen- din-4 even after conjugation to the human Fc-fragment seems to achieve more pronounced GLP-1R activation due to reduced receptor internalization and consequently leads to more potent effects. These fi ndings may explain the observed effi cacy of HM11260C in clinical trials relative to liraglutide.

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1117-P 1119-P Effects of Liraglutide or Lifestyle Counseling on Subcutaneous and In Vivo Effect of Semaglutide in Pigs Supports Its Potential as a Visceral Fat Distribution, Liver Fat Content, Insulin Sensitivity, and Long-Acting GLP-1 Analogue for Once-Weekly Dosing β-Cell Performance BIDDA ROLIN, MARIANNE O. LARSEN, BERIT O. CHRISTOFFERSEN, JESPER LAU, FRANCESCA SANTILLI, ARMANDO TARTARO, MARIA TERESA GUAGNANO, PAOLA LOTTE B. KNUDSEN, Måløv, Denmark G. SIMEONE, GIULIANA LARONGA, CRISTINA SBORGIA, MARIKA LEO, MARICA Treatment of type 2 diabetes with GLP-1 receptor agonists has proven to be MACCARONE, ERMANNO ANGELUCCI, VIRGINIA FEDERICO, LUCIA PANSA, ALES- very attractive in clinical practice due to both effi cient glucose lowering and SIA QUIRINO, CARMEN PULLARA, DOMENICO DE CESARE, FRANCA M. LATTAN- weight loss. Semaglutide is an acylated human GLP-1 analog with a half-life ZIO, LAMBERTO MANZOLI, GIOVANNI DAVI, AGOSTINO CONSOLI, Chieti, Italy of 160 h in humans, and 94% homology to human GLP-1. Semaglutide is cur- Obesity, insulin resistance and beta cell deterioration are key issues in rently in phase 3 clinical development. In these preclinical studies, pigs were type 2 diabetes (T2DM) development and progression. Given the concurrent used since the pharmacokinetics of acylated drug candidates in this species effects of GLP-1 agonists on body weight, fat mass, insulin resistance and correlate well with humans. To measure the effect on food intake we used beta cell preservation, we hypothesized that this class of drugs may exert female Landrace Yorkshire Duroc pigs (n=6). Semaglutide was dosed 4 times additional actions on top of those anticipated for lifestyle intervention- in a multiple dosing regimen (20-40 µg/kg s.c.) to obtain steady state plasma mediated weight loss. levels. Food intake was measured on day 1, 2 and 6-8 after the last dose. To Twenty-six metformin-treated obese subjects with impaired glucose study insulin secretion a hyperglycemic clamp at 8 mmol/l was performed at tolerance, impaired fasting glucose or newly diagnosed T2DM, were ran- baseline and on day 1, 3 and 7 after dosing of semaglutide (8 µg/kg) to β-cell domized to liraglutide (1.8 mg/d) or lifestyle counseling to assess whether reduced, glucose intolerant Göttingen minipigs (n=6). Semaglutide reduced changes in subcutaneous (SAT) and visceral (VAT) adipose tissue distribution food intake (kg/24 hours) to 38% of vehicle on day 1 (0.82±0.21 vs. 2.18±0.27, and non-alcoholic fatty liver disease (NAFLD) degree (all assessed by MRI) p<0.001), 47% on day 2 (0.98±0.35 vs. 2.11±0.20, p<0.001), 67% on day 6 after a modest and comparable weight loss (7% of initial body weight), might (1.61±0.48 vs. 2.40±0.30, p<0.01) and 80% on day 7 (1.94±0.43 vs. 2.43±0.18, affect insulin sensitivity (Matsuda Index) and beta cell performance (by Insu- p<0.05) whereas no reduction in food intake was seen on day 8 (96%, lin Secretion-Sensitivity Index-2 (ISSI-2)) during multiple sampling OGTT. 2.28±0.63 vs. 2.37±0.38, ns). Semaglutide increased plasma insulin during SAT and NAFLD grade were comparably reduced in both treatment groups, a hyperglycemic clamp (Area Under the Curve) signifi cantly from baseline whereas insulin sensitivity was not signifi cantly affected by any interven- (22.6±1.8 nmol/L*h) on day 1 (47.3±3.8 nmol/L*h, p<0.001), day 3 (39.5±5.0 tion. In contrast, the liraglutide arm showed a signifi cantly greater decrease nmol/L*h, p<0.05) and day 7 (33.1±4.5 pmol/L*h, p<0.05). Similarly, glucose POSTERS in median VAT (p=0.001), as compared to the lifestyle arm (-15.3% vs. -8.5%) infusion rates were increased signifi cantly compared to baseline (873±82 Therapeutics and a greater improvement in beta cell function (ISSI-2) (109% vs. 29.9%, mg/kg) on day 1 (1308±80 mg/kg, p<0.001), day 3 (1458±145 mg/kg, p<0.01) Clinical Diabetes/ p=0.006), which translated into a more pronounced reduction in both fast- and day 7 (1213±137 mg/kg, ns). Data are mean±SEM. In conclusion, sema- ing, 1-hour and 2-hour postprandial glycemia, despite comparably reduced glutide had a duration of action in pigs for up to 7 days both when measured HbA1c in both groups (by 7.1%). In the liraglutide arm, but not in the lifestyle as food intake reduction and as insulin secretion, supporting a once weekly arm, VAT values were signifi cantly related to ISSI-2 (Rho=-0.60, p=0.023) dosing regimen with very limited excursions in plasma concentration. throughout the intervention. This study may help establishing a cause-and-effect relationship between 1120-P VAT infl ammation, beta cell performance and development or progression Three-Year Effi cacy and Safety of Exenatide Once Weekly: A Pooled of T2DM, unravelling novel mechanisms by which liraglutide may favorably Analysis of 3 Trials impact T2DM pathogenesis. MICHAEL TRAUTMANN, LUC VAN GAAL, JENNY HAN, ELISE HARDY, Hamburg, Germany, Edegem, Belgium, San Diego, CA, Gaithersburg, MD 1118-P Long-term data for glucose-lowering therapies (eg, GLP-1 receptor ago- Potent Weight Loss Mechanism of the Novel Long-Acting GLP-1/ nists) help to inform drug selection for treatment strategies. This post hoc Glucagon Dual Receptor Agonist (HM12525A) analysis examined the effi cacy and safety of exenatide once weekly (QW) in SUNG YOUB JUNG, JONG SUK LEE, JIN YOUNG KIM, YOUNG-MI LEE, YOUNG pooled completer data (N=329) from extensions (2.5-3 y) of 3 trials (DURA- HOON KIM, JA HOON KANG, MICHAEL TRAUTMANN, MARCUS HOMPESCH, SE TION-1, -2, -3); 3y data for insulin glargine (IG) was included for reference CHANG KWON, Seoul, Republic of Korea, Chula Vista, CA (N=158), as IG was a long-term comparator in 1 trial (DURATION-3). Baseline HM12525A is a long-acting GLP-1/glucagon (GCG) dual agonist for once- mean age, weight, and A1C were 56/58y, 93.7/90.3 kg, and 8.3/ 8.3%, in the weekly administration. It consists of a GLP-1/GCG dual agonist conjugated exenatide QW/IG groups, respectively. After 3 y, patients (pts) receiving ex- via non-peptidyl linker to a non-glycosylated human Fc fragment. The aim of enatide QW had improvements from baseline in A1C, fasting glucose, body this development was to achieve more potent body weight loss (BWL) com- weight, and some cardiovascular risk markers (Table). For exenatide QW and pared to GLP-1 receptor agonists. This study investigated the mechanism re- IG, respectively, 101 (30.7%) and 26 (16.5%) pts achieved the stringent goal sponsible for increased BWL by HM12525A by assessing energy expenditure of A1C ≤6.5%, and 95 (28.9%) and 11 (7.0%) achieved the composite goal of (EE) and lipid metabolism. A1C <7%, no hypoglycemia, and no weight gain. Diarrhea, nausea, vomiting, First, we focused on FGF21 as a potential mediator of the anti-obesity and injection-site pruritus occurred in 24.0%, 22.2%, 10.6%, and 8.2% of pts glucagon effect. The secretion of FGF21 was signifi cantly increased in pri- receiving exenatide QW and in 8.2%, 2.5%, 3.2%, and 0% of pts receiving mary hepatocytes (2-fold vs. vehicle) as well as in DIO (diet induced obesity) IG. Major + minor hypoglycemia were more frequent with SU than without rats after HM12525A treatment. HM12525A treatment induced the expres- (exenatide QW: 32.6% vs. 10.0%; IG: 70.2% vs. 45.9%). Long-term exenatide sion of UCP-1, a well known marker of EE, and this was further enhanced by QW treatment improved outcomes in a large, pooled cohort of pts with less co-treatment of FGF21. Consistent with these in vitro results, we confi rmed weight gain and hypoglycemia, but more gastrointestinal and injection-site that HM12525A increased EE without affecting locomotor activity in DIO events, than the reference IG treatment. mice by using a combined indirect calorimetric system. Therefore, these re- Table. Changes from Baseline in Outcomes at 156 Weeks; a P<0.05 vs. Base- sults suggested that HM12525A-FGF21 axis plays an essential role in BWL line. by enhancing EE. Parameter Exenatide QW Insulin Glargine Secondly, we investigated the effect of HM12525A on lipid metabolism in (N=329) (N=158) the liver. In DIO rats, the chronically administered HM12525A ameliorated a a fatty livers together with the increase of CPT-1 expression (1.8-fold vs. Mean A1C (SE), % −1.06 (0.07) −0.82 (0.08) vehicle). To investigate the effect on nonalcoholic steatohepatitis (NASH), A1C goal <7%, n (%) 159 (48.3) 59 (37.3) we utilized ALIOS- (American lifestyle induced obesity syndrome) and me- Mean fasting glucose (SE), mg/dL −30.3 (2.8)a −49.8 (4.8)a thionine-choline defi cient (MCD) diet-mice as NASH models. In ALIOS mice, Mean body weight (SE), kg −2.4 (0.3)a 2.0 (0.4)a HM12525A resulted in greater effects on body weight and hepatic TG reduc- tion compared to liraglutide. Consistently, hepatic levels of infl ammation, Mean systolic blood pressure (SE), mmHg −1.3 (0.9) 1.5 (1.2) fi brosis marker, and histological scoring for NASH were decreased after Mean low-density lipoprotein (SE), mg/dL −5.2 (1.6)a −4.8 (2.3)a HM12525A administration in MCD mice. Mean high-density lipoprotein (SE), mg/dL 3.0 (0.4)a 1.1 (0.7) Our results suggest that the novel GLP-1/GCG dual agonist HM12525A may have clinical potential for the treatment of obesity and obesity-related Supported By: AstraZeneca liver disease.

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A287 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—NON-INSULIN INJECTABLES

1121-P expression (p<0.05). However, in beta-cells with palmitate-dependent reduc- Effi cacy and Safety of Liraglutide vs. Sulfonylurea Both in Combina- tion of GLP-1R levels, the ability of lixisenatide to activate GLP-1R signaling and tion with Metformin during Ramadan in Subjects with Type 2 Diabe- promote insulin biosynthesis and release was unaffected. Similar results were tes (LIRA-Ramadan): A Randomized Trial obtained when GLP-1R levels were reduced by 50% with a specifi c siRNA. SAMI AZAR, AKRAM ECHTAY, WAN MOHAMAD W. BEBAKAR, SUMAYYA Dose-response curves of CREB phosphorylation were left-shifted for lixisen- AL ARAJ, ABDELKRIM BERRAH, MOHAMED OMAR, ABHAY MUTHA, KAREN atide compared to exendin-4 and liraglutide (p<0.05). In conclusion, SFA-in- TORNØE, MARGIT KALTOFT, NAIM SHEHADEH, Beirut, Lebanon, Khota Bharu, duced incretin resistance of beta-cells involves the SREBP-1C/PDX-1 signaling Malaysia, Ras al-Khaimah, United Arab Emirates, Algiers, Algeria, Durban, South pathway controlling GLP-1R expression. Lixisenatide shows greater potency in Africa, Pune, India, Søborg, Denmark, Haifa, Israel activating GLP-1R than other agonists, resulting in unaltered cellular effects in Subjects with type 2 diabetes (T2D) who fast during Ramadan have a 5- the context of SFA-mediated inhibition of GLP-1R expression. and 7.5-fold increased risk of severe hyper- and hypoglycemia, respectively. Supported By: Sanofi The effect of liraglutide (lira) vs. sulfonylurea (SU), both + metformin (Met), on change in glycemic control in subjects with T2D who fasted during Ra- 1123-P madan was examined. LAPS-Exendin-4 (HM11260C) Signifi cantly Enhances Insulin Secre- In this up to 33-week, open-label trial, adults (HbA1c 7-10%; BMI >20 kg/m 2; tion and β-Cell Responsiveness in Subjects with Type 2 Diabetes stable SU + Met; intent to fast during Ramadan) were randomized to either Mellitus (T2DM) switch to once daily lira 1.8 mg (N=172) or continue pretrial SU (N=171), MARCUS HOMPESCH, JAHOON KANG, ELAINE WATKINS, MICHAEL TRAUT- both + Met. After 3-week dose escalation, a 6-19-week maintenance period MANN, SOOMIN CHOI, SOOJIN KIM, OAKPIL HAN, LINDA MORROW, Chula Vista, preceded Ramadan. Primary endpoint was change in fructosamine (FA) from CA, Seoul, Republic of Korea start to end of Ramadan (lira N=151; SU N=165) (Table). LAPSExendin-4 (HM11260C) is a glucagon like peptide-1 (GLP-1) recep- During Ramadan, despite lower FA & HbA1c at start of Ramadan in the lira tor agonist being developed to treat T2DM. GLP-1 receptor agonists can arm, a similar reduction in FA with lira and SU was seen. Confi rmed hypogly- improve β -cell function. The effects of different HM11260C regimens on cemic episodes appeared to be lower with lira & fewer subjects withdrew β-cell function Insulin Secretion Rate (ISR) and responsiveness compared to during Ramadan (lira 3, SU 11). AE frequencies appeared similar: lira 23.7%; placebo and to liraglutide were investigated. SU 20.9%. GI AEs were more common for lira (10.5%; SU 3.7%). A low inci- Subjects with T2DM received 6 mg HM11260C weekly (cohort A; age: 52.8, dence of SAEs was observed (lira 1.3%; SU 0%). POSTERS HbA1c: 8.4, n=13), 16 mg HM11260C monthly (cohort B; age: 50.1, HbA1c: 8.1, Therapeutics During Ramadan, lira showed similar improvements in glycemic control from n=13), 1.8 mg liraglutide daily (cohort C; age: 54.9, HbA1c: 8.02 n=13), or a Clinical Diabetes/ lower FA & HbA1c levels compared to SU with a similar number of AEs, appar- placebo (age: 54.1, HbA1c: 8.6, n=8). Subjects in cohorts A and C were evalu- ently fewer confi rmed hypoglycemic episodes and better weight control. ated at baseline and steady state, and cohort B was evaluated at trough (day Table. [d] 82) and peak (d89) drug concentration. Islet β-cell function was assessed during a graded IV glucose infusion (GGI); infusion steps: 2, 4, 6, 8, 12 mg/ kg/min of 20% IV glucose for 30 min each. ISR, C-peptide levels, and plasma glucose response to each GGI step were measured. ISR were determined using a population based C-peptide de-convolution model. AUC-insulin as a measure of ISR was determined for each treatment. Beta-cell responsiveness was assessed as the ratio of ISR/ Blood Glucose (BG) over the duration of the GGI, and the slope of the ISR/BG was compared between the treatments. Insulin secretion for all active treatments was increased signifi cantly compared to placebo. AUC-insulin and AUC-C-peptide were larger (p<0.05) in cohort A compared to C. Comparisons of the relationship between ISR and plasma glucose using mixed effects modeling showed a signifi cant treat- ment effect relative to placebo/baseline (p<0.0001), which was not different amongst treatments. In the monthly treatment group, there was a signifi cant diminution of effect at PK trough. In conclusion, HM11260C improved parameters of beta-cell function sig- nifi cantly compared to placebo, and for the weekly treatment regimen (co- hort A), signifi cantly compared to QD liraglutide. Supported By: Hanmi Pharm Co., Ltd.

Supported By: Novo Nordisk 1124-P 1122-P WITHDRAWN Comparison of Distinct GLP-1 Receptor Agonists in Palmitate-in- duced Incretin Resistance of Pancreatic Beta Cells ANNALISA NATALICCHIO, GIUSEPPINA BIONDI, FEDERICA TORTOSA, ROSSELLA LABARBUTA, NICOLA MARRANO, ANGELO CIGNARELLI, ANNA LEONARDINI, SEBASTIO PERRINI, LUIGI LAVIOLA, FRANCESCO GIORGINO, Bari, Italy The incretin effect is reduced in obese and type 2 diabetic patients. The aim of this study was to evaluate the ability of saturated fatty acids (SFA) to induce resistance to the effects of distinct GLP-1 agonists on pancreatic beta-cells. Action and signaling of the GLP-1 analogs exendin-4, liraglutide and lixisenatide were investigated in rat INS-1E and human 1.1B4 pancreatic beta-cells and murine islets treated with 0.5 mM palmitate for 24 h. Human islets and islets obtained from mice fed a high-fat diet for 3 weeks were also studied. Prolonged exposure of INS-1E and 1.1B4 cells and murine islets to palmitate reduced the ability of exendin-4 and liraglutide to augment proin- sulin mRNA levels and induce insulin release (p<0.05). In addition, palmitate reduced GLP-1 receptor (GLP-1R) protein levels by 50% (p<0.05) and almost abrogated both exendin-4- and liraglutide-stimulated CREB and AKT phospho- rylation. Both 1,10-phenanthroline, a SREBP-1C inhibitor, and a specifi c Srebf1 siRNA prevented SFA-mediated incretin resistance, indicating that activation of SREBP-1C is required for this response. Islets from mice fed a high-fat diet also showed increased SREBP-1C mRNA levels, and reduced PDX-1 and GLP-1R

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A288 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—NON-INSULIN INJECTABLES

1125-P metformin- and/or sulfonylurea (SU)-based therapy. Reductions from BL in Comparison of 12-Month Adherence and Health Care Costs between A1C and fasting glucose (FG) were signifi cant (Table); A1C reductions were Patients with Type 2 Diabetes Mellitus Newly Initiating Liraglutide comparable between exenatide BID and insulin and numerically greater with QD or Exenatide QW in U.S. Clinical Practice exenatide QW than insulin, whereas FG reductions were greater with insulin. STEPHEN JOHNSTON, HIEP NGUYEN, KATHERINE CAPPELL, JAMES NELSON, Notably, A1C goal achievement was higher with exenatide QW than insulin. BONG-CHUL CHU, IFTEKHAR KALSEKAR, Bethesda, MD, Fort Washington, PA Weight signifi cantly decreased with exenatide and increased with insulin. Ma- Limited data have been published comparing liraglutide once daily (QD) jor + minor hypoglycemia incidence was numerically higher in SU vs. non-SU and exenatide once weekly (QW) in real-world clinical practice. This study users and with insulin. In conclusion, exenatide BID and QW achieved marked used a retrospective cohort design and U.S. administrative claims data. Out- reductions in A1C in patients with T2DM and BL A1C ≥10%. Exenatide BID and comes were compared between commercially-insured glucagon-like pep- QW may be appropriate treatment alternatives to insulin for this population. tide-1 receptor agonist (GLP-1RA)-naïve patients with type 2 diabetes mel- Table. Endpoint Parameters in Patients with BL A1C ≥10%. *P<0.001 vs. BL. litus who newly initiated liraglutide QD or exenatide QW (index therapy) be- Parameter Exenatide Exenatide tween 2/1/2012-10/1/2012 (initiation date=index). Outcomes were measured BID Studies QW Studies over a 12-month post-index period and included index GLP-1RA adherence (proportion of days covered [PDC] during follow-up, 80%, 90%) and over- Exenatide Insulin Exenatide Insulin ≥ ≥ BID (N=85) (N=38) QW (N=168) (N=21) all/diabetes-specifi c healthcare utilization/costs. Multivariable regressions compared the outcomes between the GLP-1RAs, adjusting for demographic Mean ± SD BL A1C (%) 10.4 ± 0.4 10.5 ± 0.6 10.5 ± 0.4 10.4 ± 0.4 and clinical characteristics. In the adjusted analyses, compared with ex- Mean ± SEM change in A1C (%) -2.0 ± 0.2* -2.1 ± 0.2* -2.6 ± 0.1* -2.1 ± 0.2* enatide QW patients, liraglutide QD patients had signifi cantly lower odds of Achieved A1C <7% / ≤6.5% (%) 16.5 / 5.9 13.2 / 5.3 29.8 / 15.5 4.8 / 0.0 achieving a PDC 80% (OR=0.89, p=0.007) or PDC 90% (OR=0.76, p<0.001), ≥ ≥ Mean ± SD BL FG (mg/dL) 228.9 ± 42.8 265.0 ± 55.3 222.4 ± 54.7 226.3 ± 49.7 greater odds of inpatient admissions, and greater overall and diabetes- specifi c total costs and medical costs (Table). In real-world clinical practice, Mean ± SEM change in FG (mg/dL) -36.5 ± 7.3* -90.9 ± 13.4* -66.4 ± 5.6* -86.7 ± 53.2* treatment with exenatide QW was associated with better adherence and Minor + major hypoglycemia with SU / 18/60 (30.0) / 12/35 (34.3) / 3/84 (3.6) / 2/9 (22.2) / healthcare utilization and cost outcomes compared with liraglutide QD. no SU (n/N [%]) 3/25 (12.0) 0/3 (0.0) 1/84 (1.2) 2/12 (16.7) Table. Adherence and Healthcare Costs of Patients Treated with Liraglutide Supported By: AstraZeneca

QD or Exenatide QW in Real World. POSTERS Therapeutics

Adjusted Effect Measure* Result 1127-P Clinical Diabetes/ OR of overall inpatient admission OR=1.21, p=0.016 Once-Weekly Dulaglutide Does Not Increase the Risk for CV Events OR of diabetes-specifi c inpatient admission OR=1.30, p=0.006 in Type 2 Diabetes: A Prespecifi ed CV Meta-analysis of Prospec- tively Adjudicated CV Events Overall total costs $14,330 exenatide QW, KEITH C. FERDINAND, PHILIP T. SAGER, CHARLES M. ATISSO, FADY T. BUTROS, $15,254 liraglutide QD, p=0.005 New Orleans, LA, San Francisco, CA, Indianapolis, IN Patients with type 2 diabetes (T2D) have a 2- to 4-fold greater risk for Diabetes-specifi c total costs $6,287 exenatide QW, cardiovascular (CV) disease than those without diabetes. Dulaglutide (DU) $6,744 liraglutide QD, is a once weekly glucagon-like peptide-1 receptor agonist recently approved p=0.005 for treatment of T2D. Overall medical costs $7,432 exenatide QW, This meta-analysis evaluates the CV risk in T2D patients treated with DU $8,555 liraglutide QD, in 9 randomized safety and effi cacy trials (mean [median] treatment duration p=0.001 was 333 [358] days). Reported CV events were independently adjudicated by Diabetes-specifi c medical costs $2,124 exenatide QW, a blinded clinical endpoint committee. The primary endpoint was a compos- $2,688 liraglutide QD, ite of death due to CV causes, nonfatal MI, nonfatal stroke, or hospitaliza- p<0.001 tion for unstable angina (4-component major adverse CV event or MACE). *Exenatide QW treated as reference in odds ratios OR=odds ratio; Additional prespecifi ed endpoints, composite and individual, included ad- PDC=proportion of days covered; QW=once weekly Exenatide QW, n=3,173; judicated coronary revascularizations, hospitalization for heart failure, or Liraglutide QD, n=10,829. all-cause mortality. Cox proportional hazards regression model stratifi ed by Supported By: AstraZeneca study was used to estimate the hazard ratio (HR) and confi dence interval (CI); the model included treatment as a fi xed effect with 2 levels for the factor 1126-P (DU or control). Treatment of T2DM Patients with Baseline A1c =10% with Exenatide The analysis included 6010 randomized patients (DU: 3885; all compara- Twice Daily (BID), Exenatide Once Weekly (QW), or Basal Insulin: A tors [active or placebo]: 2125); cumulative exposure to DU or control was Pooled Analysis of 20 Randomized Controlled Trials (RCTs) 3941 and 2223 patient-years, respectively. The demographic and baseline ROBERT S. BUSCH, LETICIA FERRI, JAMES RUGGLES, ELISE HARDY, JENNY HAN, CV disease characteristics were well-balanced across groups. Albany, NY, Gaithersburg, MD, Fort Washington, PA, San Diego, CA Twenty-six (0.67%) patients in the DU group vs. 25 (1.18%) in the all com- Guidelines recommend insulin therapy for T2DM patients presenting with parators group experienced a primary MACE-4 event. Treatment with DU A1C ≥10% to rapidly minimize glucotoxicity. We explored the effects of a was not associated with an increase in the risk of experiencing a MACE-4 GLP-1 receptor agonist, exenatide, on glycemic control in patients with very endpoint compared with control therapies (HR: 0.57; adjusted 98.02% CI: high A1C. In individual RCTs, A1C reduction vs. insulin was noninferior with 0.30, 1.10). Results for the 3- and 6-component MACE, and all-cause mortal- exenatide BID and superior with exenatide QW. Using pooled ITT data from ity were consistent with the primary analysis (HR <1.0 for all). 4340 patients treated for ≥24 weeks in 20 RCTs, we evaluated the effi cacy These results indicate that DU does not increase the risk of MACE events of exenatide BID and QW, and insulin, in a subpopulation of patients with in T2D patients. The ongoing CV outcomes study, REWIND, will further as- baseline (BL) A1C ≥10%. Most patients in this subgroup (>80%) also used sess CV safety of DU. 1128-P Liraglutide Improves Metabolic Parameters and Reduces Carotid Intima-Media Thickness in Patients with Type 2 Diabetes: A 2-Year Prospective Study NOOR AL BUSAIDI, ALI A. RIZVI, GIUSEPPE MONTALTO, ANGELO MARIA PATTI, GIUSEPPA CASTELLINO, AMEDEO BONFIGLIO, ROSARIA VINCENZA GIGLIO, DRAGANA NIKOLIC, KHALID AL-WAILI, ALI AL-MAQBALI, KHALID AL-RASADI, MANFREDI RIZZO, Muscat, Oman, Columbia, SC, Palermo, Italy In addition to lowering plasma glucose levels, the anti-diabetic agent liraglutide regulates food intake and energy expenditure, and expresses a number of cardiovascular and anti-atherogenic effects. However, data on the long-term effects of liraglutide is limited. We aimed to assess its effect

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on several cardio-metabolic parameters in a 2-year prospective study in 128 1130-P patients with type 2 diabetes (T2DM) (74 men, 54 women; age: 62±10 years). Characterizing Injection Site Reactions with the GLP-1R Agonist All subjects were naïve to incretin-based therapies, were treated with Albiglutide metformin only, and were free of cardiovascular disease (CVD). Liraglutide MOLLY C. CARR, DIANE M. MILLER, TIM H. WILSON, JASON M. MALLORY, King was given at a fi xed dose of 1.2 mg/day added to metformin (1500 mg/day). of Prussia, PA, Research Triangle Park, NC Fasting plasma samples were collected at baseline and every 6 months. Potential for injections site reaction (ISR) exists for injected therapies, Carotid-intima media thickness (cIMT) was assessed by B-mode real-time particularly biologic agents like albiglutide (ALBI). In the Harmony Phase III ultrasound. Statistical analysis was performed by ANOVA. Liraglutide sig- program, incidence of ISRs was higher with ALBI. Here we characterize ISRs nifi cantly ameliorated all the metabolic parameters studied, with the only over 3 years of blinded therapy. In pooled Phase III, placebo (PBO) comparator exception of high-density lipoproteins (HDL)-cholesterol (Table). studies (funded by GSK), 923 patients (age 54, HbA1c 8.1%) received ALBI, In conclusion liraglutide seems to have a benefi cial long-term action and 468 received weekly PBO injections. ISRs occurred more frequently with on cardio-metabolic risk factors in T2DM subjects without apparent CVD. ALBI (17.6%) vs. PBO (7.5%). ISRs were generally mild. Among those report- Whether this would translate into effective CVD prevention remains to be ing an ISR, most had 1-2 events (61.7% vs. 80.0% for ALBI vs. PBO, respec- established by future studies. tively). A small number of patients accounted for a large number of events; Table. 23 ALBI patients had ≈ 620 events (n=12 with 11-20 events; n=11 with >20 events). Few patients withdrew due to ISRs (2.0% ALBI vs. 0.2% PBO). There Baseline 6 months 12 months 18 months 24 months p=(for trend) were no ISRs considered to be a serious adverse event. A majority of ISRs Waist circumference (cm) 108±16 104±13 104±13 101±17 100±15 0.005 occurred in antibody (Ab)-negative patients (85%); a larger proportion of Ab- Glycemia (mmol/l) 9.5±3.6 7.4±2.4 7.0±2.1 7.2±2.9 6.9±2.0 <0.0001 positive patients (40.5%) reported an ISR vs. Ab-negative patients (14.2%). Glycated hemoglobin (HbA1c) (%) 8.8±0.94 6.8±1.4 6.7±1.0 6.7±1.2 6.7±1.1 <0.0001 In 3 open label studies using an injectable comparator, there was rates of ISRs were: ALBI (12.9%) vs. liraglutide (5.4%); ALBI (9.5%) vs. lispro (5.3%); Total cholesterol (mmol/l) 4.7±1.4 4.3±1.0 4.2±0.9 4.3±1.0 4.3±0.9 0.002 and ALBI (16.7%) vs. glargine (10.0%). Three patients had single events of Triglycerides (mmol/l) 1.8±1.2 1.54±0.7 1.47±0.7 1.47±0.7 1.46±0.5 0.004 injection site nodule (2 events with ALBI and 1 with glargine). ALBI is as- Low density lipoproteins- 2.7±1.3 2.4±0.9 2.4±0.9 2.4±0.9 2.4±0.9 0.018 sociated with an increased incidence of ISRs, which tend to be mild; few cholesterol (mmol/l) patients withdrew due to an ISR.

POSTERS HDL-cholesterol (mmol/l) 1.16±0.3 1.20±0.3 1.21±0.3 1.20±0.3 1.22±0.3 0.592 Table. Therapeutics

Clinical Diabetes/ cIMT (mm) 0.93±0.20 0.87±0.15 0.84±0.14 0.85±0.16 0.82±0.17 <0.0001 Placebo Albiglutide (N = 468) (N = 923) 1129-P Patients with injection site reactions, n (%) 35 (7.5) 162 (17.6) The Effect of Initial Glargine (IG) Dose on Response to Added Ex- Patients withdrawn due to reaction, n (%) 1 (0.2) 18 (2.0) enatide Twice Daily (BID) or Bolus Insulin: Subgroup Analysis of the Patients who received treatment for reaction n (%) 4 (0.9) 58 (6.3) 4B Study Maximum intensity per patient1,2 BRUCE H. WOLFFENBUTTEL, MELANIE J. DAVIES, KERSTIN BRISMAR, JENNY n35162 HAN, ELISE HARDY, Groningen, Netherlands, Leicester, United Kingdom, Stockholm, Sweden, San Diego, CA, Gaithersburg, MD Mild 33 (94.3) 118 (72.8) Persistent hyperglycemia after IG up-titration necessitates treatment intensi- Moderate 2 (5.7) 41 (25.3) fi cation. This post-hoc analysis examined responses to exenatide BID or insulin Severe 0 3 (1.9) lispro (IL) added to IG + metformin in patients (pts) with T2DM according to IG Number of patients with reaction symptoms1,3 dose tertile at randomization. Post-randomization, the daily IG dose was reduced by 33-50% and converted to IL in the IL arm and by ≥10% in exenatide pts with Redness / Erythema 15 (42.9) 121 (74.7) HbA1c ≤8.0%. At baseline (BL) in tertiles 1, 2 and 3, respectively (exenatide/IL Itching / Pruritis 11 (31.4) 99 (61.1) arms), total insulin was 33/33, 53/52, and 94/96 U, weight was 81/82, 90/87 and Raised 4 (11.4) 53 (32.7) 99/98 kg, and HbA1c was 8.2/8.0, 8.2/8.1 and 8.4/8.5%. At Wk 30, HbA1c reduc- Warmth 1 (2.9) 37 (22.8) tions with exenatide and IL were similar across tertiles (Table); FPG decreased with exenatide in tertiles 1 and 3. Exenatide reduced weight, while IL numeri- Number of events 178 934 cally increased weight. Tertile 3 had the numerically greatest IG dose reductions, Duration of events (days)4 but highest endpoint total insulin dose. Adverse events were generally similar n 175 830 across tertiles within treatment groups. The major + minor hypoglycemia event Mean (SD) 7.6 (31.72) 16.1 (37.01) rate/patient-yr was lower with exenatide than IL (tertile 1: 1.7 vs. 5.2; tertile 2: 2.3 vs. 6.0; tertile 3: 2.6 vs. 4.8). Adding exenatide or IL to pts on high insulin 1. Percentages are based on the number of patients with injection site doses improved glycemic control, with weight loss and less hypoglycemia in the reactions. 2. A patient is counted once according to the maximum intensity experi- exenatide group, regardless of BL IG dose. All pts, including those on high IG enced if a patient reported multiple injection site reaction events. doses, used less total insulin with exenatide. 3. Patients with nonmissing information for reaction symptoms. Table. Outcomes Across IG Dose Tertiles after 30 Weeks’ Treatment. 4. Duration cannot be calculated for the events which are ongoing or unre- *P<0.05, **P<0.001 vs. IL. solved as the stop date is not available. Parameter Tertile 1 Tertile 2 Tertile 3 ExBID IL ExBID IL ExBID IL 1131-P (N=108) (N=102) (N=101) (N=107) (N=106) (N=103) Blinded Comparison of Expert Endocrinologists Adjustment of Insu- lin Pump Settings vs. Novel Initialization Algorithm-based Adjust- Mean HbA1c (%), 7.3 / −0.9 7.1 / −0.9 7.2 / −1.0 7.2 / −1.0 7.3 / −1.2 7.3 / −1.2 ment following a Data Gathering Period in a Multicenter Closed- endpoint / change Loop RCT HbA1c goal <7%, 48 (44) 47 (46) 45 (45) 42 (39) 41 (39) 36 (35) YOGISH C. KUDVA, STEPHEN K. PATEK, SUE BROWN, ANANDA BASU, JORDAN n (%) PINSKER, DAVID KERR, JOON BOK LEE, RAVI GONDHALEKAR, DAYU LV, MICHELE Mean FPG (mg/dL), 120 / −7* 131 / +8 120 / −4 125 / +2 120 / −15* 137 / +1.0 SCHIAVON, CHIARA DALLA MAN, BORIS P. KOVATCHEV, CLAUDIO COBELLI, endpoint / change HOWARD C. ZISSER, FRANCIS DOYLE, EYAL DASSAU, Rochester, MN, Charlottes- Mean change in -2.4** +1.4 −2.6** +1.9 −2.4** +2.2 ville, VA, Crozet, VA, Santa Barbara, CA, Padova, Italy body weight (kg) While different methods of initializing artifi cial pancreas (AP) operation by Mean change in IG −0.7 −3.2 −4.2 −5.2 −10.4* −19.9 optimizing conventional therapy parameters (insulin: carbohydrate ratio [CR] dose (U) and basal profi le) using patient data and pump settings are being studied, Mean total insulin 32.5 58.2 48.3 84.4 84.3 136.6 initialization algorithm-driven adjustment of these settings has never been (IG + IL) dose at end- compared to current clinical practice recommended by expert diabetologists point (U) based on deidentifi ed data. We present the results of a comparison of initial- ization algorithm recommendation vs. 5 expert endocrinologists. Supported By: AstraZeneca

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As part of a randomized crossover outpatient AP study, we have devel- responses to therapy are suggestive of patient response. In this post hoc oped a novel computerized initialization algorithm adjusting pump param- analysis of pooled data from 12 randomized, controlled trials, we defi ned eters based on one week of open-loop data of 27 subjects (CGM, insulin pharmacodynamic outcomes after 2, 4, and 24 wk of exenatide QW treat- delivery, meal information). In parallel, 5 expert endocrinologists reviewed ment and examined whether outcomes were secondary to weight loss. Out- the same data to suggest changes to the basal profi le and CR for each comes included A1C, fasting plasma glucose (FPG), weight, lipids, and blood patient. pressure (BP); their relationship with weight loss was examined at each time The directionality and magnitude of mean adjustments of the CR were point. At baseline, patients (N=2190) had a mean age of 55 y, weight of 87.1 in agreement, with the mean ± SD % change from the subject’s nominal kg, diabetes duration of 7 y, and A1C of 8.4%. Exenatide QW treatment re- value being an increase of 1.01±13% by the algorithm vs. an increase of sulted in improvements from baseline in A1C, FPG, weight, and systolic BP 0.97±9.7% by clinical experts. Adjustments for individual meals were also in by wk 2 and 4 and continuous improvements were seen at wk 24 (Table). No close agreement (breakfast: 3.5±13.2% vs. 2.7±10.5%; lunch: 0.94±11.8% vs. clinically meaningful correlations were observed between weight loss and 1.8±5.8%; dinner: -1.44±13.8% vs. -1.6±11.6%). The directionality of mean % any outcome at wk 2, 4, and 24. Thus, exenatide QW treatment showed early adjustment of the basal profi les as characterized by total daily basal delivery improvements in glycemia, weight, and systolic BP at wk 2 and 4 document- was also in agreement, with a reduction of 0.22±2% by the algorithm vs. a ing the onset of effects already at low plasma exenatide levels. These early decrease of 2.64±3.7% by the endocrinologists. A Cohen’s Kappa test of the effects of exenatide QW suggest that these are direct actions that do not decisions shows that this agreement is not accidental (p=0.028). appear to be related to weight loss. This comparison of changes in patient clinical parameters by an initializa- Table. Mean Change (95% Confi dence Interval) from Baseline in Pharmaco- tion algorithm vs. expert endorinologists indicates that the algorithm recom- dynamic Outcomes. mendations are ready for deployment within a real-time run to run adapta- Week 2 Week 4 Week 24 tion strategy using longer and successive data periods. Supported By: DP3DK094331 A1C, % n=89 n=960 n=1808 -0.3 -0.4 -1.4 (-0.4, -0.1) (-0.4, -0.3) (-1.5, -1.4) 1132-P FPG, mmol/L n=153 n=845 n=1768 Achieving the Composite Endpoint of A1c -0.9 -1.6 -2.1 KATHLEEN M. DUNGAN, ITAMAR RAZ, ZACHARY SKRIVANEK, WHITNEY (-1.2, -0.6) (-1.7, -1.4) (-2.3, -2.0)

SEALLS, JESSIE L. FAHRBACH, Columbus, OH, Jerusalem, Israel, Indianapolis, IN POSTERS Weight, kg n=1403 n=2035 n=1809 Therapeutics This post-hoc analysis compares the once weekly glucagon-like pep- -0.3 -0.6 -2.4 Clinical Diabetes/ tide-1 receptor agonist dulaglutide (DU) 1.5 mg and 0.75 mg with active (-0.4, -0.2) (-0.6, -0.5) (-2.5, -2.2) comparator (AC) therapies and placebo used in the AWARD program on LDL cholesterol, mmol/L n=60 n=222 n=1736 the composite endpoint of glycated hemoglobin (A1C) <7.0%, no weight -0.0 -0.1 -0.1 gain (≤0 kg) and no hypoglycemia (glucose <3.1 mmol/L or any report of (-0.2, 0.1) (-0.2, -0.1) (-0.2, -0.1) severe hypoglycemia) after 26 weeks of treatment. A logistic regression analysis was performed on the intent-to-treat population, last observation HDL cholesterol, mmol/L n=60 n=223 n=1737 -0.0 -0.0 0.0 carried forward. (-0.0, 0.0) (-0.1, -0.0) (0.0, 0.0) At 26 weeks, within each study, 37 to 58% of patients on DU 1.5 mg, 27 to 49% of patients on DU 0.75 mg, and 9 to 61% on AC achieved the com- Diastolic BP, mmHg n=1567 n=2187 n=1809 -0.5 0.0 -1.0 posite endpoint. Signifi cantly more patients reached the composite endpoint (-1.0, -0.2) (-0.3, 0.4) (-1.4, -0.6) with DU 1.5 mg than with metformin, sitagliptin, exenatide BID, and insulin glargine (odds ratio [95% CI]: 1.5 [1.0, 2.2; p<.05], 4.5 [3.0, 6.6; p<.001], 2.6 Systolic BP, mmHg n=1567 n=2187 n=1809 -1.8 -2.2 -3.4 [1.8, 3.7; p<.001], 7.4 [4.4, 12.6; p<.001], respectively); with no difference (-2.4, -1.2) (-2.8, -1.7) (-4.0, -2.7) between dulaglutide 1.5 mg and liraglutide 1.8 mg (Figure). In addition, sig- nifi cantly more patients reached the composite endpoint with DU 0.75 mg Supported By: AstraZeneca compared to sitagliptin and insulin glargine (3.3 [2.2, 4.8; p<.001], 4.5 [2.7, 7.8; p<.001], respectively). 1134-P Dulaglutide is an effective treatment option, resulting in a similar or Relationship between Weight Change and Glycemic Control with greater proportion of patients who reached the A1C target of <7.0% without Once-Weekly Dulaglutide Treatment in Patients with Type 2 Diabetes hypoglycemia or weight gain. LAURA FERNANDEZ LANDO, GUILLERMO E. UMPIERREZ, KEVIN M. PANTALONE, ANITA KWAN, ALAN G. ZIMMERMANN, Indianapolis, IN, Atlanta, GA, Cleveland, OH Dulaglutide, a once weekly GLP-1 receptor agonist, was studied in the AWARD clinical trial program in adult patients with type 2 diabetes. In 6 head-to-head phase 3 trials, dulaglutide demonstrated signifi cant A1C re- duction and weight control effects. To assess the relationship between weight change and glycemic control in dulaglutide-treated patients, A1C and body weight data at 26 weeks from the 6 trials were analyzed. Due to differences in design, background therapy and baseline characteristics, analyses were conducted by trial rather than by pooling. Across the studies 87%-97% and 83%-95% of patients treated with du- laglutide 1.5 mg and 0.75 mg, respectively, demonstrated A1C reduction. Among the patients with A1C reduction, the majority of patients receiving dulaglutide 1.5 mg experienced weight loss (55%-83%) while 41%-79% in the dulaglutide 0.75 mg arm lost weight. Minimal correlation was observed between the changes in A1C and weight (IRI <0.3, all). Baseline characteris- Supported By: Eli Lilly and Company tics of gender, age, duration of diabetes, A1C, body weight and BMI did not correlate with different weight responses. 1133-P In summary, dulaglutide demonstrated a dose-dependent effect on both Early Pharmacodynamic Effects of Exenatide Once Weekly Are In- weight loss and A1C reduction. Dulaglutide is an effective treatment option dependent of Weight Loss with both A1C reduction and weight loss observed across the type 2 diabe- MICHAEL TRAUTMANN, WENYING HUANG, JAMES RUGGLES, Hamburg, Ger- tes treatment spectrum. many, San Diego, CA, Fort Washington, PA Exenatide once weekly (QW) is a GLP-1 receptor agonist that achieves the minimal effective concentration (50 pg/mL) for glucose lowering with regular QW dosing in 2 wk and steady-state plasma levels by wk 6-8. Sus- tained metabolic control is optimal to minimize T2D complications, but rapid

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A291 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—NON-INSULIN INJECTABLES

1136-P Prominent Improved Glycemic Control and Anti-obesity Effects alongside Signifi cant Elongated Pharmacokinetic Profi le following Administration of MOD-6031—A Novel Long-Acting Dual GLP-1/ Glucagon Agonist LITAL ISRAELI YAGEV, AHUVA BAR ILAN, VERED LEV, GILI HART, OREN HERSH- KOVITZ, Ness Ziona, Israel OPKO Biologics (f.k.a PROLOR) is developing long acting Oxyntomodulin (OXM) for treatment of type 2 diabetes and obesity, utilizing reversible PEGy- laton technology. The technology core is a spacer that links between the PEG and the peptide. Once injected, a fi rst order hydrolysis slowly releases the intact OXM, enabling a prolonged exposure of the peptide while maintaining its biological activity and ability to pass throw the blood brain barrier. Study objective was to characterize the effectiveness and prolonged anti- diabetic and anti-obesity activity of MOD-6031 in different obesity and dia- betic rodent models, with correlation to pharmacokinetic profi le. The pharmacological effects of MOD-6031 have been evaluated in sev- eral mice models following once/twice a week subcutaneous injections for 30 days. Body weight and food intake were monitored daily and OGTT was performed at the beginning and towards the end of studies. At the end of Supported By: Eli Lilly and Company the studies, plasma samples were collected for analysis of glucose, insulin and cholesterol. In parallel, MOD-6031 and its subproducts (OXM peptide 1135-P and PEG-linker) were examined for their pharmacokinetic profi les, utilizing Low Incidence of Anti-drug Antibody in Type 2 Diabetes Patients sensitive LC-MS-MS method. Treated with Once-Weekly Dulaglutide MOD-6031 induced a remarked weight loss and food intake inhibition in both animal models which were superior compared to those with bi-daily in- POSTERS ZVONKO MILICEVIC, GREG ANGLIN, KRISTINE HARPER, ROBERT KONRAD, Therapeutics jections of native OXM or of existing marketed drugs. In addition, MOD-6031

Clinical Diabetes/ ZACHARY SKRIVANEK, WOLFGANG GLAESNER, KENNETH MACE, Vienna, Aus- tria, Toronto, ON, Canada, Indianapolis, IN, San Diego, CA was found to improve glycemic control by a direct and indirect mechanism. In Dulaglutide (DU), a once weekly GLP-1 IgG4-Fc fusion protein for type 2 addition, an elongation of OXM half life up to 9 or 11 hr was observed in lean diabetes treatment, was structurally modifi ed to reduce immunogenic po- rats and ob/ob mice, respectively. tential by eliminating T-cell epitopes based on the results of the EpiVax al- Our data suggest that MOD-6031 is a potent long acting OXM having a poten- gorithm. Immunogenicity of DU was assessed in 9 clinical studies. Blood tial for a once weekly treatment of obese and type 2 diabetic human subjects. samples collected serially were assayed for DU anti-drug antibody (ADA) using validated ELISAs. Samples with treatment-emergent (TE) ADA were 1137-P tested for DU-neutralizing Ab and native sequence GLP-1 (nsGLP-1) cross- Placebo Effect of Hypoglycemic Drugs in Type 2 Diabetes—A Meta- reactivity, and then neutralization of nsGLP-1. Associations between ADA analysis and hypersensitivity AE, injection site reactions (ISR), and A1C changes XIAOLING CAI, WENJIA YANG, LINGLI ZHOU, XUEYAO HAN, LINONG JI, Beijing, were assessed. A total of 3907 DU and 1114 non-GLP-1 receptor agonist China comparator patients were tested. The incidence of TE ADA with DU was Placebo has been defi ned as any therapy that is used for its nonspecifi c 1.6% vs. 0.7% with non-GLP-1 receptor agonist comparator. DU-neutralizing psychological and physiologic effect but has no specifi c pharmacologic im- Ab, nsGLP-1 cross-reactivity, and nsGLP-1 neutralizing Ab were observed in pact on the condition being treated. The aim of this study is to evaluate 0.9%, 0.9%, and 0.1% of DU patients, respectively. There was no evidence placebo effect of hypoglycemic treatment in type 2 diabetes. of an effect of ADA on A1C change after 26 or 52 weeks of treatment. Only The MEDLINE®, EMBASE®, CENTRAL were searched until Dec 2013 and quali- 19 (0.5%) of DU patients had a hypersensitivity AE, none had TE ADA. There fi ed studies were included. All the studies were double blind, placebo-controlled were 20 (0.5%) DU-exposed patients with potentially immune mediated ISR; randomized trials in type 2 diabetes patients; study length of ≥12 weeks with the 2 of them (0.05% of 3907) had TE ADA. Incidence of ADA in patients exposed effi cacy evaluated by changes in HbA1c from baseline in groups. to DU was low. No association between DU ADA and hypersensitivity AEs, 248 studies were included. In studies compared SU with placebo, treat- ISR, or A1C changes was observed. ment with placebo led to a HbA1c change of 0.03% (95% CI, −0.37% to 0.44%, p>0.05); in studies compared MET with placebo, treatment with placebo led to a HbA1c change of 0.19% (95% CI, −0.18% to 0.57%, p>0.05); in studies compared AGI with placebo, treatment with placebo led to a HbA1c change of 0.06% (95% CI, −0.12% to 0.23%, p>0.05); in studies compared TZD with pla- cebo, treatment with placebo led to a HbA1c change of 0.09% (95% CI, -0.06% to 0.23%, p>0.05); in studies compared DPP-IV inhibitors with placebo, treat- ment with placebo led to a HbA1c change of -0.09% (95% CI, -0.20% to 0.03%, p>0.05); in studies compared SGLT2 with placebo, treatment with placebo led to a HbA1c change of -0.26% (95% CI, -0.54% to 0.02%, p>0.05); in studies compared GLP-1 analogue with placebo, treatment with placebo led to a HbA1c change of -0.11% (95% CI, -0.30% to 0.08%, p>0.05). Totally, in all studies, treatments with placebo led an HbA1c change from baseline of -0.03% with- out signifi cance (95% CI, -0.17% to 0.11%, p>0.05). Meta-regression analyses revealed that the age of patients and percentage of female were negatively associated with HbA1c changes from baseline in placebo group. Supported By: Eli Lilly and Company This meta-analysis provided comprehensive clinical evidence on placebo effect of hypoglycemic treatment in type 2 diabetes. Treatment with pla- cebo led an HbA1c change from baseline of -0.03% without signifi cance.

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A292 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—NON-INSULIN INJECTABLES

1138-P Table. Insulin and Glucose Measures On and Off HYA (Mean±SD or Median Comparative Usability Study of Two Once-Weekly GLP-1RA Pen In- (25th %ile, 75th %ile)). jector Products: Tanzeum™ and Bydureon® ANTHONY D. ANDRE, CATHERINE WANG, BARBARA BERRY, ALICE LOPER, Sara- On HYA Off HYA Delta P-value (n=13) (n=13) (off HYA - on HYA) toga, CA, King of Prussia, PA, Menlo Park, CA Albiglutide (Tanzeum™) and exenatide extended-release (Bydureon®) are Total Daily Dose Insulin (units) 51.0±14.4 51.3±14.4 -0.2 (-2.2, 1.5) 0.95 once-weekly GLP-RAs for T2DM in prefi lled injectors requiring a reconsti- Insulin use (units/kg/day) 0.64±0.14 0.65±0.14 0.00 (-0.03, 0.02) 0.89 tution of drug. This study compared the dosing success, ease of use and Average daily meter glucose (mg/dl) 187±21 180±24 -12 (-23, 11) 0.11 preference differences between 2 pens. This was a randomized, cross-over, open label, simulated-injection study Average daily sensor glucose (mg/dl) 186 (178, 189) 183 (168,190) 0 (-8, 8) 1.00 (funded by GSK). Total 48 participants with T2DM (age range: 30-75, 50% Percent sensor glucose in target range 17.5±4.5 18.6±5.2 1.1±4.6 0.42 with self-injection experience and all naïve to either of the pens tested) were (70-150 mg/dl) randomized into 2 groups with or without training before unaided use. The Supported By: JDRF order of presentation for each device was alternated. Performance, behavior and subjective measures were recorded during unaided use. ™ 1140-P Tanzeum pen resulted in higher success rate and less errors than Bydure- Semaglutide, a Once-Weekly Glucagon-Like Peptide 1 (GLP-1) on® pen. The majority (77%) of subjects preferred Tanzeum™ pen over Bydure- ® ™ Analog, Reduces Bodyweight and Promotes a More Healthy Food on (Table 1). Tanzeum pen was also preferred for its design/shape, smaller Choice in Diet-induced Obese Rats needle, the ease of drug reconstitution and allowable storage conditions. KIRSTEN RAUN, JOHANNES J. FELS, CHRISTIAN ROSENQUIST, LOTTE BJERRE Table 1. Summary of Key Measures and Findings. KNUDSEN, Måløv, Denmark Observation/Measures Tanzeum™ Pen Bydureon® Pen GLP-1 receptor agonists have favorable effects on blood glucose as well as body weight (BW) in the treatment of type 2 diabetes. Obesity is an im- Trained Untrained Overall Trained Untrained Overall (N=24) (N=24) (N=48) (N=24) (N=24) (N=48) portant risk factor for diabetes. In humans, energy intake is affected by many factors including the abundant availability of palatable and calorie- Percentage of Successful Unaided Injections (%) 100% 85% dense snacks. An altered food choice towards healthier food could be an POSTERS

important factor for future treatments. Semaglutide is a potent GLP-1 analog Therapeutics Failure to Dose 0 2/24 5/24 7/48

for once weekly dosing in humans, and is currently in phase 3 clinical testing Clinical Diabetes/ Total Number of Procedural Errors Observed 733for the treatment of type 2 diabetes. In the present study, the BW lowering effect of semaglutide as well as the effect on food intake (FI), food choice Final Overall Preference after Experiencing 21/24 16/24 37/48 3/24 8/24 11/48 and selected plasma parameters was evaluated in diet induced obese (DIO) both Injectors (88%) (67%) (77%) (12%) (33%) (23%) rats after once daily injection. Injection into a body-worn injection pad; only based the data from partici- Forty female 14 months old Wistar rats, were offered ad libitum chow and pants using the pens for the fi rst time. various chocolate supplements (C+CH) for 9 months. A control group (n=5) From the objective measure of dosing, Tanzeum™ pen emerged as an was offered chow only (C). easier to learn and use pen. Based upon participant comparisons of vari- The rats preferred chocolate resulting in the consumption of more than ous attributes, the majority (77%) of subjects preferred Tanzeum™ pen over 90% of calories as chocolate, which led to obesity. When the (C+CH) rats Bydureon® pen after experiencing both injectors. had reached an average BW of 454 g semaglutide treatment (1 or 4 ug/kg/ day s.c., n=13-14 rats per dose group) was initiated. The (C) group weigh- ing 343 g was dosed with vehicle. After 11 weeks of treatment the (C+CH) 1139-P semaglutide treated rats had a signifi cant and dose-dependent lower BW Hyaluronidase Use with Insulin Pumps Does Not Change Insulin Use (427.6 ± 18.2 g for 1 ug/kg and 373.7 ± 14.8 g for 4 ug/kg, data are given as or Glucose Control in Type 1 Diabetes mean ± SEM ) as compared to the vehicle treated (C+CH) rats (492.7 ± 24.0 g) R. PAUL WADWA, DANIEL J. DESALVO, EMILY WESTFALL, LAURA L. PYLE, LAU- and (C) rats (330.8 ± 14.5). BW was lost primarily as fat mass. The high dose REL MESSER, TRANG T. LY, DAVID M. MAAHS, BRUCE A. BUCKINGHAM, Aurora, semaglutide group had an overall decrease in FI measured as calorie intake CO, Stanford, CA of 28% with a 32% decrease in chocolate intake and 25% increase in chow Recombinant hyaluronidase (HYA), an enzymatic tissue modifi er, has been intake, demonstrating an altered food choice. Leptin, total cholesterol and shown to accelerate subcutaneous insulin absorption and improve postpran- FFA were signifi cantly decreased after treatment with semaglutide. dial glycemic control in a limited number of controlled inpatient studies. It In conclusion, semaglutide led to weight loss and promoted a more healthy is unclear whether HYA use in an outpatient setting would lower total daily food choice in DIO rats. dose of insulin (TDD) or affect mean glucose values. The objective of this analysis was to determine how TDD and average daily glucose are affected by HYA use in adults with type 1 diabetes. Inclu- 1141-P sion criteria included insulin pump use >1 year and A1C <10%. Effect of Liraglutide on Postprandial Glucagon, Carbohydrate In- Subjects were studied over 4 weeks at home. Infusion sets remained in take, and on Infl ammation in Patients with Type 1 Diabetes situ for up to 7 days or removed earlier due to infusion set failure. HYA was PARESH DANDONA, NITESH D. KUHADIYA, SANDEEP DHINDSA, HUSAM injected with the insertion of a new infusion set on day 0, and again on day GHANIM, MANAV BATRA, KELLY GREEN, ROBIN GIRDHAR, ANTOINE MAKDISSI, 3 during 2 of the 4 weeks. In the remaining two weeks, no HYA was injected. AJAY CHAUDHURI, Buffalo, NY Subjects wore Dexcom G4P glucose sensors for the duration of the study. To We have recently shown that liraglutide, a GLP-1 receptor agonist im- examine effects of HYA on insulin TDD and glucose measures, a delta value proves glycemic control in patients with type 1 diabetes. The mechanism was calculated for each participant. underlying these effects is not clear. We hypothesized that liraglutide sup- To date, 13 subjects (age 32±4 years, HbA1c 7.5±0.8%) have completed the presses post prandial glucagon increase and the intake of carbohydrates. study. No differences were seen in insulin TDD, average daily glucose or per- Thirty two patients were randomized into two groups (Liraglutide 1.8 mg cent of sensor glucose in target (Table). In this initial cohort, HYA use at pump daily and the other with placebo for 12 weeks). HbA1c fell by 0.43% in the li- infusion sites did not affect insulin TDD or alter glycemic control. Further work raglutide group with a 20% reduction in insulin dose while it was reduced by is needed to determine the impact of HYA use at pump infusion sites. 0.3% in the placebo group with unchanged insulin dose. C-peptide concen- trations were non-detectable both at the beginning and at the end. Fasting levels of glucagon were unchanged while there was a signifi cant increase in fasting GLP-1 and GIP concentrations in the liraglutide group by 19±6% and 15±6% after 12 weeks (P<0.05). Before start of interventions, the consump- tion of a high fat and high carbohydrates (HFHC) meal induced a signifi cant increase in plasma glucagon levels in both study groups. After 12 weeks, there was in increase by 35±7% (P=0.018) in the liraglutide group compared to baseline. Glucose excursions fell by 21±8% (P=0.017) at 12 weeks while this was unchanged in the placebo group. Carbohydrate intake fell by 30±5% (from 153±18 grams to 107±15 grams, p<0.05 along with frequency of daily

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A293 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—NON-INSULIN INJECTABLES

helpings (from 3.5 to 3/day). In liraglutide group there was a signifi cant re- Table. Characteristics of Patients Treated with Exenatide, Insulin and Piogli- duction in basal plasma concentration of CRP, FFA and endotoxin by 19±8, tazone at Baseline, after Treatments and Change from Baseline to 24-week. 21±5% and 24±6%, respectively (P<0.05) and in basal mRNA expression of Characteristics Exenatide Insulin Pioglitazone p value IL-1β, JNK-1, and SOCS-3 in peripheral blood mononuclear cells (MNC) by 22±7%, 19±6% and 23±6%, respectively (p<0.05) as reported. These param- Overall Exenatide Exenatide vs. Insulin vs. vs. insulin pioglitazone pioglitazone eters were unchanged in the placebo group. We conclude that the liraglutide improves glycemic control in patients with type 1 diabetes by reducing post Body weight (Kg) prandial glucagon increments and carbohydrate intake. The anti-infl ammato- Baseline 68.20±3.17 68.29±3.20 73.66±3.09 0.354 NA NA NA ry actions may also contribute to insulin sensitivity and glucose disposal. Change from baseline -4.30±1.06 -0.88±0.74 -0.34±0.92 0.036 0.018 0.029 0.857 p value* 0.002 0.261 0.715 1142-P BMI (Kg/m2) Patient Characteristics Associated with Initiation of GLP-1RA Ther- apy in Germany Baseline 26.25±1.02 25.67±0.76 27.16±0.78 0.498 NA NA NA QING QIAO, SUSAN GRANDY, JENNIE MEDIN, JOSH HILLER, KAREL KOSTEV, Change from baseline -1.60±0.36 -0.37±0.29 -0.14±0.34 0.038 0.020 0.029 0.894 Mölndal, Sweden, Gaithersburg, MD, London, United Kingdom, Frankfurt, Germany p value* 0.001 0.237 0.697 Patient characteristics associated with initiation of GLP-1 receptor ago- Waist-to-hip ratio nists (GLP-1RA) therapy were investigated among type 2 diabetes (T2D) patients. Baseline 0.90±0.01 0.92±0.02 0.96±0.04 0.592 NA NA NA A total of 938 adult T2D patients (men 55.5%) who initiated therapy with Change from baseline -0.03±0.01 0.01± 0.02 -0.05± 0.03 0.242 0.235 0.751 0.110 a GLP-1RA and 5197 patients (men 54.6%) who were not prescribed with p value* 0.088 0.646 0.129 GLP-1RA but used other glucose lowering drugs (metformin, sulfonylurea, Fat mass percentage (%) DPP-4, GLP-1RA, thiazolidinediones, alpha-glucosidase-inhibitors glinids and insulin) between January 1, 2011 and March 30, 2014 were retrospec- Baseline 30.18±1.77 29.56±1.42 29.88±1.21 0.874 NA NA NA tively studied based on a primary care database in Germany (IMS® Disease Change from baseline -1.66± 0.86 0.18± 0.50 0.77± 0.55 0.036 0.048 0.013 0.522 Analyzer). Odds ratio (95% confi dence interval) for initiation of GLP-1RA p value* 0.076 0.732 0.185

POSTERS was estimated using step-wise multivariate logistic regression analysis. 40 2 Therapeutics Fat Mass Index (Kg/m ) baseline sociodemographic and diabetes-related variables including prior Clinical Diabetes/ diagnoses of diabetes complications, cardiovascular diseases and obesity, Baseline 7.99±0.64 7.61±0.47 8.13±0.40 0.748 NA NA NA Charlson comorbidity index, baseline HbA1c and fasting glucose levels, an- Change from baseline -0.87± 0.28 -0.06± 0.21 0.18± 0.22 0.037 0.042 0.014 0.607 tihypertensive, lipid modifying, antidepressive and antiepileptic drugs etc p value* 0.009 0.781 0.436 were assessed in the models as covariates. Abdomen-to-hip fat ratio GLP-1RA users were younger than non-users (57.8 vs. 67.4 years; p<.0001). They were more often privately health insured (12.0% vs. 6.1%; p<.0001) and Baseline 1.18±0.03 1.24±0.05 1.27±0.05 0.839 NA NA NA were more frequently treated by diabetologists (22.8% vs. 10.9%; p<.0001). Change from baseline -0.06± 0.03 -0.04± 0.03 -0.07± 0.04 0.749 0.492 0.891 0.552 The mean BMI was higher among GLP-1RA users than in non-users (36.1 vs. p value* 0.086 0.243 0.091 31.3 kg/m2; p<.0001). Trunk-to-lower limbs fat ratio Multivariable adjusted odds ratios (95% confi dence intervals) for GLP-1RA initiators as compared with non-initiators were 2.42 (1.89-3.09) for private Baseline 1.11±0.04 1.14±0.03 1.19±0.04 0.449 NA NA NA health insurance, 2.11 (1.73-2.57) for diabetologist care, 0.94 (0.93-0.95) cor- Change from baseline -0.04± 0.03 0.01± 0.02 -0.10± 0.02 0.016 0.041 0.540 0.006 responding to a one year increase in age, 1.68 (1.34-2.10) for a obesity diag- p value* 0.171 0.530 <0.001 nosis, 1.77 (1.48-2.11) for being co-prescribed with angiotensin II receptor Trunk-to-upper limbs fat ratio antagonists and 0.81 (0.69-0.95) with analgesics. In Germany, T2D patients were more likely to receive a prescription with Baseline 1.20±0.05 1.19±0.04 1.37±0.06 0.261 NA NA NA GLP-1RA if they had private health insurance, were young but obese, and Change from baseline -0.03± 0.04 -0.03± 0.02 -0.10± 0.04 0.332 0.284 0.833 0.167 were cared for by a diabetologist. p value* 0.491 0.258 0.03 1143-P Effect of Exenatide, Insulin, and Pioglitazone on Body Weight and 1144-P Body Fat Distribution in Newly Diagnosed T2DM Real-World Adherence in Patients Aged = 65 years with Type 2 Dia- RENYUAN LI, WEN XU, SHUO LIN, JING LV, LONGYI ZENG, JIANPING WENG, betes Mellitus for Exenatide QW, Liraglutide QD, and Exenatide BID Guangzhou, China ROBERT DUFOUR, HIEP NGUYEN, AMANDA TARR, MICHAEL BULLANO, Carmel, The majority of patients with T2DM are overweight or obese. Evidences IN, Philadelphia, PA, Columbus, OH show that exenatide, insulin and pioglitazone have impact on body weight, Diabetes affects 9.3% of the U.S. population (29.1 million). The prevalence as well as body fat distribution. This study was designed to directly compare and incidence of type 2 diabetes mellitus (T2DM) increases in people aged the effects of these hypoglycemic agents on body weight and fat distribu- ≥ 65 years and approximately 25% of this population is affected by the dis- tion in newly diagnosed T2DM. ease. Patient adherence to an antidiabetes regimen is a clinical challenge This was a prospective, randomized clinical trial. Thirty-nine patients with when considering the medical complexities of T2DM in elderly patients and newly diagnosed T2DM (male: 53.8%, age: 49.0±1.6 years, BMI: 26.4±0.5 other comorbidities associated with aging (e.g., loss of manual dexterity). Kg/m2, HbA1c: 8.5±0.2%) were randomized to exenatide (n=13), mixed Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are an increasingly Protamine Zinc Recombinant Human Insulin Lispro Injection (25R) (n=12) or used class of drugs with proven effi cacy and tolerability. Real-world evi- pioglitazone (n=14) for a 24-week treatment, along with life style interven- dence on adherence to GLP-1RAs in elderly patients is limited. The current tion. Body weight, waist-to-hip ratio and fat mass distribution by DEXA were study examined adherence to medication in aged patients with T2DM initiat- assessed at baseline and week 24. ing a GLP-1RA. At week 24, body weight and fat mass index were decreased in patients The study used medical and pharmacy claims between 2010 and 2013 for treated with exenatide, while remained stable in those treated with insu- Medicare members in a U.S. health plan who had a diagnosis of T2DM and lin and pioglitazone. Waist to hip ratio and fat mass percentage were un- were new initiators of either exenatide QW (n=537), liraglutide (n=3673) or changed in all patients, regardless of treatments. Pioglitazone was shown exenatide BID (n=923) during that time frame and 6 months of continuous to shift fat from trunk to limbs (Table 1). enrollment pre- and post-index. Proportion of Days Covered (PDC) ≥ 80% In newly diagnosed T2DM, 24-week treatment with exenatide reduces was used to determine post-index adherence. Logistic regression models body weight and fat mass index; pioglitazone has effect on shifting fat from controlled for baseline demographics, comorbidities and T2DM treatments. trunk to limbs without infl uencing body weight and fat mass index; while Exenatide QW had a signifi cantly higher percentage of patients with a insulin does not affect either body weight or body fat distribution (Table 1). PDC ≥ 80% (43.2%) than either liraglutide (35.0%, χ2, p<.01) or exenatide BID (33.3%, χ2, p<.01). The adjusted results indicate that patients on lira- glutide or exenatide BID are 13.5% (p<.01) and 15.1% (p<.01) less likely to

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A294 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—NON-INSULIN INJECTABLES be adherent than patients on exenatide QW. Other signifi cant factors are: 1146-P evidence for cardiovascular disease, prescription for insulin and plan type. The Liraglutide Effect in Ambulatory Blood Pressure Monitoring in Results from this retrospective study suggest that patients age ≥ 65 years Type 2 Diabetes Mellitus Patients: A Proof-of-Concept Study treated with exenatide QW had a signifi cantly higher adherence rate com- PEDRO ROZAS-MORENO, JOAQUÍN CASTRO-GIMÉNEZ, ANTONIO SÁENZ- pared to other GLP-1RAs. Further research is needed to validate these fi nd- GUTIÉRREZ, JESÚS MORENO-FERNÁNDEZ, CÉSAR LOZANO-SUÁREZ, MIGUEL ings in other patient populations. AGUIRRE-SÁNCHEZ-COVISA, Ciudad Real, Spain, Manzanares, Spain Liraglutide is a long acting GLP-1 receptor agonist approved for the treat- 1145-P ment of type 2 diabetes mellitus (T2DM), which, in addition to its potent Predictors of Outcomes in T2DM Patients (Pts) in the GetGoal Trials effect on glycemic control, induces a signifi cant improvement in body weight Adding Lixisenatide (LIXI) to Oral Antihyperglycemic Drugs (OADs) and several cardiovascular risk factors, with low risk of hypoglycaemia. In or Basal Insulin (BI) both clinical trials and real world-setting, liraglutide lead to a reduction in LAWRENCE BLONDE, PAVAN CHAVA, TERRY DEX, JAY LIN, ELENA NIKONOVA, blood pressure by 1 to 6 mmHg. To our knowledge no study has analyzed RONALD GOLDENBERG, New Orleans, LA, Bridgewater, NJ, Flemington, NJ, Thorn- the effect of liraglutide in ambulatory blood pressure monitoring (ABMP) in hill, ON, Canada T2DM. This analysis explored the effect of baseline characteristics and treatment We performed a Proof-of-Concept, prospective and observational study. on outcomes in pts initiating LIXI. Pooled pt data from eight 24-week phase We included data from 23 patients with T2DM. Anthropometrics and a 24 h 3 trials of adults with T2DM initiating LIXI was analyzed by baseline therapy ambulatory systolic (SBP), diastolic blood pressure (DBP) and median blood (BI or OADs) and treatment (LIXI or placebo [PBO]). Effi cacy and safety out- presure (MBP) monitoring was performed before and one month after the comes were assessed descriptively and by multivariate regression. fi rst dose of liraglutide. No changes in antihypertensive drugs were al- Overall, 2,760 pts on OADs and 1,198 on BI were included; mean baseline lowed. age, body mass index (BMI), and A1C were comparable. Compared with PBO, Mean age was 50.3±10.38 years and 60.8% were males. Mean HbA1c LIXI signifi cantly improved glycemic outcomes (except fasting plasma glu- was 7.8±1.33 and mean body mass index was 35.3±3.4 Kg/m2. After 1 month cose [FPG] in the BI group), weight, and composite endpoints. Incidence of of treatment with liraglutide we observed a reduction in SBP (-3.23 mmHg, symptomatic hypoglycemia was higher with LIXI, but low in the OAD group, p=0.07) and an increase in heart rate (3.22 bpm, p=0.02). There was no signif- and generally low for severe hypoglycemia. Regression analysis identifi ed icant reduction in DBP (-0.39 mmHg, p=0.85) and MBP (-1.34 mmHg, p=0.59). The proportions of patients achieving SBP targets ( 130 mmHg) increased LIXI as a strong predictor of changes in all endpoints except FPG in the BI ≤ POSTERS group; baseline A1C was also a predictor of outcomes across groups except 4,4% after 1 month of treatment (65,2% vs. 69,6%, p>0,05). The change in Therapeutics for symptomatic hypoglycemia (Table). Baseline BMI was a weak predictor SBP was positively correlated with values of SBP, DBP and MBP measured 1 Clinical Diabetes/ of changes which varied across groups (Table), as was baseline FPG, age, month after initiation of the treatment (r=0.433, p=0.039; r=0.434, p=0.038; gender, and diabetes duration. r=0.453, p=0.03, respectively). In three patients gastrointestinal symptoms This analysis shows LIXI treatment, vs. PBO, was a signifi cant predictor were recorded but only one patient discontinued the treatment. of improved clinical outcomes (except for symptomatic hypoglycemia) when Our study suggests that in patients with T2DM and ABPM, liraglutide is added to OADs and BI, whereas other factors (e.g. baseline BMI) had smaller associated with a small increase in heart rate and modest reductions in SBP predictive effects. in a real-life and clinical practice setting. This data confi rm previous results but new studies with ABPM and a larger sample of patients are needed. Table. Results of Multivariate Predictor Analysis for the Outcomes. OADs BI 1147-P Outcome LIXI vs. Baseline Baseline LIXI vs. Baseline Baseline Effects of Once-Daily Morning Dosing of Lixisenatide on Glucose PBO BMI A1C PBO BMI A1C Excursion after Dinner and Usefulness of Its Divided Dosing (per 1 kg/m2) (per 1.0%) (per 1 kg/m2) (per 1.0%) NANAKO KITAGAWA, YUTAKA MORI, YUKIKO TANIGUCHI, YUI WATANABE, A1C change, %, (95% CI) −0.54 −0.01 −0.52 −0.45 −0.01 −0.35 HIROSHI SUZUKI, KAZUNORI UTSUNOMIYA, Komae, Japan, Higashimurayama, [P value] (−0.61, −0.47) (−0.01, 0.01) (−0.57, −0.48) (−0.58, −0.33) (−0.02, −0.01) (−0.44, −0.25) Japan, Tokyo, Japan [< 0.0001] [0.6111] [< 0.0001] [< 0.0001] [0.0348] [< 0.0001] Objective: It is unclear how potent the postprandial glucose-lowering ef- FPG change, mg/dL, (95% CI) −12.29 0.39 2.02 −4.0 0.36 5.94 fi cacy of lixisenatide (Lixi) may be at dinner time when the drug is assumed to [P value] (−15.04, −9.54) (0.17, 0.60) (−0.24, 3.80) (−9.17, 1.19) (−0.09, 0.81) (1.92, 9.97) be almost eliminated after its morning dosing. In this study, we investigated [< 0.0001] [0.0005] [0.0264] [0.1313] [0.1135] [0.0038] the effect of once-daily morning dosing of Lixi on glucose excursions after PPGa change, mg/dL, (95% CI) −88.28 1.65 −16.42 −81.31 0.31 9.23 dinner as well as the usefulness of its divided dosing between morning and [P value] (−100.38, −76.18) (0.71, 2.59) (−24.25, −8.58) (−91.54, −71.08) (−0.54, 1.15) (1.64, 16.82) evening. [< 0.0001] [0.0006] [< 0.0001] [< 0.0001] [0.4783] [0.0172] Methods: This study included a total of 9 type 2 diabetic patients in whom Weight change, kg, (95% CI) −0.67 −0.07 0.28 −0.98 −0.03 0.44 stable preprandial glucose control had been ensured with long-acting insulin [P value] (−0.91, −0.43) (−0.09, −0.05) (0.12, 0.43) (−1.36, −0.61) (−0.06, 0.01) (0.14, 0.73) alone. After undergoing CGM while being treated with insulin alone, these [< 0.0001] [< 0.0001] [0.0005] [< 0.0001] [0.1114] [0.0035] patients started to receive Lixi as add-on treatment and were evaluated for Symptomatic hypoglycemia,b OR 1.91 0.99 0.85 2.01 0.99 0.92 diurnal glucose variability with the once-daily morning injection versus the (95% CI) (1.22, 3.00) (0.96, 1.03) (0.65, 1.11) (1.41, 2.87) (0.96, 1.02) (0.71, 1.20) dosing of the same daily dose of Lixi divided between morning and evening [P value] [0.0050] [0.6923] [0.2196] [0.0001] [0.6136] [0.5434] on CGM when their dose had been titrated up to 20 µg/day. Pts achieving A1C < 7.0% with no 2.93 1.00 0.41 2.28 1.03 0.29 Results: With morning Lixi dosing, the post-breakfast glucose increases symptomatic hypoglycemia and no (2.37, 3.61) (0.98, 1.02) (0.36, 0.48) (1.50, 3.46) (1.00, 1.06) (0.20, 0.41) were potently suppressed, but post-dinner glucose increases were not as weight gain, OR (95% CI) [< 0.0001] [0.9797] [< 0.0001] [0.0001] [0.0935] [< 0.0001] potently suppressed. In contrast, with divided dosing, the postprandial glu- [P value] cose increases were suppressed to a similar degree both after breakfast aPPG measured by standardized meal-test (breakfast); bSymptomatic and and dinner. A comparison of glycemic variability outcomes between the two confi rmed blood glucose < 60 mg/dL. schedules showed that signifi cant decreases were seen in SD of glucose as OR, odds ratio; PPG, postprandial plasma glucose. well as in total area for glucose fl uctuations with divided dosing compared to Other outcomes assessed and not shown: Pts achieving A1C < 7.0%, Pts achieving A1C < 7.0% with no symptomatic hypoglycemia, Pts achieving morning dosing (both P < 0.05). Delta AUC for glucose was also signifi cantly A1C < 7.0% with no severe hypoglycemia, Pts achieving A1C < 7.0% with no decreased immediately after dinner to postprandial 3 hours with divided weight gain, and Pts achieving A1C < 7.0% with no severe hypoglycemia dosing compared to morning dosing (P < 0.05), while there was no difference and no weight gain. in this parameter after breakfast and lunch between the two schedules. Supported By: Sanofi U.S. Conclusions: Once-daily morning dosing of Lixi does not appear to offer consistent postprandial glucose lowering after each meal. Thus, divided dosing of Lixi between morning and evening may be an option worth consid- ering as a means to protect against glycemic fl uctuations.

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1148-P 1150-P The Proportion of Patients Successfully Treated with Liraglutide— In Insulin-Naïve Patients with T2DM Uncontrolled on GLP-1 Re- Results from a Post-hoc Analysis of the EVIDENCE Study ceptor Agonists (GLP-1RA), IDegLira (Novel Combination of Insulin JEAN-FRANÇOIS GAUTIER, ALFRED PENFORNIS, GUILLAUME CHARPENTIER, Degludec + Liraglutide) Resulted in Improved Patient-Reported Out- AMIRA BOUZIDI, SULIYA MADANI, LUC MARTINEZ, EVELINE ESCHWÈGE, PIERRE comes vs. Unchanged GLP-1RA GOURDY, Paris, France, Corbeil-Essonnes, France, Villejuif, France, Toulouse, France SULTAN LINJAWI, MERYL BROD, BRUCE W. BODE, LOUIS B. CHAYKIN, JEAN- EVIDENCE was a 2-year multicentre, prospective, observational, post mar- PIERRE COURREGES, YEHUDA HANDELSMAN, JENS HARALD KONGSØ, PANAG- keting outpatient study requested by the French National Health Authority in IOTA DIAMANTOPOULOU REITER, RICHARD W. SIMPSON, Coffs Harbour, Austra- order to evaluate the effectiveness and safety of liraglutide in clinical prac- lia, Mill Valley, CA, Atlanta, GA, Bradenton, FL, Narbonne, France, Los Angeles, CA, tice. Diabetologists and general practitioners recruited adult patients with Bagsværd, Denmark, Søborg, Denmark, Box Hill, Australia type 2 diabetes starting treatment with liraglutide. Assessments were made We evaluated patient-reported outcomes (PRO) from DUAL III, a 26-week at 3 and 6 months, then at 6-month intervals for a further 18 months. The open-label trial that randomized subjects with T2DM uncontrolled on maxi- primary endpoint was to determine the proportion of patients with HbA1c on mum dose GLP-1RA + metformin ± pioglitazone ± sulfonylurea to IDegLira target (< 7%) after 2 years. The population of the primary endpoint (n=2607) OD or unchanged GLP-1RA. In summary, IDegLira provided superior glycemic included not only patients still taking liraglutide after two years of follow up, control vs. unchanged GLP-1RA (end of trial A1C 6.4% vs. 7.4%, p<0.001). As but also patients who prematurely discontinued treatment with liraglutide expected with insulin use, more hypoglycemia and weight gain occurred. for adverse events. We used validated instruments to assess PRO: TRIM-D for the 5 subdomains Based on the same population, we report here the proportion of patients treatment burden, daily life, diabetes management, compliance and psy- achieving the primary endpoint or decreasing at least 1% in HbA1c after 2 chological health; and DTSQs for treatment satisfaction (sum of 6 items), years. The characteristics of the study sample were described by the mean perceived hypoglycemia and perceived hyperglycemia. and standard deviation (mean±SD) for continuous measures, and frequency Improvement in TRIM-D scores was greater with IDegLira vs. unchanged for categorical measures. GLP-1RA for all subdomains (p<0.05) and total score (p<0.001). Change in Baseline data were collected from 3152 patients (53% men, mean age total score (Table) exceeded the minimally important difference of 7.8 points. 59±11 years, diabetes duration 10±6 years, mean HbA1c 8.5±1.5%), and most DTSQs total score was higher with IDegLira (p<0.001). Perceived frequency of them (n=2804, 90%) exceeded the ADA/EASD target with an HbA1c ≥7% of hyperglycemia was lower (p<0.001), and perceived frequency of hypogly- at baseline. At the end of the study 2029 patients (64.4%) were still taking cemia was higher (p<0.01), with IDegLira vs. unchanged GLP-1RA. POSTERS Therapeutics liraglutide after 2 years of follow-up. 29.5% (769) reached the primary end- IDegLira vs. unchanged GLP-1RA produced a clinically relevant improvement Clinical Diabetes/ point and 49.2% (n=1282) when we include those who had a reduction of at in PRO as assessed by TRIM-D, and a greater increase in DTSQs treatment sat- least 1% in HbA1c from inclusion. isfaction. In summary, this post hoc analysis showed a clinically relevant contribu- Table. tion of liraglutide (HbA1c <7% and/or decrease of ≥ 1%) in routine clinical practice, in about half of the patients after 2 years of follow-up. A limitation of this study is the lack of control arm, making it diffi cult to evaluate whether observed improvements are attributable to liraglutide alone. Supported By: Novo Nordisk A/S

1149-P Real-World 1-Year HbA1c and Weight Outcomes in Patients Treated with Exenatide Once Weekly or Liraglutide Once Daily CARRIE MCADAM-MARX, HIEP NGUYEN, MARISA SCHAUERHAMER, XIANG- YANG YE, MUKUL SINGHAL, DAVID COBDEN, Salt Lake City, UT, Fort Washington, PA Small differences in HbA1c reductions were observed in a clinical trial comparing exenatide once weekly (ExQW) and liraglutide once daily (LiraQD). Supported By: Novo Nordisk We investigated whether differences in HbA1c and weight effi cacy were detected in the real-world setting. This historical cohort study compared 1151-P HbA1c and weight outcomes in GLP1-RA naïve patients with T2DM initiated Development of a New Questionnaire Assessing Nausea and Vomit- on ExQW (available 2012) or LiraQD (available 2010) between 02/01/2012 ing for Use in Patients with Type 2 Diabetes Mellitus and 03/31/2013 (index date) in a national electronic medical record dataset. SUSAN MATHIAS, PAM C. BERRY, HILARY COLWELL, MIRKO SIRKIRICA, ANTO- Other GLP-1RA were not included as suffi cient follow-up data were lacking NIO NINO, Winter Park, FL, Middlesex, United Kingdom, King of Prussia, PA due to relatively recent approval dates. Of 1.69 million patients with T2DM, The goal was to develop a patient-reported outcome (PRO) measure for use 5141 were included with 808 prescribed ExQW and 4333 prescribed LiraQD. with patients with type 2 diabetes mellitus (T2DM) who experience nausea (N) Mean (SD) age was 57 (11) and 57 (11) years (p=.73), with 49% and 46% and/or vomiting (V) while receiving a GLP-1 receptor agonist (GLP-1). Following male (p=.15) in the ExQW and LiraQD groups, respectively. Mean HbA1c and IRB approval, patients > 40 years of age with T2DM, with a history of cardiovas- weight in the ExQW and LiraQD groups were 8.3% (1.5) vs. 8.4% (1.6) (p=.66) cular disease, currently or within the last 3 months receiving a GLP-1 receptor and 107 kg (24.8) vs. 108 kg (24.8) (p=.38), respectively. A total of 96 (12%) agonist associated with N or V, took part in a telephone interview containing ExQW and 1854 (43%) LiraQD patients were also started on insulin on index concept elicitative (CE) questions about N and V (e.g., frequency/severity of N date (p<.001). At 12-month follow-up, HbA1c was lowered by 0.5% (SD 1.3 and V, how N and V impacts daily activities.). A draft Nausea and Vomiting Ques- and 1.5) in both groups; 254 (32%) ExQW and 1327 (31%) LiraQD patients tionnaire (NVQ) was developed based on the interview data. For subsequent in- had an HbA1c <7.0% (p=.75). Multivariable linear regression analysis control- terviews, the same CE questions were asked, then subjects completed the draft ling for confounders including insulin use identifi ed no difference in HbA1c NVQ and answered cognitive debriefi ng (CD) questions to evaluate its content, change for ExQW vs. LiraQD (coef=-0.001, 95% CI -0.106, 0.104). Patients clarity, and relevance. Eleven subjects were interviewed (n=6 completed CE por- in the ExQW and LiraQD group lost a mean of 2.3 kg (6.4) and 2.3 kg (7.1) tion only; n=5 completed both CE and CD portions) [65% male; mean age 60; at the 12-month follow-up, respectively. This study found that ExQW and mean duration with T2DM 12 years]. N only or N with dry heaving (DH) was LiraQD were associated with similar reductions in HbA1c and weight in the reported by 57%, and 43% experienced both N and V +/- DH. No subjects ex- real-world despite insulin being initiated signifi cantly more frequently with perienced V alone. Most subjects experienced N and/or V within 1-3 weeks of the fi rst prescription for LiraQD than with ExQW. ExQW and LiraQD are ap- the fi rst GLP-1 receptor agonist dose (Exenatide, Liraglutide). Approximately half propriate options for patients needing antidiabetic therapy to lower HbA1c reported N and/or V within 2 hours of receiving the GLP-1. 54% experienced N while promoting weight loss. and/or V for > 3 months. 71% discontinued treatment with GLP-1 primarily due Supported By: AstraZeneca to N and V. 86% reported an impact on daily activities due to N and/or V. Other impacts included emotional (71%), social (64%), physical (64%), and work (80% of those who work). In general, the NVQ was found to be clear, comprehensive, and relevant. Revisions were made to the NVQ based on CD fi ndings. The fi nal NVQ contains 16 items assessing how N and/or V at its worst impacts daily activi-

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A296 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—NON-INSULIN INJECTABLES ties (doing household chores, going to work, social and leisure activities). These 1154-P results provide initial support for the content validity of the NVQ. Lixisenatide vs. Exenatide on Metabolic Control, Insulin Secretion, and Insulin Sensitivity in Impaired Glucose Tolerance Patients 1152-P MANUEL GONZÁLEZ-ORTIZ, KARINA G. PÉREZ-RUBIO, ESPERANZA MARTÍNEZ- Reasons for Discontinuation of GLP-1 Receptor Antagonists: Data ABUNDIS, Guadalajara, Mexico from a Large Cross-Sectional Survey of Physicians and Type 2 Dia- Currently glucagon-like peptide-1 receptor agonists could be recommend- betic Patients ed in the treatment of impaired glucose tolerance (IGT) patients. Lixisenatide MIRKO SIKIRICA, ALAN A. MARTIN, ANDREA LEITH, ROBERT WOOD, JAMES and exenatide have distinct pharmacokinetic profile and molecular structure PIERCY, VICTORIA HIGGINS, King of Prussia, PA, Wendover, United Kingdom, with potential clinical implications. Cheshire, United Kingdom The aim of this study was to evaluate the effect of lixisenatide vs. ex- GLP-1 receptor agonists (GLP-1) have been shown to have high discontinua- enatide on metabolic control, insulin secretion and insulin sensitivity in IGT tion rates in the fi rst year after initiation. Understanding patient and physician patients. experience with GLP-1s may help to improve medication choice and patients A randomized, open-label, clinical trial was carried out in 24 adults volun- to remain on therapy. Our aim is to understand reasons for discontinuation; to teers with IGT. They received lixisenatide (10 mg once daily for 2 week and describe and rank the extent to which treatment-related problems were expe- then 20 mg once daily) or exenatide (5 mg twice daily for 4 weeks and then rienced by patients, and whether physician perceptions refl ect this. 10 mg twice daily) SC for 3 months. At the beginning and at the end of the Data were taken from the 2014 Adelphi Diabetes Disease Specifi c Programme, study, weight, BMI, waist, blood pressure, glucose, insulin and lipid profi le a survey (supported by GSK) of physicians and a convenience sample of their pa- were measured. Glucose and insulin levels were measured every 30 min dur- tients across U.S./EU5. Physicians completed an interview and patient record ing 120 min after a 75-gram oral dextrose load. Areas under the curve (AUC) forms. The patients were invited to complete a self-completion form (PSC). An of glucose and insulin were calculated. Total insulin secretion (Insulinogenic oversample was included to ensure suffi cient numbers discontinuing a GLP-1 in Index), first-phase of insulin secretion (Stumvoll Index) and insulin sensitivity the last 6 months. Ranking, percents and descriptive statistics were used. (Matsuda Index), were assessed. Statistical analyses were performed with Including the oversample, 452 patients were reported by the physician to Wilcoxon and Mann-Whitney U tests. have discontinued a GLP-1 in the last 6 months (199 patients reported discon- Both groups decreased weight, BMI, waist circumference, systolic and tinuing a GLP-1 in the PSC). Top 5 physician-reported reasons for changing diastolic blood pressures, as well as, glucose and insulin at 120 min; be- sides increased the Matsuda index. Lixisenatide decreased fasting glu- a GLP-1 were: lack of blood glucose control (46%), nausea/vomiting (44%), POSTERS GI side effects (37%), patient request (18%) and lack of patient compliance cose (5.7±0.8 vs. 5.0±0.5 mmol/l, p=0.008), AUC of glucose (1252±150 vs. Therapeutics (10%). Top 5 patient-reported reasons were: “made me feel sick” (nausea) 1032±157 mmol/l, p=0.008) and HDL-C (1.1±0.1 vs. 1.0±0.1 mmol/l, p=0.025), Clinical Diabetes/ (64%), “made me throw up” (vomit) (45%), “prefer medications I can take by and increased LDL-C (2.5±0.8 vs. 3.0±0.9 mmol/l, p=0.016), whereas exenati- mouth instead of injections” (40%), “it didn’t help control my glucose levels de decreased triglycerides (2.4±1.0 vs. 2.1±1.0 mmol/l, p=0.050). enough” (35%) and “caused me to experience diarrhea/gas/bloating” (26%). In conclusion, both treatments decreased the same metabolic measure- This research shows that while physicians focused on effi cacy, they recog- ments, with exception of lixisenatide that also decreased fasting glucose, nized some GI side effects of GLP-1s as reasons for discontinuation. Patients AUC of glucose and HDL-C and increased LDL-C, and exenatide that de- focused most emphasis (3 of 5 top reasons) on the GI profi les as leading creased triglycerides. reasons for discontinuation. This research shows that the impact of GLP-1 related GI side effects on patients may be underestimated by physicians. 1155-P Exenatide BID Improves β-Cell Function More than Liraglutide QD 1153-P in Patients with Type 2 Diabetes: A Propensity Score Matched Ret- Albiglutide Provides Effective Glycemic Lowering Across Diabetes rospective Cohort Study (ELENA-β) Duration Subgroups YOSHINOBU KONDO, SHINOBU SATOH, URU NEZU OSADA, YASUO TERAUCHI, PHILIP D. HOME, DIANE M. MILLER, MOLLY C. CARR, Newcastle upon Tyne, Unit- Kanagawa, Japan ed Kingdom, King of Prussia, PA Previous studies reported the positive effects of glucagon-like peptide-1 Incretin therapies work in part by stimulating insulin secretion, so it is impor- receptor agonists (GLP-1-RA) on β-cells. However, no comparative studies tant to characterize their effi cacy in people with longer-standing diabetes and existed for the effects of short-acting GLP-1-RA (Exenatide BID, Exe) and less residual β-cell function. Here we test the hypothesis that albiglutide will long-acting GLP-1-RA (Liraglutide QD, Lira) on β-cell function. These condi- have similar effi cacy and safety profi le independent of diabetes duration. Pooled tions inspired us to compare their effects on β-cell function in patients with phase-3 data were from 1391 particpants in placebo comparator studies funded type 2 diabetes (T2D) using a propensity score (PS)-matched retrospective by GlaxoSmithKline, randomized 923 to albiglutide and 468 to placebo, ± oral cohort study. We included patients with T2D who were continuously treated with Exe or Lira for 24 weeks and whose -cell function was measured using agents. Effi cacy analyses use the primary outcome variable (HbA1c) and other β measures pooling data 6 months from randomization. Baseline characteristics a 1-mg intravenous glucagon stimulation test (GST) at baseline and after were generally well balanced vs. placebo and typical of people with T2DM (age 24 weeks of treatment. PSs were generated based on age, sex, duration 2 of diabetes, body mass index, estimated glomerular fi ltration rate, baseline 54 yr, HbA1c 8.1%, BMI 33.1 kg/m ). Change in HbA1c for albiglutide vs. placebo varied from a difference of -0.93 (-1.08,-0.79) %-units) in the <5-yr group to -0.70 HbA1c level, previous diabetes treatment and residual β-cell function. The (-0.90, -0.50)%-units in the ≥10-yr group (Table). The fasting plasma glucose primary endpoint was the inter-group difference in the change in the area difference was -1.65 (-2.03, -1.27) mmol/L at short duration, -1.30 (-1.75, -0.86) under the curve (AUC) of serum C-peptide immunoreactivity (CPR) during the mmol/L in the middle group, and -1.44 (-1.97, -0.92) mmol/L at ≥10-yr duration. GST (AUC-CPR = [sum of CPR levels before and 6 min after GST] × 6 min/2). Adverse events did not differ between albiglutide groups except for injection Through screening and matching by PS analysis, 26 Exe-treated patients and site reactions (fewer at longer duration). Serious adverse events were similar by 26 Lira-treated patients were included in the analysis. The baseline charac- duration of diabetes for the albiglutide group. Thus, albiglutide had good effi cacy teristics of the two groups were similar. The fi nal dose was 12.7 ± 4.5 µg/ independent of diabetes duration with no deterioration of adverse event profi le. day in the Exe group and 0.9 mg/day in the Lira group. No signifi cant differ- Table. ence in change in HbA1c levels was observed between the two groups after 24 weeks of treatment (Exe: −0.76 ± 0.44%; Lira: −1.25 ± 0.44%, p = 0.36). albiglutide placebo The AUC-CPR increased in both groups (Exe: +4.34 ± 0.85 ng/mL·min, p <

Duration of diabetes n HbA1c (%-units) n HbA1c (%-units) 0.001; Lira: +1.78 ± 0.85 ng/mL·min, p = 0.03), although the improvement was <5 yr signifi cantly greater in the Exe group (p = 0.02). In conclusion, intermittent change (SD) 403 -0.91 ± 0.85 205 -0.01 ±.90 stimulation by short-acting GLP-1-RA was more effective than continuous stimulation by long-acting GLP-1-RA with respect to improving -cell func- difference (95% CI) -0.93 (-1.08,-0.79) β tion in patients with T2D. ≥5 – 10 yr change (SD) 301 -0.79 ± 0.83 145 -0.06 ± 1.17 difference (95% CI) -0.75 (-0.92,-0.58) ≥10 yr change (SD) 200 -0.73 ± 0.74 109 -0.06 ± 0.92 difference (95% CI) -0.70 (-0.90, -0.50)

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1156-P Liraglutide Added to Insulin: Beyond the Intensifi cation of Basal Insulin AGUSTÍN A. MERCHANTE, ROSA CASAÑ, PABLO ABELLÁN, JAVIER SANZ, AMPARO FABRA, CARLOS SÁNCHEZ, Castellón, Spain, Xàtiva, Spain, Valencia, Spain Long-acting GLP-1 RA Liraglutide added to basal insulin is a new therapeu- tic strategy and may provide an alternative to prandial insulin for advancing basal insulin therapy. We evaluate the effi cacy and safety of the combination of basal insulin and Liraglutide (1,8 mg OD) in obese type 2 diabetic patients (T2DM) with poor glycemic control (HbA1c 7-10,5 %), in two different clinical settings 1) Intensifi cation of the prior treatment with basal insulin + antidiabetic drugs (OAD) (BI-Lira) 2) Simplifi cation of the prior basal/bolus insulin therapy (BB- Lira), with the goal of withdrawing the bolus of rapid-acting insulin. In this prospective, real-life, observational study, carried out in three hos- pitals in Valencia (Spain) a total of 112 subjects were included (mean age (± SD) 61,2 ± 8,4 years, mean body mass index 38,3 ± 5,8 kg/m2, mean HbA1c 9,2 ± 1,2%), 55 in BI-Lira group and 57 in BB-Lira group. After a period of treatment optimization with basal insulin, we evaluated changes in HbA1c, weight, insulin dose, hypoglycemia and other adverse events at baseline and 6 months. At 6 months, HbA1c decreased from baseline by -1.5 ± 1.3% with BI-Lira 1158-P and -1.3 ± 1,2% with BB-Lira (p < 0.001 vs. baseline in both groups). Weight Physician-Reported Use of GLP-1 Receptor Agonists in the UK decreased -4.9 ± 4.4 kg with BI-Lira and -6.8 ± 3.4 kg with BB-Lira (p < 0.001 SARAH CURTIS, JESSICA B. JORDAN, KRISTINA S. BOYE, LOUIS S. MATZA, vs. baseline in both groups). The mean insulin dose decreased from 51 to 33 POSTERS OMOLARA ADETUNJI, SHERRY A. MARTIN, Indianapolis, IN, Bethesda, MD, Bas- Therapeutics IU with BI-Lira (-35%), and from 89 to 40 IU with BB-Lira (-55%). Insulin was ingstoke, United Kingdom Clinical Diabetes/ withdrawn in fi fteen patients. At study end only six patients continued in GLP-1 receptor agonists (GLP-1 RAs) have been used to treat patients with the BB-Lira group (89%, n=51, became to BI-Lira). The main adverse effects type 2 diabetes for almost a decade, and new treatments in this class have were gastrointestinal (nausea 12%, vomiting 4%), and the patients had no recently been introduced. The purpose of the current study was to exam- severe hypoglycemia. ine self-reported practice patterns of physicians who prescribe GLP-1 RAs Conducted in real-life conditions, in poorly controlled T2DM patients in the UK. A total of 670 physicians (226 diabetes specialists; 444 general treated with basal insulin + OADs or with basal/bolus insulin therapy, the practice [GP] physicians) completed a survey in September or October 2014. addition of Liraglutide is an effective and safe option. It improves glycemic On average, physicians reported seeing 86 patients per month with type 2 control, reducing weight and reducing insulin dose. Most patients treated diabetes (specialists 134; GP 61). Almost all physicians had prescribed GLP-1 with BB-Lira can withdraw the bolus of rapid-acting insulin. RAs (95.4% total sample; 99.1% specialists; 93.5% GP), and they reported writing or authorizing an average of 9 new GLP-1 RA prescriptions per month 1157-P (16.8 specialists; 4.8 GP). When asked to list the types of patients who are Characteristics Associated with Glycemic Control in Adults with most frequently prescribed a GLP-1 RA, physicians most commonly reported Type 2 Diabetes (T2D) Initiating Incretin Therapies patients whose glucose levels are not adequately controlled with oral medi- SANJEEV N. MEHTA, WILLIAM MCMULLEN, MONIKA A. NIEWCZAS, ALF GRU- cations (85.9% of physicians) and obese/overweight patients (83.7%). When ENER, ALESSANDRO DORIA, Boston, MA, Bridgewater, NJ asked to list the types of patients that receive the greatest benefi t from GLP- Incretin therapies [GLP-1 agonists (GLP-1a) and DPP-4 inhibitors (DPP- 1 RAs, the most common responses were obese/overweight patients (listed 4i)] are 2nd line options for adults with T2D. To identify predictors of the by 92.7%), patients at high risk for hypoglycemia (53.3%), younger patients effectiveness of these therapies upon glycemic control, we evaluated (25.7%), and recently diagnosed patients (17.8%). The majority of physicians A1c changes 1 year after initiation of GLP-1a or DPP-4i in 1220 T2D adults (76.6% total sample; 70.8% specialists; 79.5% GP) reported that there was at a single center from 2007-11. For GLP-1a users (n=603), mean A1c was no HbA1c cut off above which they would not prescribe a GLP-1 RA. Almost 8.2±1.4% and fell 0.4% (p<.05) after 1 year. For DPP-4i users (n=617), mean all diabetes specialists (99.1%) believed they had suffi cient knowledge to A1c was 7.8±1.1% and fell 0.3% (p<.05) after 1 year. In both groups, higher prescribe a GLP-1 RA, compared with only 76.1% of GPs. Overall, results baseline A1c, older age, and not using insulin were associated with larger highlight the widespread use of GLP-1 RAs for treatment of type 2 diabetes A1c reductions at 1 year (Figure, p<.05 for all). In GLP-1a users, no concomi- in the UK. However, almost a quarter of general practice physicians report tant thiazolidinedione (TZD) use was also associated with larger A1c reduc- that they still do not have enough knowledge to prescribe medications in tion. By contrast, in DPP-4i users, no concomitant sulfonylurea (SU) use was this class. associated with larger A1c reduction (Figure, p<.05 for all). Patient sex, BMI, diabetes duration, insurance type and visit frequency were not associated 1159-P with A1c changes in these multivariable linear regression models. Findings A Cross-Sectional Survey of Patient-Reported Factors Associated suggest that incretin therapies are especially effective early in the course of with Initiation and Persistence of Pramlintide Use among Adults T2D (before insulin), with largest A1c reductions observed in patients with with Type 1 Diabetes (T1DM) highest A1c values. Discrepant associations between A1c changes and other MARK PEYROT, ASHER RUNION, AMY KRAUS, PRAVEEN DHANKHAR, TAISIA diabetes medications may provide mechanistic insights into incretin thera- ISUPOV, IFTEKHAR KALSEKAR, Baltimore, MD, Boston, MA, Gaithersburg, MD, Fort pies and warrant investigation. Washington, PA This study assessed patient-reported factors associated with initiation and persistence of pramlintide (Symlin) use in clinical practice. Participants (N=89) were adults (age > 18) with T1DM from a large clinical practice net- work who completed an online survey on pramlintide use; all data were self- reported. Respondents included 17 current pramlintide users (CU), 44 former pramlintide users (FU), and 28 who had discussed pramlintide use with their physician but never used (NU). Respondent demographics: age (43+14 yr), gender (67% female), race/ethnicity (93% white non-Hispanic), education (80% college graduates), T1DM duration (24+13 yr); respondent groups were not signifi cantly (P<.05) different. Although 87% of respondents used insulin pumps, CU were more likely (P<.05) to use injections (29%) than FU (11%) or NU (7%). Discussion of pramlintide use was more often initiated by physi- cians than patients (55% vs. 45%). Physician encouragement of pramlintide

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A298 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—NON-INSULIN INJECTABLES use (vs. describing it as one option or discouraging use) was more com- Data derived from a fi xed effect meta-analysis with inverse variance mon among those who initiated use (CU/FU) than NU (54% vs. 11%, P<.05). weights. Changes in A1C and body weight were analyzed using an analysis Among NU 55% said they would initiate pramlintide use if recommended of variance (ANOVA) using last observation carried forward at Week 24. by their physician. CU rated the effi cacy of appetite control by pramlintide SE, standard error. higher than FU and NU rated their current non-pramlintide regimens (P<.05). Supported By: Sanofi U.S. Changing insulin dose with initiation of pramlintide use was associated with higher persistence (32% vs. 0%, P<.05). Reasons for non-persistence reported by FU were inconvenience (21%), lack of adequate anti-hyperglyce- 1161-P mic benefi t (20%), increased hypoglycemia (20%), and stomach discomfort Minimal Self-Reported Injection and Injection Site Pain with Ex- (14%). Among FU 23% said they were likely to resume pramlintide use. Al- enatide Suspension Administration though discussion of pramlintide use may be initiated by patients, physician DANIELLE ARMAS, ELISE HARDY, JAMES RUGGLES, SUDIPTA BHATTACHARYA, recommendation was the key factor associated with initiation of therapy, Tempe, AZ, Gaithersburg, MD, Fort Washington, PA and a substantial portion of non-users would initiate pramlintide therapy if Injection fear may discourage patients from initiating effective type 2 dia- physician-recommended. betes therapy. Aspects of needle design (eg, bevel, overall size) may lessen Supported By: AstraZeneca injection and injection site pain. A study in adults with no signifi cant health issues evaluated injection confi gurations for monthly exenatide-containing microspheres (dia <0.1 mm) in medium chain triglyceride suspension using 1160-P a 23g, 7 mm extra-thin walled, beveled needle and included subject ratings Achieving Postprandial Glucose Control with Lixisenatide (LIXI) of injection and injection site pain. Study staff administered exenatide by Improves Glycemic Control in T2DM Patients (Pts) on Basal Insulin autoinjector (Cohort 1; N=264) or syringe (Cohorts 2 [N=265], 3 [N=263]; 4 JAIME A. DAVIDSON, WILLIAM STAGER, SACHIN PARANJAPE, RACHELE BER- [N=266], and 5 [N=266]), with varying exenatide microsphere mass and vehi- RIA, LAWRENCE A. LEITER, Dallas, TX, Bridgewater, NJ, Toronto, ON, Canada cle volume among cohorts. The validated 11-point Injection Pain Assessment LIXI is a prandial glucagon-like peptide-1 receptor agonist. Given the ra- (0=no pain; 10=as bad as it could be) was used to rate injection pain immedi- tionale for combining complementary therapies to improve glycemic control, ately after and injection site pain 5 min after administration. Both measures we examined the impact of LIXI on postprandial plasma glucose (PPG) target had generally similar results across cohorts. Most subjects rated injection achievement (measured 2 h after a standard liquid breakfast), and subse- (77.0%-83.7%) and injection site pain (96.2%-98.5%) as 0 or 1. Mean scores

quent effi cacy and safety in T2DM pts on basal insulin. The hypothesis was POSTERS

for each cohort (Figure) were <1 for both measures (median 0). Scores ≥4 Therapeutics that achieving PPG targets with LIXI increases the likelihood of reaching A1C

were infrequent for injection (3.0%-5.2%) and injection site pain (0%-0.8%). Clinical Diabetes/ goals. Maximum score was 8 for injection and 5 for injection site pain. Our fi ndings Data from GetGoal-L, GetGoal-Duo1, and GetGoal-L Asia studies (LIXI add- suggest that injection and injection site pain associated with exenatide sus- ed to basal insulin) were analyzed. Pts (LIXI: n = 587, 47% male, mean weight pension administration via 23g needle are typically minimal. 82 kg, A1C 8.1%; placebo: n = 484, 50% male, mean weight 81 kg, A1C 8.1%) were categorized by baseline fasting plasma glucose (FPG) < 126 or ≥ 126 mg/dL. LIXI-treated pts were grouped as PPG responders or non-responders (< 180 or ≥ 180 mg/dL). In both FPG categories, more LIXI pts reached target PPG vs. placebo (< 126 mg/dL: 55% vs. 18%; ≥ 126 mg/dL: 48% vs. 10%). Greater reductions in A1C and weight were seen in LIXI-treated pts; effi cacy was superior in pts meeting both FPG and PPG targets (Table). Such pts were more likely to achieve A1C < 7.0% and had no increased risk of symptomatic hypoglycemia (Table). These results support the hypothesis that achieving PPG targets with LIXI increases A1C goal achievement in T2DM pts with uncontrolled A1C on basal insulin, and highlights the importance of PPG control. Table. Effi cacy and Safety Outcomes in Pts Treated with LIXI. Baseline FPG < 126 mg/dL Baseline FPG ≥ 126 mg/dL Supported By: AstraZeneca PPG PPG Difference PPG PPG Difference responders non- between groups responders non- between 1162-P (PPG < 180 responders (SE), (PPG < 180 responders groups (SE), The Relationship of Exenatide Exposure with Glycemic and Weight mg/dL) (PPG ≥ 180 P value mg/dL) (PPG ≥ 180 P value Outcomes in Patients Treated with Exenatide Once Weekly (QW) LIXI n = 156 mg/dL) LIXI n = 147 mg/dL) THOMAS C. BLEVINS, JAMES RUGGLES, ELISE HARDY, Austin, TX, Fort Washing- Placebo LIXI n = 127 Placebo LIXI n = 157 ton, PA, Gaithersburg, MD n = 47 Placebo n = 23 Placebo Plasma concentration of exenatide QW increases with weekly admin- n = 210 n = 204 istration to reach steady-state in 6-8 wk, but response may begin before Pts with A1C this. This post hoc analysis examined the relationship between exenatide < 7.0% at Week 24, % concentration and fasting plasma glucose (FPG), A1C, weight, and nausea LIXI 61.6 30.9 −26.7 (5.6), < 0.001 52.3 16.1 −32.7 (5.0), < 0.001 Placebo 55.3 12.9 −27.2 (8.2), < 0.001 39.0 7.2 −17.3 (10.7), 0.107 over 24 wk in pts with T2D using data from a randomized, open-label trial (DURATION-5). Endpoints were assessed in pts on exenatide QW in the ITT Change in A1C from population (N=129); plasma exenatide concentrations were available for a baseline to Week 24, mean (SE) pt subset (PK population; N=72). In the ITT/ PK populations, baseline FPG, LIXI −0.93 (0.07) −0.37 (0.07) −0.55 (0.10), < 0.001 −1.07 (0.08) −0.40 (0.08) −0.65 (0.12), < 0.001 A1C, and weight were 173/173 mg/dL, 8.5/8.4%, and 97/98 kg. Exenatide Placebo −0.50 (0.11) −0.11 (0.06) −0.34 (0.13), 0.008 −0.71 (0.19) −0.22 (0.07) −0.40 (0.21), 0.055 concentration gradually increased until reaching steady-state at ~8 wk (Fig). Rate of symptomatic By Wk 4, 94% of the Wk-24 steady-state response for FPG occurred with a hypoglycemia during reduction of 32.4 mg/dL. A1C reductions of −0.6% occurred at Wk 4 before the 24 week study stabilizing (Wk 24 A1C: −1.6%). Weight reductions were observed at Wk 4 period, mean (SE) (-0.7 kg) and decreased linearly (Wk 24: −2.3 kg). Nausea and/or vomiting LIXI 0.40 (0.04) 0.36 (0.04) 0.03 (0.06), 0.609 0.26 (0.04) 0.19 (0.03) 0.06 (0.05), 0.259 occurred in 5 of 72 pts (PK pop); event onset occurred before steady-state Placebo 0.13 (0.05) 0.23 (0.03) −0.05 (0.06), 0.418 0.12 (0.07) 0.16 (0.03) −0.04 (0.08), 0.645 (exenatide concentration <250 pg/mL) in 4 of 5 pts. Mean exenatide concen- Body weight change trations were similar in pts with or without nausea/vomiting (308 vs. 293 pg/ from baseline to mL). Exenatide QW treatment resulted in clinically relevant improvements Week 24, mean (SE) in A1C and FPG, and weight reductions by Wk 4, before exenatide reached LIXI −1.22 (0.23) −0.10 (0.25) −1.23 (0.34), < 0.001 −0.73 (0.19) −0.27 (0.19) −0.62 (0.28), 0.024 steady-state. Placebo 0.99 (0.41) 0.55 (0.19) 0.09 (0.47), 0.852 0.05 (0.54) 0.01 (0.16) −0.05 (0.57), 0.934

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A299 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS

3rd daily metformin doses. Subjects discontinued Met dosing if symptoms became intolerable. Blood glucose was measured with a glucometer by fi n- ger stick each morning before eating and dosing. Subjects recorded daily their glucose and their responses to questionnaires evaluating GI symptoms (stool consistency, urgency to evacuate, bloating sensation, fl atulence, and evacuation completeness). A composite tolerability score was calculated us- ing ratings of severity of the symptoms, which were combined into a single score for each participant. A higher score indicates a greater tolerability. The combination of Met and GIMM produced better tolerance to Met than the placebo combination (6.78±0.65 (mean ± SEM) vs. 4.45±0.69; p=0.0006). Mean fasting glucose levels were signifi cantly (p<0.02) lower with the Met- GIMM combination (121.3±7.8mg/dl) than with Met-placebo (151.9±7.8mg/ dl). This observation could have positive public health consequences since combining the GIMM with Met might allow greater use of metformin in T2D subjects and improve treatment of the disease.

& 1165-P A Novel Dual Pancreatic and Hepatic Acting Glucokinase Activator, HMS5552: Phase I Studies in Healthy Subjects and T2DM Patients Supported By: AstraZeneca DALONG ZHU, YANHUA DING, DAWEI XIAO, HONGWEI FAN, PEI HU, XUENING LI, XIN GAO, XIAOYING LI, YONGGUO LI, YI ZHANG, LI CHEN, Nanjing, China, Changc- 1163-P hun, China, Beijing, China, Shanghai, China The Effect of Liraglutide as Subsequent Treatment after Short-Term HMS5552 is a novel allosteric GK activator (GKA) targeting both pancre- Intensive Insulin Therapy on Glucose Control and β-Cell Function in atic and liver GK that enhances glucose stimulated insulin release (GSIR) Newly Diagnosed Type 2 Diabetic Patients and suppress hepatic glucose (glc) production. Here, we present two RDBPC

POSTERS WEIJIAN KE, JUAN LIU, HAI LI, LIEHUA LIU, YANBING LI, Guangzhou, China Phase I studies of HMS5552: A single-ascending dose study (SAD) in Chinese Therapeutics healthy subjects (HS) and a multiple-ascending dose study (MAD) in Chinese

Clinical Diabetes/ In order to estimate the effect of liraglutide after intensive insulin therapy (ITT), newly diagnosed and drug naïve type 2 diabetic patients were enrolled T2DM patients. Safety, PK and PD effects on glc and insulin release were and randomly assigned to therapy with CSII (Group 1, n=19 ) or liraglutide at assessed. a dose of 0.6 mg injected subcutaneously per day combined with CSII (Group HMS5552 was well tolerated in single doses in sixty HS (5, 10, 15, 25, 35 2, n=20). ITT was stopped after normoglycaemia maintained for 2 weeks. All and 50mg) and in multiple BID doses for 8 days in fi fty-three T2DM patients patients were guided with diet and physical exercise, while the patients in (25, 50, 100, 150 and 200mg). No serious or severe AEs, including severe Group 2 continued to use liraglutide 1.2mg per day until fi nishing the 12-week hypoglycemia reported. No signifi cant clinical laboratory fi ndings. course of treatment. Intravenous glucose tolerance tests (IVGTTs) were con- HMS5552 was rapidly absorbed with dose-proportional increases in plas- ducted to investigate acute insulin response (AIR) and blood glucose, HbA1c, ma exposure. No appreciable drug accumulation, food-effect or differences insulin were measured at baseline, after ITT and 12-week follow up. In each due to gender seen. There were no differences in PK parameters between group, 4 patients were failed to follow up at 12 weeks. At the 12-week fol- HS and T2DM patients. low up, there was no difference of the level of HbA1c between two groups HMS5552 showed signifi cant dose-related effects in glc lowering and in- (Group 1: 6.3±0.7% vs. Group 2: 6.0±0.5%, p=0.325). The results of fasting sulin secretion with a low risk of causing hypoglycemia both in HS and T2DM glucose were similar (Group 1: 6.2±1.1 vs. Group 2: 6.9±1.1, p=0.721). We found patients. Daily fasting glc and 2-h post meal glc levels were reduced by up to remarkable improvement of AIR after ITT in Group 2 [168.63 (350.95) (uU·min/ 34% and 51%, respectively while 24-h glc AUC was reduced by up to 36%, ml)] compared with Group 1 [52.05 (100.55) (uU·min/ml)]. However, the advan- depending on dose. An effect attributed to GSIR which accelerated the timing tage of liraglutide disappeared after the 12-week course of treatment, the and increased the magnitude of insulin and C-peptide release was observed. AIR of Group 2 had decreased to the level of Group 1 [Group 1: 47.40 (70.95) Signifi cant increases in insulin after meals but not during fasting were consis- (uU·min/ml) vs. Group 2: 50.43 (70.40) (uU·min/ml), p=0.921]. Our study shows tent with GK’s dual-acting MOA. Early phase indexes of insulin secretion after 12-week treatment of liraglutide as subsequent treatment is not enough to treatment (ΔI30/ΔG30 and insulin AUC0-30min) increased signifi cantly in most maintain the further improvement of β cell function after ITT. groups, indicating potential improvement in β-cell function. These results support continuing development of HMS5552 as dual act- ing GKA for T2DM having low hypoglycemia risk with potential to improve CLINICAL THERAPEUTICS/NEW TECHNOLOGY— β-cell function in clinic, and provides additional guidance for trial design and ORAL AGENTS optimal patient selection in future Phase 2 trials. Supported By: 2014ZX09101002004, 14431908300

Guided Audio Tour: Novel Oral Agents (Posters: 1164-P to 1171-P), see page & 1166-P 13. PBI-4050 Protects against Pancreatic Fibrosis in Type 2 Diabetes LYNE GAGNON, MING-ZHI ZHANG, BRIGITTE GROUIX, KATHY HINCE, FRANÇOIS & 1164-P SARRA-BOURNET, LIETTE GERVAIS, MIKAËL TREMBLAY, MARIE-PIER CLOUTIER, Addition of a Gastrointestinal Microbiome Modulator to Metformin LILIANNE GEERTS, RAYMOND HARRIS, Laval, QC, Canada, Nashville, TN Improves Metformin Tolerance and Fasting Glucose Levels Introduction: PBI-4050, a novel orally active compound, has been shown JEFFREY H. BURTON, MATTHEW JOHNSON, JOLENE JOHNSON, DANIEL S. to exhibit anti-fi brotic/infl ammatory properties in different in vivo models, in- HSIA, FRANK L. GREENWAY, MARK L. HEIMAN, Baton Rouge, LA, New Orleans, cluding diabetic nephropathy. In this study, we examined whether PBI-4050 LA, Indianapolis, IN affected hyperglycemia, insulin resistance and the development of pancreatic Adverse effects of metformin (Met) are related to gastrointestinal (GI) in- fi brosis in two models of type 2 diabetes (db/db and eNOS-/- db/db). tolerance that could limit titration to an effi cacious dose or cause discontinu- Methods: db/db mice received vehicle (water) or PBI-4050 (200 mg/kg/day) by ation of the medication. Because some Met side effects may be attributable daily gastric gavage from 6 to 24 weeks of age and BKS db/db with eNOS knock- to the GI microbiome, we tested whether a GI microbiome modulator (GIMM) out (eNOS-/- db/db) mice received the same treatment either from 8 to 20 weeks used in combination with Met would ameliorate the GI symptoms. A two- of age (early treatment) or from 16 to 24 weeks of age (late treatment). period crossover study design was used with two treatment sequences, Results: Early PBI-4050 treatment ameliorated the fasting hyperglycemia either placebo in period 1 followed by GIMM in period 2 or vice versa. Study and abnormal glucose tolerance tests seen in vehicle-treated controls in periods lasted for two weeks, with a two-week washout period between. both mouse models. In addition, PBI-4050 led to higher blood insulin lev- During the fi rst week, T2D patients who experienced metformin GI intoler- els (1.9±2.2 vs. 9.7±6.8 ng/ml, p=0.025, n=10 in db/db mice at 23 weeks; ance took 500mg Met along with their assigned NM504 (GIMM) or placebo 5.29±1.10 vs. 2.23±0.42 ng/ml, p<0.05. n=4 in eNOS-/- db/db mice at 20 treatment with breakfast and with dinner. In week 2, the 10 subjects esca- weeks). Pancreatic insulin mRNA expression was also increased 3-fold in lated to 500mg Met (t.i.d.), with GIMM or placebo consumed with the 1st and PBI-4050-treated db/db mice. In eNOS-/- db/db untreated mice, plasma insu-

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A300 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS lin levels decreased gradually over time (p<0.05 vs. 8 weeks and 16 weeks). glucose, liver glycogen and triglycerides (TG) were evaluated after chronic Early treatment with PBI-4050 (8 to 20 weeks) prevented the decline of treatment with TTP399 in ob/ob mice and minipigs. Our results demonstrate plasma insulin concentration (p<0.05 vs. vehicle). Furthermore, late treat- that TTP399 is a liver-selective GKA that does not disrupt the interaction ment with PBI-4050 (16 to 24 weeks) not only prevented the further loss of between GK and GKRP. Further in vivo evidence confi rms that at anticipated pancreas function, but restored pancreas function to that seen at 8 weeks of therapeutic concentrations, TTP399 stimulates the liver to metabolize glu- age (p<0.01 vs. vehicle; p<0.05 vs. baseline at 16 weeks of age) as indicated cose while inducing little or no insulin secretion, no dyslipidemia and no in- by decreased pancreas islet fi brosis. In addition, PBI-4050 inhibited mac- crease in glycogen or TG in the liver. These results indicate that TTP399 has rophage and CD8 lymphocyte infi ltration in pancreas. a superior profi le compared to previous GKAs by greatly reducing the risk of Conclusion: These studies suggest that PBI-4050 improves hyperglyce- hypoglycemia and dyslipidemia while maintaining durability. mia, preserves insulin production, and prevents pancreas islet fi brosis in as- sociation with decreases in macrophage and CD8 lymphocyte infi ltration. & 1169-P Dose-Ranging Study to Determine the Optimum Dose for Imeglimin, & 1167-P a Novel Treatment for Type 2 Diabetes Clinically Differentiated Glucokinase Activator HMS5552: Effective PASCALE FOUQUERAY, SEBASTIEN BOLZE, VALDIS PIRAGS, CLIFFORD J. BAILEY, Control of 24-Hour Glucose and Improvement of β-Cell Function in GUNTRAM SCHERNTHANER, SILVIO E. INZUCCHI, JOHN E. GERICH, MICHAEL T2DM Patients RODEN, HAROLD E. LEBOVITZ, Lyon, France, Riga, Latvia, Birmingham, United Kingdom, DALONG ZHU, YANHUA DING, DAWEI XIAO, HONGWEI FAN, PEI HU, XIAOYING Vienna, Austria, New Haven, CT, Wayne, PA, Düsseldorf, Germany, New York, NY LI, YONGGUO LI, YI ZHANG, LI CHEN, Nanjing, China, Changchun, China, Beijing, Imeglimin is the fi rst in a novel class of glucose-lowering drugs, which China, Shanghai, China restores mitochondrial function, leading to an improved insulin secretion and Glucokinase (GK) is a glucose-sensing enzyme predominantly expressed action. This study assessed the effi cacy and tolerability of imeglimin in type in pancreatic β-cells and liver that is involved in glucose homeostasis. 2 diabetes patients, 75% of whom had previously been managed on oral HMS5552 is a novel allosteric GK activator (GKA) targeting both pancreatic antihyperglycemic monotherapies. and liver GK that has shown the ability to enhance glucose stimulated insu- This multi-center, randomized, double-blind, placebo-controlled, parallel- lin release (GSIR) and suppress hepatic glucose production. In this First-in- group 24-week Phase IIb study assessed the effect of twice-daily imeglimin Patient clinical study, we explore the safety, tolerability, PK, PD and glucose 500 mg, 1,000 mg, 1,500 mg, 2,000 mg or placebo. Patients with type 2 dia-

response profi les of HMS5552 in Chinese patients with T2DM and further betes (n=382, 60% female; mean age, 58 years; A1C, 7.94%; BMI, 31.2 kg/ POSTERS characterize its mechanism of action (MOA). m2) were randomized following a 3-6 week wash-out/placebo run-in period. Therapeutics HMS5552 was evaluated in a randomized, double-blind, placebo-con- The primary effi cacy endpoint was the placebo-adjusted dose-dependent Clinical Diabetes/ trolled Phase 1b multiple-ascending dose study. 53 T2DM patients received reduction in A1C from baseline; secondary endpoints included changes in HMS5552 (25, 50, 100, 150 or 200mg) or placebo twice daily orally for 8 days fasting plasma glucose (FPG), % responders (A1C ≤ 7%), body weight, insulin in hospital. and C-peptide and lipid concentrations. HMS5552 was generally safe and well tolerated. No serious or severe Imeglimin reduced A1C in a dose-dependent manner from baseline; the AEs, including severe hypoglycemia were reported. No signifi cant clinical most effective dose was 1,500 mg BID (placebo-adjusted A1C reduction laboratory fi ndings. No appreciable drug accumulation, food-effect or differ- -0.63%, P <0.001). Maximal effi cacy for all doses was obtained after 18 ences due to gender seen. T1/2 was ~10 hours. Both Cmax and AUC showed weeks of treatment. 33.3% of patients receiving imeglimin 1,500 mg BID linear dose proportionality. No major metabolites found in plasma. achieved an A1C ≤ 7% after 24 weeks compared with placebo (12.5%), HMS5552 showed signifi cant dose-related effects in glucose lowering (P=0.005). Reductions in FPG were greatest for imeglimin 1,500 mg BID and insulin secretion with a low risk of causing hypoglycemia. Daily fasting (placebo-adjusted decrease 1.25 mmol/L (22.5 mg/dL) (P=0.001). No subjects glucose and 2-h post meal glucose levels were reduced by 11.5 to 34% and receiving the 1,500 mg BID dose required rescue therapy. Imeglimin had a 12 to 51%, respectively while 24-h glucose AUC was reduced by 11 to 36% in neutral effect on body weight. the dose range of 25 to 200 mg BID. An effect attributed to enhanced GSIR Imeglimin was generally well tolerated at all doses with no hypoglycemia, which accelerated the timing and increased the magnitude of insulin and C- no serious related treatment-emergent adverse events. The most frequent peptide release was observed. Early phase indexes of insulin secretion after reported adverse events with imeglimin 1,500 mg BID were gastrointestinal treatment (ΔI30/ΔG30 and insulin AUC0-30) increased signifi cantly in most related. groups, indicating potential improvement in β-cell function. This study demonstrates that imeglimin 1,500 mg BID is effi cacious, This study supports continuing development of HMS5552 as a dual acting weight neutral, and well tolerated with no increased risk of hypoglycemia. GKA for T2DM having low hypoglycemia risk with potential to improve β-cell function in clinic. & 1170-P Supported By: 2014ZX09101002004, 14431908300 D-Chiro-Inositol as Adjuvant Treatment Improves Glycaemic Con- trol in Overweight Type 1 Diabetes Patients & 1168-P ANNA RITA MAURIZI, ROSSELLA DEL TORO, MARIANGELA DE PASCALIS, MARI- TTP399, a Liver Selective Glucokinase Activator (GKA) that Pre- KA MENDUNI, ANGELO LAURIA PANTANO, SHADI KYANVASH, SILVIA MAN- serves the Physiological Regulation of Glucokinase (GK) by GK FRINI, PAOLO POZZILLI, Rome, Italy Regulatory Protein (GKRP) With the increase of obesity, insulin resistance is now occurring more CARMEN VALCARCE, OTIS C. ATTUCKS, TUNG M. FONG, JENNIFER L.R. FREE- frequently in type 1 diabetes (T1D) patients. Therefore, to achieve optimal MAN, High Point, NC, Somerset, NJ glycaemic control and to improve insulin sensitivity, insulin sensitizing drugs GK acts as a glucose sensor to elicit glucose specifi c responses, primarily such as metformin are commonly added to insulin therapy in overweight and from hepatocytes and pancreatic β-cells. Previously identifi ed GKAs evalu- obese T1D patients. Similarly to metformin, D-Chiro-Inositol (DCI), as puta- ated in the clinic for the treatment of type 2 diabetes demonstrate improved tive mediator of intracellular insulin action can accelerate glucose disposal glucose control; however these GKAs show increased incidence of hypogly- and act as insulin sensitizer. Moreover signifi cant reduction of DCI plasma cemia and hyperlipidemia and an apparent lack of durability. These liabilities levels and a relationship between its decreased urinary excretion and the have been correlated to hyperstimulation of the β-cells and/or the accumu- degree of insulin resistance were observed. The aim of this prospective, lation of lipids in the liver, consistent with the disruption of GK and GKRP randomized controlled trial was to evaluate the effi cacy of DCI on glycaemic interaction. Thus, liver selective GKAs that do not activate GK in β-cells control in T1D patients undergoing insulin therapy. 25 T1D patients aged 17- or affect the GK-GKRP interaction are expected to demonstrate a superior 50 years, with disease duration > 1 year and BMI >25, were enrolled in the profi le. TTP399 is a novel liver selective GKA that has shown normalization study. Patients were randomized to 1 g DCI plus 400 mcg folic acid once daily of glycemic control in animal models and type 2 diabetic subjects without (treated group) or to 400 mcg folic acid once daily (control group). HbA1c and inducing hypoglycemia or dyslipidemia. BMI were evaluated at entry into the trial and at 3 and 6 months follow-up. The purpose of the studies described herein was to evaluate TTP399 ef- Paired t test (two tailed) and analysis of variance were used to evaluate dif- fects on GK and GKRP interaction in vitro and to examine in vivo evidence ferences in HbA1c and BMI at different time points. HbA1c at entry was 8.3% of hypoglycemia, dyslipidemia or changes in hepatic glycogen/lipid content. ± 0.14 (SD) in treated group and 7.9% ± 0.28 (SD) in control group(p:NS). After Experiments were conducted in vitro to evaluate the effects of TTP399 on 3 months follow-up a signifi cant reduction of HbA1c was observed in treated the nuclear localization of GK at various glucose concentrations in hepa- group vs. control group (7.4% ± 0.8 vs. 7.7% ± 1.0, respectively, p:<0.05). At tocytes to measure the GK-GKRP interaction. In vivo, changes in plasma the end of the study period HbA1c reduction in DCI treated group vs. control

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group was statistically confi rmed. BMI at entry was 25.6 ± 1.8 (SD) in treat- ed group and 27.1 ± 2.2 (SD) in control group (p: NS). After 3 and 6 months follow-up there was a tendency for a reduction in BMI in the DCI treated group vs. control group. This trial demonstrated for the fi rst time that the oral supplementation of DCI to insulin therapy improves glycaemic control as shown by a signifi cant reduction of HbA1c levels.

& 1171-P Colonic Delivery of L-Glutamine Augments GLP-1 and Insulin Secre- tion after Oral Glucose JERZY SZEWCZYK, ROGER NOLAN, JOANN GIANNONE, STEFAN MARCUARD, Chapel Hill, NC, Durham, NC, Greenville, NC It is now widely accepted that malabsorptive surgeries like RYGB, BPD, and BPD with duodenal switch resolve or improve diabetes. It has been suggested that an increase in gut hormone secretion following surgery is the most likely reason for this effect. Increased concentration of nutrients such as L-glutamine and butyrate in distal small intestine and colon, where most of GLP-1 secreting L-cells are expressed, could explain this increase. Validation of this hypothesis could constitute an important step towards developing new therapeutic approaches for treatment of diabetes that take advantage of physiologic responses. Ten type 2 diabetes patients with good glycemic control (HbA1c=6.9%, range 6.1-7.9; average fasting plasma glucose = 135mg/dL, range 101-151) at the time of treatment visits, treated with diet or oral agents participated in a clinical study to determine the effect of rectally administered L-glutamine,

POSTERS butyrate, or placebo on secretion of GLP-1 and insulin after an oral glucose Therapeutics challenge (50g). The design was a single-center, single-dose, double-blind, Clinical Diabetes/ placebo-controlled, crossover study. Treatment visits were at least 7 days Supported By: Boehringer Ingelheim apart. Drugs (1g)/placebo were infused into the sigmoid colon over 15min, and 3min later 50g of glucose solution was administered orally. Nine (9) & 1173-P blood samples were collected over 150 min and analyzed for glucose, GLP-1 Safety and Tolerability of Empaglifl ozin in Patients with Type 2 Dia- and insulin. betes (T2DM) Administration of a single dose of colonic L-glutamine signifi cantly in- SVEN KOHLER, AFSHIN SALSALI, STEFAN HANTEL, GABRIEL KIM, HANS J. WO- creased GLP-1 and insulin during the oral glucose tolerance test. Despite this ERLE, ULI C. BROEDL, Ingelheim, Germany, Ridgefi eld, CT, Biberach, Germany there was no difference in blood glucose. Colonic butyrate effects were not We assessed the safety and tolerability of empaglifl ozin (EMPA) using different than placebo treatment. These results demonstrate that delivering data pooled from patients with T2DM from Phase I, II and III trials (including L-glutamine to the colon can stimulate GLP-1 secretion associated with a extensions) who received placebo (PBO; N=3695), EMPA 10 mg (N=3806) or rise in plasma insulin in humans with T2DM. EMPA 25 mg (N=4782). Adverse events (AEs) were assessed descriptively in patients who took ≥1 dose of study drug. Total exposure was 3254, 3840 and 5649 patient-years in the PBO, EMPA Guided Audio Tour: Growing Understanding of SGLT2 Inhibitors (Posters: 10 mg and EMPA 25 mg groups, respectively. The incidence of any AE(s), seri- 1172-P to 1179-P), see page 13. ous AE(s), severe AE(s), AE(s) reported as drug-related by the investigator, and AE(s) leading to treatment discontinuation were similar in the PBO, EMPA 10 & 1172-P mg and EMPA 25 mg groups (Table). The incidence of confi rmed hypoglycemic The Effects of Empaglifl ozin (EMPA) on Blood Pressure (BP) and AEs (plasma glucose ≤70mg/dl and/or requiring assistance) was similar with Markers of Arterial Stiffness and Vascular Resistance in Patients PBO, EMPA 10 mg and EMPA 25 mg (Table). The incidence of events consis- with Type 2 Diabetes by Subgroups of Age, Sex, and Degree of Hy- tent with urinary tract infections (UTI) was similar with PBO, EMPA 10 mg and pertension EMPA 25 mg, and was higher in female than male patients. The incidence of ROBERT J. CHILTON, CHRISTOPHER P. CANNON, ILKKA TIKKANEN, SUSANNE events consistent with genital infection was higher with EMPA than PBO, and CROWE, THOMAS HACH, HANS-JUERGEN WOERLE, ULI C. BROEDL, ODD ERIK higher in female than male patients. The incidence (rate per 100 patient-years) JOHANSEN, San Antonio, TX, Boston, MA, Helsinki, Finland, Ingelheim, Germany, of AEs consistent with volume depletion (based on 8 preferred terms) was 1.6 Asker, Norway on PBO, 1.5 on EMPA 10 mg and 1.3 on EMPA 25 mg. EMPA improves glycemia and reduces weight, BP, central and peripheral In conclusion, in a pooled analysis of data from >12000 patients with hemodynamic parameters. Differential effects of EMPA on this by age, sex T2DM, EMPA 10 mg and 25 mg were well tolerated. and degree of hypertension are unknown. We assessed the hypothesis Table. that EMPA would reduce BP, pulse pressure (PP = SBP -DBP), a validated surrogate marker of the stiffening of the conduit vessels and mean arte- rial pressure (MAP = ([2 x DBP]+SBP)/3), refl ecting cardiac output multiplied by vascular resistance across these subgroups. It was also postulated that greater reductions would be seen in those with highest baseline SBP and advanced age. Overall 2477 patients were analyzed from four 24-week phase III randomized trials (on no, one or two background glucose lowering drugs) of EMPA 10 mg or 25 mg (n=1652) versus placebo (n=825) (mean± SD age 55.6±10.2 yrs, HbA1c 8.0±0.9%, SBP/DBP 129.1±15.0/78.3±8.8 mmHg, heart rate 74±10, BMI 28.7±5.5 m/kg2). HbA1c was signifi cantly reduced with EMPA (pooled dosages) compared to placebo (mean [SE]):-0.65% (0.03), p<0.001). SBP, DBP, PP and MAP were reduced in all subgroups. For SBP and MAP, greater reductions were observed in those with highest SBP whereas PP was reduced most in those with advanced age (Table). EMPA-REG OUT- COME™ (NCT01131676), reporting 2015, will evaluate if these benefi ts will translate into CV risk reduction.

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& 1174-P Comparison of Pharmacodynamics of Dapaglifl ozin in Patients with Type 1 or Type 2 Diabetes Mellitus WEIFENG TANG, RENÉ BOUW, EVA JOHNSSON, DAVID W. BOULTON, TAREK A. LEIL, FRANK LACRETA, Gaithersburg, MD, Mölndal, Sweden, Princeton, NJ Dapaglifl ozin (DAPA) has been approved for use in adults with type 2 dia- betes mellitus (T2DM). To explore the potential of DAPA as add-on therapy to insulin in patients (pts) with type 1 diabetes mellitus (T1DM) we com- pared the pharmacodynamics of DAPA in pts with T1DM or T2DM. A model- based analysis of the relationship between DAPA systemic exposure and urinary glucose excretion (UGE) was conducted to characterize any differ- ence between pts with T1DM or T2DM. Data from 160 pts were analyzed (T1DM, n=70, and T2DM, n=90). DAPA exposure (Cmax and AUC) increased in a dose-related manner and was similar between the 2 populations at the same dose. The 24-hour UGE increased with increasing doses of DAPA up to 10 mg/d in pts with T1DM or T2DM. T1DM pts had higher UGE than pts Supported By: AstraZeneca with T2DM at equivalent doses. Following normalization for baseline fasting plasma glucose (FPG), eGFR and glucosuria, the UGE potency of DAPA was & 1176-P similar in the 2 populations (T1DM, mean [95% CI] EC50, 8.12 [2.95, 14.6] ng/ Dapaglifl ozin Reduces Albuminuria on Top of Renin-Angiotensin mL; T2DM, EC50, 7.75 [1.35, 18.1] ng/mL). The predicted UGE dose response System Blockade in Hypertensive Diabetic Patients POSTERS from 1-25 mg of DAPA for pts with T1DM or T2DM (Figure) indicates that H.J. LAMBERS HEERSPINK, EVA JOHNSSON, INGRID GAUSE-NILSSON, KRIST- Therapeutics the dose response to DAPA, after correction for baseline characteristics, OFFER JOHANSSON, C. DAVID SJÖSTRÖM, Groningen, Netherlands, Mölndal, Clinical Diabetes/ is similar between T1DM and T2DM. Based on these data, the potential for Sweden DAPA as an add-on therapy to insulin in T1DM will be examined in a phase 3 Hypertension (HTN) and albuminuria are risk factors for cardiovascular randomized clinical trial. (CV) and renal disease in patients (pts) with T2DM. Glycemic, blood pressure (BP) and albuminuria control are critical to reducing CV and renal risk. Dapa- glifl ozin (DAPA) reduces HbA1c and BP in patients with T2DM. The aim of the study was to characterize the effect of DAPA on albuminuria and eGFR. Data was pooled from two studies of pts with T2DM, micro- or macroalbuminuria, and HTN, (NCT01137474, NCT01195662) who were assigned to DAPA 5 mg (n=87), 10 mg (n=167) or placebo (PBO; n=189). All pts were on stable ACEi or ARB therapy. At 12 weeks, DAPA resulted in greater reductions from baseline vs. PBO in albuminuria (as assessed by albumin: creatinine ratio [ACR]). Re- ductions in HbA1c and systolic BP vs. PBO were also observed (Table). There was a decrease in eGFR with DAPA vs. PBO which was readily reversed 1 week after last dose. DAPA’s ACR-reducing effect was also present after adjusting for changes in HbA1c, SBP and eGFR. There were no increases in serum creatinine ≥ 1.5 x baseline for DAPA 5 or 10 mg vs. PBO (0%, 1.2%, 1.1%, respectively). Potassium ≥ 6 MEQ/L values were also similar for DAPA 5 or 10 mg vs. PBO (1.2%, 2.4%, 2.2%, respectively). There were no serious Supported By: AstraZeneca renal-related AEs in any group. DAPA reduces ACR in T2DM pts with HTN using renin-angiotensin system blockade without increasing any renal AEs. & 1175-P Table. Renal Safety with Dapaglifl ozin in an Asian Population PBO DAPA 5 mg DAPA 10 mg WENYING YANG, HIROSHI MAEGAWA, SOO LIM, KRISTINA M. JOHNSSON, EVA JOHNSSON, DAVID SJÖSTRÖM, Beijing, China, Shiga, Japan, Seongnam, Republic ACR Baseline, mg/g (SD) 380.7 (843.1) 419.8 (948.7) of Korea, Mölndal, Sweden Adjusted % change from baseline* (95%CI) 320.3 (674.8) -47.4 (-57.3, -35.3) -45.8 (-53.1, -37.3) Dapaglifl ozin (DAPA) reduces hyperglycemia by inhibiting renal glucose re- Difference vs. PBO, (95% CI) -18.9 (-29.5, -6.7) -35.2 (-49.5, -16.8) -33.2 (-45.4, -18.2) absorption from the proximal tubules. Renal safety of DAPA in Asian T2DM eGFR,mg/mL/1.73 m2 patients (mainly Chinese and Japanese) was assessed in data pooled from Baseline (SD) 85.8 (21.0) 85.3 (24.3) 82.1 (19.7) 8 phase 2b/3 trials (≤24 weeks) comparing placebo (PBO: N=497) with DAPA Adjusted change from baseline (95% CI) -0.3 (-2.1,1.5) -1.5 (-4.2, 1.3) -3.1 (-5.0, 1.2) 5 mg (N=491) and 10 mg (N=465). Most patients had normal renal function 1 week after cessation -0.9 (-2.8,1.1) 0.9 (-2.0, 3.7) 0.7 (-1.4, 2.7) (54%) or mild impairment (43%), and normoalbuminuria (77%). Baseline char- HbA1c, % acteristics were similar across treatment groups. Mean eGFR showed small Baseline (SD) 8.1 (0.9) 8.1 (0.9) 8.1 (1.0) reductions with DAPA at Week 1, but returned to near baseline by Week 24 Adjusted change from baseline (95% CI) 0.01 (-0.1, 0.1) -0.5 (-0.7, -0.3) -0.5 (-0.6, -0.4) (Figure). Adverse events (AEs) related to renal function occurred in 8 (1.6%), SBP, mmHg 5 (1.0%) and 11 (2.4%) patients with PBO, DAPA 5 and 10 mg, respectively. All Baseline (SD) 151.4 (8.0) 150.6 (7.3) 151.9 (9.0) events were mild in intensity. No AEs of acute tubular necrosis, interstitial Adjusted change from baseline (95% CI) -6.3 (-8.0, 4.6) -12.5 (-15.0, 10.0) -9.8 (-11.6,-8.0) nephritis or renal failure, or serious AEs related to renal function, occurred *Analysis based on log-transformed values. with DAPA. No meaningful changes in serum electrolytes were observed in any group. For potassium (K), changes were 0.03, 0.01 and −0.02 mEq/L with Supported By: AstraZeneca PBO, DAPA 5 and 10 mg, respectively. Marked abnormalities (MAs) of K (≥6 mEq/L) occurred in 0, 1.2 and 0.9% of groups, respectively. No MAs of blood urea nitrogen occurred. MAs of creatinine occurred in 0.8, 0 and 0.4% of groups, respectively, when defi ned as ≥1.5 pre-treatment, and in 0.2, 0 and 0.2% of groups when defi ned as ≥2.5 mg/dL. In conclusion, DAPA was gener- ally well tolerated and not associated with renal toxicity in Asian patients.

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& 1177-P absorption and increasing urinary glucose excretion, a mechanism of action Contrasting Infl uences of Renal Function on Blood Pressure and associated with an increased incidence of GMIs. The incidence of GMIs was HbA1c Reductions with Empaglifl ozin: Pooled Analysis of Phase III evaluated over 2 years in a pooled analysis of 2 randomized, clinical studies Trials including 2,164 pts with T2DM; pts received CANA 100 mg or 300 mg, and DAVID CHERNEY, MARK E. COOPER, SUSANNE CROWE, ODD ERIK JOHANSEN, glimepiride (GLIM) in Study 1 or placebo (PBO) in Study 2. The incidence of SØREN S. LUND, HANS J. WOERLE, ULI C. BROEDL, THOMAS HACH, Toronto, ON, GMIs was monitored and evaluated overall and at 3-month intervals. The Canada, Melbourne, Australia, Ingelheim, Germany, Asker, Norway cumulative incidence of GMIs was higher with CANA 100 mg and 300 mg The SGLT2 inhibitor empaglifl ozin (EMPA) reduces HbA1c, weight and blood versus GLIM/PBO in females (17.2% and 16.5% vs. 3.2%) and males (8.2% pressure (BP) in patients with type 2 diabetes (T2DM). While glucose lower- and 9.7% vs. 1.7%). The highest incidence of GMIs occurred in the fi rst 3 ing with EMPA is dependent on renal function, it is less well understood how months of treatment in both females and males, and then declined with time chronic kidney disease (CKD) infl uences BP modulation with EMPA. (Fig). GMIs were characterized by the investigators as generally mild to mod- In fi ve randomized Phase III trials, 2286 patients with T2DM received erate in intensity and responded to standard treatment. In the CANA-treated EMPA 25 mg or placebo (PBO) for 24 weeks as monotherapy or add-on thera- groups, ~1% (4 men and 6 women) discontinued treatment due to a GMI. In py. Using pooled data from these trials, we assessed changes from baseline summary, GMIs associated with CANA occurred early in treatment, were in systolic BP (SBP) and HbA1c with EMPA 25 mg vs. PBO in subgroups by mild to moderate in intensity, and decreased over time in pts with T2DM. baseline eGFR (MDRD equation), adjusting for differences in baseline SBP (SBP analyses only), HbA1c, region, treatment, study, eGFR and treatment by eGFR interaction between groups. In patients with normal renal function, or stage 2 or 3 CKD, EMPA signifi - cantly reduced HbA1c and SBP vs. PBO. As expected, PBO-corrected HbA1c reductions with EMPA decreased with decreasing eGFR. In contrast, PBO- corrected reductions in SBP with EMPA appeared to be maintained with decreasing eGFR. Unlike HbA1c, reductions in SBP with EMPA in patients with T2DM ap- peared to be maintained in patients with lower eGFR, indicating that SBP

POSTERS modulation with EMPA may involve pathways other than urinary glucose Therapeutics excretion such as diuretic effects, weight loss, reduced arterial stiffness or Clinical Diabetes/ direct vascular effects. Table.

& 1179-P Dapagliflozin and Insulin Resistance in Patients with Type 2 Diabetes ARIE KATZ, HELEN YEH, Fort Washington, PA Insulin resistance (IR) plays an important role in the pathophysiology of type 2 diabetes (T2D). We assessed the correlation between dapaglifl ozin (DAPA)- induced reductions in HbA1c, body weight (BW), and systolic blood pressure (SBP) and baseline IR, and change in IR with DAPA treatment. Data from 3 phase 3 trials were analyzed: DAPA (uptitrated to a max of 10 mg/d) vs. glipiz- Supported By: Boehringer Ingelheim/Eli Lilly and Company ide (GLIP) as add-on to metformin (MET) for 52 weeks (N=814, NCT00660907), and 2 pooled 24-week studies of DAPA 10 mg/d vs. placebo in patients with & 1178-P cardiovascular disease (CVD) ± hypertension (NCT01031680, N=922 and Incidence of Genital Mycotic Infections Decreases Over Time in NCT01042977, N=964). IR was assessed using Homeostatic Model Assess- Patients with Type 2 Diabetes Mellitus Treated with Canaglifl ozin ment (HOMA-IR) and Quantitative Insulin Sensitivity Check Index (QUICKI). over 2 Years Baseline HOMA-IR and QUICKI were similar between treatment groups in both JACK D. SOBEL, RONALD M. GOLDENBERG, KAMLESH KHUNTI, MICHAEL DA- analyses (Table). There was no correlation between change from baseline in VIES, UJJWALA VIJAPURKAR, GARY MEININGER, Detroit, MI, Thornhill, ON, HbA1c, BW, or SBP and baseline IR estimated by both indices (Table). There Canada, Leicester, United Kingdom, Raritan, NJ was a substantial reduction in HOMA-IR and an increase in QUICKI with DAPA Patients (pts) with type 2 diabetes mellitus (T2DM) are at increased risk vs. GLIP over 52 weeks and with DAPA vs. placebo over 24 weeks (Table). DAPA of genital mycotic infections (GMIs), and those with poorly controlled dia- lowered HbA1c, BW, and SBP regardless of baseline IR, consistent with its betes have higher risks. Sodium glucose co-transporter 2 inhibitors, such as insulin-independent mechanism of action. DAPA decreased IR and improved canaglifl ozin (CANA), improve glycemic control by inhibiting renal glucose re- glycemia in T2D patients with CVD, and improved insulin sensitivity in patients

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A304 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS with T2D for up to 52 weeks compared with GLIP with similar reduction in production (EGP) was measured using 6,6-[2H2] glucose after an overnight HbA1c, suggesting reduction in glucotoxicity. fast during three consecutive stages: 1) the basal state, 2) intravenous infu- sion of somatostatin (93 ng/kgFFM/min) and 3) somatostatin plus glucagon (3 ng/kgFFM/min). Body weight and composition were not different between treatments. Besides signifi cantly reducing fasting plasma glucose (107±3 vs. 94±3 mg/dL; p<0.05), metformin improved oral glucose tolerance. In the basal state metformin increased plasma glucagon (95±10 vs. 123±11 pg/ mL; p<0.05) while the somatostatin blockade lowered glucagon, c-peptide and insulin followed by a designed increase in glucagon in both treatments (157±8 vs.158±12 pg/mL). Plasma glucose was lower with metformin dur- ing somatostatin infusion (103±7 vs. 85±5 mg/dL; p<0.05) but increased to similar values with infusion of glucagon (214±8 vs. 212±10 mg/dL). Glucagon infusion under somatostatin blockade increased EGP but was not different between treatments (23.6±2.0 vs. 24.7±2.0 µmol/kgFFM/min). These results suggest that two weeks of metformin, which improves glucose homeostasis, fails to inhibit glucagon-induced endogenous glucose production and plasma glucose levels in obese humans with impaired fasting glucose. Supported By: National Institutes of Health (DK41973, DK100469)

1182-P The Effect of Metformin-induced Glucagon-Like Peptide-1 Action Supported By: AstraZeneca on Postprandial Physiology in Type 2 Diabetes MORTEN HANSEN, DAVID P. SONNE, EMILE BAHNE, JENS F. REHFELD, JENS 1180-P JUUL HOLST, TINA VILSBØLL, FILIP K. KNOP, Hellerup, Denmark, Copenhagen, Hepatic Glucose Production Increases in Response to Metformin Denmark

Treatment in the Glycogen-depleted State Metformin have been suggested to increase glucagon-like peptide-1 POSTERS METTE MARIE H. CHRISTENSEN, KURT HØJLUND, OLE HOTHER-NIELSEN, (GLP-1) secretion. By the use of the GLP-1 receptor antagonist exendin9-39 Therapeutics Clinical Diabetes/ TORE B. STAGE, PER DAMKIER, HENNING BECK-NIELSEN, KIM BRØSEN, (Ex9-39), we evaluated the hypothesis that the acute effect of metformin on Odense, Denmark postprandial glucose excursions is GLP-1-dependent. Metformin is believed to reduce glucose levels primarily by inhibiting he- Twelve patients with type 2 diabetes (age: 60.8 ± 8.8 years (mean ± SD); 2 patic glucose production, but at the same time do not cause hypoglycemia. BMI: 29.8 ± 3.0 kg/m ; HbA1c: 6.5 ± 0.5% (48 ± 6 mmol/mol)) were included Recent data indicate that metformin antagonizes the major glucose coun- in this placebo-controlled, double-blinded study. On 4 separate days the pa- terregulatory hormone, glucagon suggesting that other mechanisms protect tients received metformin (1.5 g), and placebo suspended in a 302-kcal liquid against hypoglycemia. Here, we examined the effect of metformin on whole- meal with 1.5 g acetaminophen (for evaluation of gastric emptying), with body glucose metabolism after a glycogen-depleting 40 h fast and the role of subsequent iv infusion of exendin9-39 (Ex9-39) or saline. Ex9-39 was infused reduced-function alleles in OCT1. at a rate of 450 pmol × kg body weight-1 × min-1. At baseline and during 240 In a randomized cross-over trial, 34 healthy volunteers with known OCT1 min blood was sampled, gallbladder volume was evaluated by ultrasound genotypes (12 with two wild-type alleles, 13 with one and 9 with two re- and appetite was evaluated by visual analogue scale. At the end of each day duced-function alleles) were fasted for 42 h twice. In one of the periods, ad libitum food intake was evaluated. before the fasting, the volunteers were titrated to steady-state with 1 g On the 2 days with Ex9-39 infusion, mean basal concentrations of plasma metformin twice daily for seven days. Parameters of whole-body glucose glucose were higher compared with the 2 days of saline infusion (9.8 ± 0.58 metabolism were assessed using [3-3^H] glucose, indirect calorimetry and mmol/L vs. 8.7 ± 0.52 mmol/L, P<0.05). Metformin + saline reduced the post- measurement of substrates and counterregulatory hormone levels. prandial plasma glucose iAUC by 58% vs. placebo + saline (P<0.05), and while All volunteers completed the glycogen-depleting fast without hypogly- the difference was still signifi cant, metformin + Ex9-39 only reduced iAUC by cemia. Metformin signifi cantly stimulated glucose disposal rates (GDR) 25% vs. saline + Ex9-39 (P<0.05). C-peptide: glucose ratios were signifi cantly (p=3*10^-13) and non-oxidative glucose metabolism (NOGM) (p=0.001) with higher after metformin + saline vs. placebo + saline (P<0.05), whereas the no effect on glucose oxidation. The increases in both GDR and NOGM were difference was no longer signifi cant with Ex9-39 infusion. Metformin did not fully explained by a concomitant increase in glycolytic fl ux (p=1.7*10^-11). affect gastric emptying and gallbladder contraction vs. placebo, irrespective This was accompanied by increased hepatic glucose production (p=8*10^- of Ex9-39. None of the interventions affected appetite perceptions or ad 13), most likely mediated by increased plasma lactate levels (p=0.00004), libitum lunch intake. a small decrease in glucose, and increased levels of glucagon (p=0.03) and In conclusion, we show that acute administration of metformin reduces cortisol (p=0.002). There was no effect of reduced-function OCT1 alleles on postprandial plasma glucose excursions vs. placebo, and that a substantial any of these measures. part of this effect appears to be GLP-1-dependent. In the glycogen-depleted fasting state, metformin stimulates glycolytic Supported By: Novo Nordisk Foundation Center for Basic Metabolic Research glucose utilization and lactate production. This may trigger a rise in glucose counterregulatory hormones and subsequently an increase in hepatic glu- 1183-P cose production, which protects against hypoglycemia. Resveratrol Improves Endothelial Function and Mitochondrial Bio- Supported By: Odense University Hospital genesis in Older Adults with IGT, without Effect on Glucose Me- tabolism 1181-P RENA M. POLLACK, AARON GOLDEN, VALENTIN ANGHEL, SHARON KIM, MI- Does Metformin Antagonize Glucagon-induced Endogenous Glu- CHELLE CAREY, MEREDITH HAWKINS, KEHAO ZHANG, DANIELLE POWELL, cose Production in Humans? NOAH BLOOMGARDEN, NIR BARZILAI, JILL P. CRANDALL, Bronx, NY ADAM R. KONOPKA, RAUL RUIZ ESPONDA, ANTIGONI LALIA, MATTHEW L. Resveratrol (RSV), a plant-derived polyphenol and SIRT1 activator, improves JOHNSON, MATTHEW M. ROBINSON, IAN R. LANZA, K. SREEKUMARAN NAIR, glucose metabolism and extends lifespan in animal models, has antioxidant Rochester, MN and cardioprotective properties, but its effects in humans are not established. Metformin is the most widely prescribed anti-hyperglycemic medication, We studied whether RSV improves glucose tolerance, insulin sensitivity, vas- however, the mechanism of action is incompletely defi ned. Basic science cular function and mitochondrial biogenesis in metabolically compromised models suggest metformin inhibits glucagon action leading to reductions in older adults. 30 subjects (age 67±7 yrs) with impaired glucose tolerance (IGT) fasting glucose but this has yet to be tested in humans. Therefore to test this were enrolled in a 15-week randomized, double blind, placebo (PLA) controlled hypothesis, we studied metformin naïve individuals (n=8; BMI=36 kg/m2) crossover study of RSV 2 g daily. Glucose tolerance and insulin sensitivity were with impaired fasting glucose after 14 days of metformin (1000 mg, twice assessed after a standard mixed meal. Endothelial function was measured daily) versus placebo using a randomized, double-blinded, crossover study by peripheral arterial tonometry (reactive hyperemia index, RHI). Biopsies of design with more than 6 weeks between treatments. Oral glucose tolerance skeletal muscle were obtained for gene expression profi ling. After 6 weeks was determined after a mixed-meal and the next day endogenous glucose of RSV, fasting and peak post-meal plasma glucose, 3-hr glucose AUC, insulin

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sensitivity (Matsuda index), insulin secretion (C-peptide deconvolution), HbA1c measured. Fibrosis- and infl ammation-related mRNA levels were quantifi ed and body weight were unchanged. RHI improved with RSV (RSV 2.02±0.36 vs. using quantitative real-time PCR. Mice fed an MCD diet showed a rapid PLA 1.76±0.28, p=0.002). Deep transcriptomic study using RNA-Seq yielded induction of hepatic steatosis, infl ammation and 2-fold increase in fi brosis 140 differentially expressed transcripts (corrected p-value ≤ 0.05); dominant vs. controls, and increased procollagen α1(I), TGFβ1, αSMA, MMP-3 and -9, transcripts were associated with mitochondrial genes and non-coding RNA. TIMP-1, CCL3 and TNFα mRNA levels by up to 10-fold. LINA 10 and 50 mg/ Ingenuity Pathway Analysis confi rmed mitochondrial dysfunction and oxida- kg/d for 4 wks lowered serum ALT, AST, ALP and triglyceride levels. LINA tive phosphorylation were the most signifi cantly perturbed pathways follow- 50 mg/kg/d decreased αSMA, procollagen α1(I), TIMP-1 and MMP-3 mRNA ing RSV treatment. Other differentially expressed genes (ENDOG, IGFBP7 and levels vs. controls. LINA 5 mg/kg/d for 6 wks attenuated steatosis, infl am- QDPR) were previously implicated in modulating mitochondrial function. mation, macrophage infi ltration and the number of activated hepatic stellate Conclusions: While high-dose RSV improved vascular function and induced cells. In line with macrophage levels, circulating proinfl ammatory cytokines signifi cant transcriptome changes consistent with improved mitochondrial were reduced. In Mdr2KO mice, LINA 10 and 50 mg/kg/d decreased procol- function, it had no effect on glucose metabolism or insulin resistance in older lagen α1(I), TGFβ1, TIMP-1 and MMP-8 mRNA levels, and increased MMP-9 subjects with IGT. Consistent with other studies, RSV may target pathways and -13 levels. Despite a decrease in Sirius red stained collagen area, bio- of human aging independent of glucose metabolism. chemical hepatic collagen accumulation (hydroxyproline) was not reduced in Supported By: American Diabetes Association (1-11-CT-12 to J.P.C.) either model. In conclusion, in experimental biliary fi brosis and NASH mod- els, LINA reduced hepatic steatosis and infl ammation, and mildly attenuated 1184-P fi brosis progression, independent of an antifi brotic effect. Varying Degrees of Renal Impairment Do Not Impact the Pharma- Supported By: Boehringer Ingelheim cokinetics of LY2409021 JILL C. CHAPPELL, DARLENE K. SATONIN, ERIC CHEN QUIN LAM, GERNOT K. 1186-P KLEIN, PARAG GARHYAN, Indianapolis, IN, Singapore, Singapore, Munich, Ger- Systemic and Low Systemic Available TGR5 Agonists Lead to Histo- many pathological Findings in Pancreas, Liver, and Gallbladder LY2409021 (LY), an oral glucagon receptor antagonist intended for chronic THOMAS KISSNER, MANUELA STOLTE, ANDREAS CZICH, FRIEDEMANN use in patients with type 2 diabetes mellitus (T2DM), is minimally excreted SCHMIDT, GERNOT ZECH, STEFAN THEIS, MARIA MÉNDEZ PÉREZ, KATRIN by the kidneys (1.6%). Renal failure is a common sequela in T2DM patients, SCHROETER, THOMAS HUEBSCHLE, PHILIP JUST LARSEN, Frankfurt, Germany

POSTERS so it is important to understand the potential infl uence of differing degrees The seven transmembrane receptor TGR5 is expressed by enteroendo- Therapeutics of renal impairment on the pharmacokinetics (PK) of LY. PK was evaluated crine cells. Activation by its endogenous ligands, bile acids, leads to release Clinical Diabetes/ after an 80-mg single dose of LY in subjects with mild, moderate, or severe of the incretin hormone, glucagon like peptide-1 (GLP1). Due to its incretin renal impairment or end stage renal disease (ESRD) and was compared to releasing properties it has been speculated that TGR5 agonists constitute subjects with normal renal function. Plasma samples for LY concentration a therapeutic option for prevention and ailment of diabetes and associated measurement were drawn up to 14 days postdose. No statistically signifi - diseases. However, potential risks associated with continuous TGR5 activa- cant difference was seen in AUC(0-∞) and Cmax between the mild, moderate, tion need thorough mapping before the medical value of TGR5 agonists in or severe renal impairment groups compared to those of the control group. diabetes management can be assessed. In mice, systemic available TGR5 ESRD subjects showed lower AUC(0-∞) and Cmax, although there was no dif- agonists induce marked dilatation of the gall bladder while TGR5 knockout ference for ESRD patients during dialysis and between dialysis sessions. animals have been shown to have lower susceptibility to biliary pancreatitis There was no statistical difference in the tmax of LY between all groups and than wild type mice. no statistically signifi cant relationship between LY clearance and creatinine To further understand long term pathoanatomical changes associated clearance. LY was well tolerated in this patient population. No clinically sig- with continuous TGR5 receptor activation, H.E. stained sections were nifi cant adverse events were reported. Impaired renal function had little or examined microscopically from pancreas, liver and gall bladders of 10 fe- no infl uence on LY PK; therefore, dose adjustment in T2DM patients with male db/db mice per group treated orally for 4 weeks with a systemically renal impairment would not be required. (RO5527239) or low systemically (RA450) available TGR5 agonist each at Table. doses of 3 or 30 mg/kg/day. Pancreatitis/fat necrosis was seen with both TGR5 agonists and in gall bladder, diffuse hyperplasia of the epithelium and neutrophilic infl ammation was found in both with both doses of RO5527239 and with 30 mg/kg RA450. In addition, hyperplasia of the periportal bile ducts, periportal vasculitis/ perivasculitis and multifocal hepatocellular necrosis was observed in liver of animals from the RO5527239 dose groups. In db/db mice, systemically available and low systemic TGR5 agonists lead to similar effects of pancreatitis/fat necrosis, hyperplasia of biliary epithe- lial cells in gall bladder and in liver to hyperplasia of bile duct, periportal vasculitis/perivasculitis and hepatic necrosis. Based on these results, both types of TGR5 agonists have similar safety profi le in animal models suggest- ing a target relationship of these effects.

1187-P Effect of Saroglitazar on Fatty Acid Metabolism in Zucker Fa/Fa Rats MAHMOUD ELAZZOUNY, NATHAN QI, MELANIE L. SCHMITT, ELIZABETH LIM- 1185-P BACK, SURESH GIRI, MUKUL R. JAIN, CHARLES F. BURANT, Ann Arbor, MI, Ahme- Linagliptin-mediated DPP-4 Inhibition Ameliorates Infl ammation da bad, India and Fibrosis in Models of Biliary Fibrosis and NASH Saroglitazar is a novel dual PPARα/g agonist recently approved in India for XIAO-YU WANG, SHIH-YEN WENG, YONG OOK KIM, THOMAS KLEIN, DETLEF the treatment of diabetic hypertriglyceridemia. To understand the mecha- SCHUPPAN, Mainz, Germany, Biberach, Germany, Boston, MA nisms of action of saroglitazar in vivo, we treated Zucker fa/fa (n=10-12 in Non-alcoholic steatohepatitis (NASH) is characterized by steatosis, lobu- each group) with vehicle, fenofi brate (F) (150 mg/kg) or saroglitazar (Saro) lar infl ammation and progressive pericellular fi brosis. Glucagon-like peptide (0.4 or 4 mg/kg/day) for 14 days. On day 15, rats were gavaged with 5ml/kg (GLP)-1, an attractive target for the treatment of insulin resistance and of corn oil which contained [U-13C] Palmitic Acid (PA) (1 gm/5ml). Plasma was therefore NASH, is inactivated by dipeptidyl peptidase (DPP)-4. We studied obtained hourly for 8 hours. Adiopose and skeletal muscle was collected at the effect of the DPP-4 inhibitor linagliptin (LINA) on liver infl ammation and 8 hours. Only 4 mg/kg/day Saro increased body weight (p<0.01) and reduced fi brosis in models of biliary fi brosis and NASH. LINA was administered by fasting insulin (p=<0.01 vs. vehicle) as well as reducing plasma triglyceride gavage at 0.5, 5, 10 and 50 mg/kg/d to Mdr2KO mice (aged 7-11 wks) for 4 (TG) at 0 and 2 hour post corn oil treatment (p<0.01 and p<0.001, respective- wks, and to 8-wk old C57BL/6 mice fed a methionine and choline defi cient ly). LC-MS and GC-MS were used to assess the incorporation of 13C-lipids (MCD) diet for 4 and 6 wks. Liver tissue was examined using histological, im- into plasma and tissue lipids (n=5 for tissue metabolomics studies). The ma- munohistochemical and biochemical methods. Serum biochemistries were jor M+16 isotopomers of the major TG species, TG (52:3) and TG (52:4), rose

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A306 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS in the fi rst two h following gavage (likely refl ecting chylomicron production) Twenty unmedicated males with prediabetes received 100mg b.i.d RVX- and declined over the next 4 hours with a secondary rise at 6-8 h. In contrast, 208 and placebo each for 29-33 days separated by a wash-out period of F-treatment caused a greater increase in M+16 TG species; both low and 21-35 days in a randomised, cross-over design. Plasma HDL-cholesterol and high dose Saro signifi cantly attenuated the appearance of M+16 TG. In all apoA-I were assessed as well as lipoprotein particle size using nuclear mag- animals, Major M+16 phosphatidyl choline PC (34:1), carried primarily in HDL netic resonance (NMR) spectroscopy. A modifi ed frequently sampled OGTT 13 2 and VLDL, rose at similar rates, however the % labeling in the F-treated ani- (fsOGTT) protocol with both oral ([U- C]D-glucose) and infused ([6,6- H2]D- mals was signifi cantly lower, suggesting a reduction in liver derived lipids by glucose and [1,1,2,3,3-D5]glycerol) stable isotope tracers was employed to F. Low and high dose Saro signifi cantly increased the accumulation of M+16 assess postprandial plasma glucose, indices of insulin secretion and insulin palmitate in adipose tissue (by 86% and 247%, respectively, p<0.01). F, low sensitivity, glucose kinetics and lipolysis. and high dose Saro decreased Gastrocnemeous M+16 palmitate labeling, RVX-208 did not change plasma HDL-cholesterol or apoA-I concentra- which could be due to induction of lipid oxidation by F and potentially Saro tion, but increased the concentration of medium-sized HDL particles and and reduced plasma levels of TG in Saro. In conclusion, Saro signifi cantly decreased both intermediate-density lipoprotein (IDL) particle and small- reduces fasting and postprandial TG levels through enhanced clearance of sized HDL particle concentration (all p<0.05). In response to a glucose load, TG into adipose tissue and works by a mechanism distinct from that of F, a after RVX-208, plasma glucose concentration peaked at a similar level to “pure” PPARα activator. placebo, but 30min later and the elevation was more sustained (treatment Supported By: National Institutes of Health (DK097153) effect, p=0.002). There was a reduction and delay in total (p=0.001) and oral (p=0.003) glucose rate of appearance in plasma and suppression of endog- 1188-P enous glucose production (p=0.014) after RVX-208 treatment. The rate of Effi cacy and Safety of Retagliptin in Chinese Patients with Type 2 glucose disappearance was also lower following RVX-208 (p=0.016), but Diabetes Mellitus there was no effect on glucose oxidation. CHANGYU PAN, JUMING LU, XUEFENG LI, GANGYI YANG, YONGYI GAO, LIAN The effects of RVX-208 on oral glucose absorption and endogenous glu- GUO, HONG JIANG, YADONG SUN, Beijing, China, Shiyan, China, Chongqing, cose production have potential implications for long term glycemic control. China, Haikou, China, Shenyang, China, Changchun, China 1. Drew, et al. Circulation 119, 2103-2111 (2009). Retagliptin (SP2086) is a new DPP-IV inhibitor innovated in China. In this 2. Drew, et al. Nat Rev Endocrinol 8, 237-245 (2012). randomized, double-blind, placebo-controlled study the effi cacy and safety Supported By: Australia National Health and Medical Research Council; Res- verlogix Corp. of SP2086 were evaluated in Chinese patients with type 2 diabetes mel- POSTERS litus who have inadequate glycemic control with diet and exercise. After a Therapeutics 2-week placebo run-in period, 461 patients with glycated hemoglobin level 1190-P Clinical Diabetes/ of 7-10.5% were randomized 1:1:1 to receive SP2086 100mg q.d, SP2086 MTBL0036, a Potential Antidiabetic Drug, Is a Mitochondrial Un- 50mg b.i.d or placebo for 24 weeks. Baseline characteristics of mean age, coupler in the Liver BMI and HbA1c were 53 years, 25.03 kg/m2 and 8.35% respectively. Groups GABRIEL BAVEREL, MAHA EL HAGE, GERARD MOINET, BERNARD FERRIER, REMI of SP2086 100mg q.d (n=154) and 50mg b.i.d (n=153) showed signifi cantly NAZARET, GUY MARTIN, AGNES DUPLANY, Lyon, France adjusted mean decreases from baseline to week 24 compared with placebo Mitochondrial dysfunction is associated with type 2 diabetes. Using a (n=154) in HbA1c (-1.07%, -1.20% vs. -0.34%; P<0.01), FPG (-0.77mmol/L, precursor of 2,4-dinitrophenol and niclosamide ethanolamine, recent stud- -1.03mmol/L vs. -0.22 mmol/L; P<0.025), and PPG AUC0-120 (-3.20 mmol·h /L, ies (Cell Metab 2013,18:740; Nat Med, 2014,20:1263) have highlighted the -3.96 mmol·h /L vs. -1.28 mmol·h /L; P<0.01). A signifi cantly greater propor- possibility of inducing mitochondrial uncoupling for treating type 2 diabetes. tion of patients achieved a therapeutic glycemic response (HbA1c <7.0%) Here, we demonstrate that MTBL0036, a novel antidiabetic drug candidate with SP2086 100mg qd (44.44%) and 50mg bid (53.42%) versus placebo in late preclinical development, has a mild and benefi cial uncoupling effect in (26.39%; P<0.01). The proportions of patients who experienced adverse liver mitochondria. Thanks to an oxymeter equipped with a Clarke electrode, events were 27.78% for SP2086 100mg qd, 20.55% for 50mg bid and 15.97% oxygen consumption was measured in mitochondria isolated from Wistar for placebo. The most common AEs included URTI, nasopharyngitis, UTI. A and STZ-N0 (an animal model of type 2 diabetes) rats treated for 5 days with few AEs were considered by the investigator to be treatment related. A few MTBL0036 (200 mg/kg/day) or the vehicle. We found that MTBL0036 greatly patients reported hypoglycaemic events. stimulated the mitochondrial oxygen consumption (+ 30-45%) both in state 3 and state 4 in the presence of substrates of complex I and complex II of the respiratory chain (n = 4). Using isolated liver cells from 48hr-fasted rats and 5 mM 13C-lactates as substrates, complete oxidation of lactate (+16%) and the intramitochondrial transport of reducing equivalents were also found to be increased or induced whereas the cellular ATP level (- 23%) and gluco- neogenesis (- 24%) were diminished in the presence of 0.5 mM MTBL0036 (n= 4). Moreover, we observed that, in rat liver cells incubated with 5 mM glucose for 24 hours, the production of beta-hydroxybutyrate and the beta- hydroxybutyrate/acetoacetate ratio (which refl ects the mitochondrial redox state) were reduced in a dose-dependent manner by MTBL0036 whereas these parameters were greatly elevated by metformin (n = 4). Taken into ac- count its pKa and log P values and the fact that hepatocytes do not express uncoupling proteins, we propose that MTBL0036 acts as a protonophore to exert its uncoupling activity. Given its very large safety margin and since it inhibits hepatic gluconeogenesis and stimulates both muscle glucose con- sumption and insulin secretion, MTBL0036 appears to be a very promising antidiabetic drug candidate.

1191-P 1189-P Effects of the ApoA-I Inducer RVX-208 on Glucose Metabolism in WITHDRAWN Individuals with Prediabetes ANDREW L. SIEBEL, MELISSA F. FORMOSA, ALAINA K. NATOLI, MEDINI REDDY- LUTHMOODOO, ANDREW L. CAREY, GERRIT VAN HALL, JIM D. OTVOS, KERRY- ANNE RYE, JAN JOHANSSON, ALLAN GORDON, NORMAN WONG, PHILIP BARTER, STEPHEN J. DUFFY, BRONWYN A. KINGWELL, Melbourne, Australia, Copenhagen, Denmark, Raleigh, NC, Sydney, Australia, Calgary, AB, Canada High-density lipoprotein (HDL) and its major apolipoprotein, apoA-I modu- late glucose metabolism through multiple mechanisms.1,2 This study deter- mined the effects of the putative apoA-I inducer, RVX-208 on glucose me- tabolism in individuals with prediabetes.

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for 14 days. Consistent with observations in a single dose trial, LGD-6972 had a 51 hour elimination half-life. Repeat dosing resulted in approximately 2.5-fold accumulation of plasma LGD-6972 concentrations. Steady state concentrations of LGD-6972 (AUC=30,519 ng*h/mL; Cmax=708 ng/mL) were reached prior to day 14. There were no serious adverse events in NHV and all subjects completed the 14 day treatment period. Mild treatment emergent adverse events occurred in one subject (33.3%) in the placebo group and four subjects (44.4%) in the LGD-6972 treated group (headache, nasal conges- tion, skin lesion, and transaminases 1.2 x ULN). At baseline, FPG was 97.3 mg/dL and 96.3 mg/dL in the placebo and LGD-6972 groups, respectively. A consistent decrease in FPG was observed in the LGD-6972 treatment group throughout the dosing period. On day 14, FPG was decreased by 2.0 mg/dL in the placebo group and decreased by 10.0 mg/dL in the LGD-6972 group compared to baseline. No cases of hypoglycemia (glucose <70 mg/dL) were observed. In contrast to the glucose reductions, total GLP1, active GLP1, and glucagon were increased from baseline on day 14 in the LGD-6972 treated group. The pharmacokinetics, safety profi le, and pharmacodynamic re- sponse observed in NHV support further development of LGD-6972 in T2DM subjects. The multi-dose study of LGD-6972 in T2DM subjects is ongoing.

1194-P Improvement in Patient-assessed Quality of Life, Eating Behavior, and Sexual Function after 26 Weeks of Naltrexone/Bupropion Com- pared with Usual Care 1192-P KENNETH FUJIOKA, BRANDON WALSH, AMY E. HALSETH, KEVIN SHAN, THOM-

POSTERS Change in A1c Associated with Adherence to Newly Initiated Met- AS A. WADDEN, La Jolla, CA, Philadelphia, PA Therapeutics formin Therapy Sustained-release naltrexone/bupropion (NB) is approved in the U.S. Clinical Diabetes/ GREGORY A. NICHOLS, KAAN TUNCELI, A. GABRIELA ROSALES, KAREN KURTY- for chronic weight management as an adjunct to diet and physical activity. KA, PANAGIOTIS MAVROS, Portland, OR, Whitehouse Station, NJ, Piscataway, NJ This analysis examined patient-reported outcomes (PROs) after 26 weeks Adherence to newly prescribed anti-hyperglycemic agents is fundamental of open-label treatment in subjects randomly assigned to NB plus a com- to the attainment of glycemic goals. We estimated the A1C reduction associ- mercially-available telephone/web-based lifestyle intervention program ated with adherence to a fi rst-ever dispense of metformin. (N=153), or usual care (UC; periodic diet/exercise advice; N=89). Consistent We studied 3,109 patients who newly initiated metformin monotherapy, with prescribing information, this study prospectively required NB subjects calculating change in A1C as the difference between values recorded prior to to exhibit ≥5% weight loss at Week 16, with no sustained increase in blood and within 6-12 months after their fi rst metformin dispense. Using the date pressure, to continue treatment. Impact of Weight on Quality of Life-Lite of the post-metformin A1C, we used a modifi cation of the proportion of days (IWQoL-Lite), the Binge Eating Scale (BES), and the Arizona Sexual Function covered (PDC) method to estimate adherence over the 90-day period pre- Scale (ASEX) were assessed at baseline (BL) and Weeks 16 and 26. Analyses ceding the A1C to produce a “biologic response based” PDC (BRB-PDC). We were performed on subjects who remained on treatment through Week 26 categorized BRB-PDC into 4 levels: 0% (no refi ll of initial dispense), 1-49%, (per protocol [PP] population): NB n=71, UC n=82, 84% female, 80% white, 48 50-79%, and >80%. Change in A1C was modeled as a function of BRB-PDC years, and 36 kg/m2. At Week 26, NB elicited greater weight change (-9.5% category using 0% as the reference group, and adjusting for age, sex, race, vs. -0.9%, p<0.001) and improvement in all 3 PROs vs. UC. IWQoL-Lite total diabetes duration, initial metformin dose and A1C prior to metformin initia- score (BL: 67 NB, 64 UC) improved with NB (+16.4 [1.5]; least squares mean tion. change [SE]) vs. UC (-1.0 [1.4]; p<0.001); signifi cant improvement was also Mean age of the study sample was 59 years, 54% were men and 82% seen in all 5 subdomains. At BL, 34% of NB subjects and 44% of UC subjects were White. At metformin initiation, mean A1C was 8.2%. Most patients met the ASEX criteria for sexual dysfunction; at Week 26, over half (58%) of were adherent to metformin: 66% had a BRB-PDC >80% and 21% had a these NB subjects no longer met such criteria, compared to 19% of UC sub- BRB-PDC of 50-79%. However, 8% had a BRB-PDC 1-49% and 5% had no jects. BES total score (BL 15 NB; 16 UC) was also signifi cantly improved with metformin refi ll (BRB-PDC=0%). There was a graded relationship between NB (-6.8 [0.7]) vs. UC (+1.1 [0.7]; p<0.001). In subjects with moderate/severe adherence and change in A1C. Relative to the non-adherent group, BRB-PDC BES scores at BL (32% of NB, 41% of UC subjects), categorical improvement 1-49% was not signifi cantly associated with a change in A1C. However, was observed in 91% of these NB subjects vs. 18% in UC. Treatment with NB BRB-PDC 50-79% was associated with a change of -0.45% (95% CI -0.64, in a manner consistent with clinical practice was associated with improved -0.26), and BRB-PDC >80% was associated with an A1C change of -0.70% weight-related quality of life, control of eating, and sexual function. Larger (-0.87, -0.53). studies to confi rm these outcomes are warranted. Estimating adherence over a biologically relevant time period produces a stronger association with glycemic control than has been previously reported. 1195-P Marginal adherence (<50%) provides no benefi t, but full adherence is associ- Pioglitazone Is Equally Effective for Diabetes Prevention in Older ated with a nearly 1% A1C reduction. Because we controlled for a wide range Compared with Younger Prediabetic Adults of covariates, these results may generalize to other hypoglycemic therapies. SARA ESPINOZA, CHEN-PIN WANG, STEPHEN CLEMENT, DAWN SCHWENKE, Supported By: Merck Sharp & Dohme MARY ANN BANERJEE, GEORGE BRAY, THOMAS A. BUCHANAN, ROBERT HEN- RY, ABBAS KITABCHI, SUNDER MUDALIAR, ROBERT RATNER, FRANKIE STENTZ, 1193-P PETER REAVEN, RALPH A. DEFRONZO, DEVJIT TRIPATHY, NICOLAS MUSI, San Pharmacokinetics and Pharmacodynamics of the Glucagon Recep- Antonio, TX, Falls Church, VA, Tempe, AZ, Brooklyn, NY, Baton Rouge, LA, Los Ange- tor Antagonist LGD-6972 in a Multi-dose Clinical Trial les, CA, La Jolla, CA, Memphis, TN, Alexandria, VA, Phoenix, AZ ERIC G. VAJDA, DOUGLAS LOGAN, KENNETH LASSETER, DANIELLE ARMAS, DI- Older adults are at increased risk for type 2 diabetes (T2D). However, little ANE PLOTKIN, J.D. PIPKIN, YONG-XI LI, RONG ZHOU, DAVID KLEIN, XIAOXIONG is known about preventative strategies in this population. Our goal was to WEI, STACY DILZER, LIN ZHI, KEITH B. MARSCHKE, La Jolla, CA, Cincinnati, OH, determine whether pioglitazone prevents T2D conversion in older adults Miami, FL, Phoenix, AZ, San Diego, CA with pre-diabetes. Subjects were participants in ACT NOW, a randomized Elevated glucagon concentrations in combination with decreased insulin double blind placebo controlled trial of pioglitazone for T2D prevention in sensitivity contribute to the increased gluconeogenesis associated with adults with IGT (2-h glucose 140-199 mg/dL during an OGTT) and at least one untreated T2DM. LGD-6972 is an orally bioavailable small molecule com- high-risk characteristic for T2D. Subjects were randomized to 45 mg piogli- petitive glucagon receptor antagonist. A randomized, double-blind, placebo- tazone vs. placebo and followed for 2 y. Conversion to T2D was defi ned as 2 controlled, multiple ascending dose clinical trial was conducted with LGD- hr glucose ≥200 mg/dL and/or fasting glucose ≥126 mg/dL; OGTT confi rmed 6972 in normal healthy volunteers (NHV) and is ongoing in T2DM subjects. the diagnosis. Insulin sensitivity was estimated using the Matsuda index. LGD-6972 (n=9) or placebo (n=3) was administered orally to NHV at 15 mg/d Cox proportional hazard regression was used to compare time to develop-

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A308 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS ment of T2D between participants ≤60 y (n=184; mean age=66.1± 4.9) vs. (−0.73%, −0.82%, −0.74%, and −0.85%, respectively). The changes in BW >60 y (n=418; mean age=46.9±8.9), adjusted for sex and baseline laboratory (−3.52, −3.23, −3.34, and −3.08 kg in Groups A, B, C, and D, respectively) measures. In the overall cohort, T2D incidence was reduced by 72% in the and percent changes (−2.5%, −2.0%, −3.0%, and −2.5%) were similar in each pioglitazone group (HR=0.28, 95% CI: 0.16-0.49; p<0.0001). Incidence was group. The incidence of treatment-emergent adverse events (TEAEs) was reduced by 85% in older (HR=0.15, 95% CI: 0.05-0.50; p<0.01) and by 69% similar in each BMI group. The incidence of hypoglycemia was similar in in younger (HR=0.31, 95% CI: 0.17-0.57, p<0.01) subjects. T2D incidence did all patients (IPRA vs. PBO: 1.0% vs. 0.9%), and in each BMI group (Group A: not differ by age (p=0.41). Matsuda index increased 82% in older and 65% in 1.8% vs. 1.1%; Group B: 0% vs. 2.7%; Group C: 2.1% vs. 0%, Group D: 0% vs. younger participants (p=0.43). Triglyceride concentrations fell 14% in older 0%). The incidences of TEAEs related to urinary tract infection and genital vs. 9% in younger subjects (p=0.28). PAI-1 also fell by similar fractions (27% infection were similar in each BMI group. These results demonstrate that vs. 25%, p=0.79). Pioglitazone was more effective in increasing adiponectin the effi cacy and safety of IPRA in T2DM is independent of BMI. in older vs. younger subjects (2.9- and 2.2-fold, respectively; p<0.05). Similar Supported By: Astellas Pharma Inc. metabolic and laboratory fi ndings were observed using the near median age cutpoint (55 y) instead of the arbitrary cutpoint of 60 y. In summary, older 1198-P pre-diabetic adults demonstrated similar reductions in conversion to T2D Reductions in HbA1c and Systolic Blood Pressure in Patients with and similar or better improvements in metabolic risk factors with pioglita- Type 2 Diabetes Treated with Dapaglifl ozin zone, showing that pioglitazone is useful to prevent T2D in older adults. JASON MORAN, ARIE KATZ, HELEN YEH, Fort Washington, PA Supported By: Takeda Pharmaceutical Company Limited Hypertension is common in patients with type 2 diabetes (T2D) and is as- sociated with increased morbidity. Increasing renal glucose excretion with 1196-P dapaglifl ozin (DAPA) improves glycemic control as well as providing a sec- Bromocriptine-QR Improves Glycemic Control in Type 2 Diabetes ondary benefi t of blood pressure (BP) reduction. The proportion of patients (T2D) Subjects Poorly Controlled on High Dose Insulin Therapy who had an HbA1c reduction ≥0.5%, a systolic BP (SBP) decrease ≥5 mmHg, BINDU CHAMARTHI, Boston, MA and a reduction in both HbA1c and SBP with DAPA 5 or 10 mg/d or placebo T2D patients in poor glycemic control on high dose insulin therapy are dif- (PBO) was assessed in this post hoc analysis. Data were pooled from 10, fi cult to manage due to risk of hypoglycemia and weight gain with increasing 24-week monotherapy and combination therapy clinical trials and separately doses of insulin and refractoriness to insulin, mainly from insulin resistance. from 2, 12-week trials in patients with T2D and established hypertension re-

The concurrent use of an insulin sensitizer may offer a strategy to improve ceiving glucose-lowering medications and an ACEi or ARB. The proportion of POSTERS Therapeutics glycemic control while limiting further insulin requirement in these patients patients who had an HbA1c ≥0.5% reduction, an SBP decrease ≥5 mmHg, or but safe, effective options for such agents are limited. Previous studies indi- both was greater with DAPA vs. PBO across the 2 pools (Table). The propor- Clinical Diabetes/ cate that bromocriptine-QR (BQR), a quick release formulation of bromocrip- tions of patients with an HbA1c ≥0.5% reduction and a combined reduction tine, a dopamine D2 receptor agonist, is a postprandial insulin sensitizer and in HbA1c and SBP increased with higher baseline HbA1c. Improvements in hence would be expected to improve responses to prandial insulin therapy. SBP were more common in patients treated with DAPA 5 and 10 mg/d com- This study therefore evaluated the effect of once-daily morning administra- pared with PBO, including in patients receiving ACEi/ARB therapy. Safety tion of BQR on dysglycemia in T2D subjects in poor glycemic control (HbA1c fi ndings by baseline HbA1c or ACEi/ARB use were not notably different from [A1c] ≥7.5) on high dose basal-bolus insulin therapy (≥70 units/day). The the known DAPA safety profi le. study population, well matched at baseline, included subjects (N=85: BQR Table. 52, placebo [PL] 23) from the Cycloset Safety Trial meeting the above A1c and insulin criteria at baseline (A1c [%] - BQR: 8.52 ± 0.1, PL: 8.69 ± 0.1; Total daily insulin [TDI; units] - BQR: 117 ± 6, PL: 113 ± 10; means ± SEM). Subjects were on either insulin alone or in combination with one oral agent, on this stable treatment regimen for ≥30 days prior to randomization and continued on this regimen for 12 weeks except for dose changes if needed. After 12 weeks of treatment, BQR therapy resulted in a signifi cant between group mean A1c difference of -0.81% (-0.64% BQR vs. +0.17% PL; p=0.003). This BQR-induced A1c reduction was even greater in subjects with baseline A1c ≥8.5% (N=25 BQR, 14 PL) with a between group difference of -1.1% (-0.97% BQR vs. 0.13% PL; p =0.008). There was no signifi cant change in TDI in either group. These fi ndings suggest that bromocriptine-QR therapy may be an ef- fective strategy to improve glycemic control in T2D patients inadequately controlled on high dose basal-bolus insulin therapy.

1197-P Effi cacy and Safety of Ipraglifl ozin (IPRA) in Japanese Patients with Type 2 Diabetes Mellitus (T2DM) Stratifi ed by Body Mass Index (BMI) Supported By: AstraZeneca ATSUNORI KASHIWAGI, SATOSHI YOSHIDA, ICHIRO NAKAMURA, KENICHI KAZUTA, EIJI UEYAMA, HIDEYUKI TAKAHASHI, HAYATO SATOMI, YOSHINORI 1199-P KOSAKAI, KOUSEI KAWAMUKI, Kusatsu, Japan, Tokyo, Japan Benefi cial Effect of Pitavastatin on the Incidence of Diabetes in We sought to examine the effi cacy and safety of IPRA, a selective sodium- Lean Subjects with IGT: Subanalysis of J-PREDICT glucose co-transporter 2 inhibitor, in Japanese T2DM patients by performing TERUO SHIBA, KENTARO SAKAMOTO, JUNJI KISHIMOTO, TSUTOMU YAMAZA- a pooled analysis of 5 randomized, placebo (PBO)-controlled clinical trials. KI, Tokyo, Japan, Fukuoka, Japan We included 2 monotherapy studies and 3 studies in which patients received Obesity is one of major risk factors for new-onset DM (NOD), and statins IPRA or PBO with ongoing metformin, sulfonylurea, or pioglitazone. Overall, reportedly increased NOD in subjects with BMI≥30kg/m2 in JUPITER and high 508 IPRA- and 321 PBO-treated patients were analyzed. The mean ages and dose atorvastatin study. We assessed differential effect of pitavastatin on BMI (IPRA vs. PBO) were 57.8 vs. 57.5 years and 26.0 vs. 25.4 kg/m2, re- NOD among those with either obesity or not in this sub-analysis of J-PREDICT, spectively. The mean changes (IPRA vs. PBO) in hemoglobin A1c (A1c) after prospective RCT evaluating the effect of pitavastatin (PIT) on NOD (n=1,269; starting treatment were −0.8% vs. +0.4%, respectively; thus, the change vs. 635 Control, 634 PIT) in Japanese subjects with IGT. The primary outcome was PBO was -1.2% (P<0.001). However, 11.2% and 69.2% of patients in IPRA incidence of DM defi ned as a 2h-PG of ≥200 mg/dl or a FPG of ≥126 mg/dl mea- and PBO, respectively, did not show improvement after treatment. The mean sured at least once in 75g OGTT performed every six months. The HR for con- body weight (BW) changes (IPRA vs. PBO) were −2.2 vs. −0.5 kg, respective- version to DM in PIT was 0.82 (95% CI, 0.68-0.99; p=0.041). They were divided ly, and 15.6% vs. 2.5% of patients had BW loss of ≥4 kg, respectively. The into 3 groups according to tertile of baseline BMI (T1: <23.4, T2: 23.4≤ <26.1, IPRA dose was 50 mg or PBO. Patients were divided into quartiles by BMI: and T3: 26.1≤). Event rate in the incidence of DM (per 1,000 person-yr) was in- <23 (Group A), ≥23 to <25 (Group B), ≥25 to <28 (Group C), and ≥28 kg/m2 creased along with the increase in BMI among each tertiles in the Control (T1: (Group D). The changes in A1c were not signifi cantly correlated with the 169.9, T2: 181.9, T3: 208.8) and in PIT (T1: 121.2, T2: 179.1, T3:181.2). The event changes in BW. The changes in A1c were similar in Groups A, B, C, and D rate in PIT was signifi cantly lower only in T1 compared to the control (HR 0.61,

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95% CI 0.42-0.89, p=0.0096). Serum level of adiponectin was reduced, and Patients experiencing hypoglycaemia: Odds ratio between treatments at 52 HOMA-IR index, HOMA-beta and insulinogenic index at 30 min were increased weeks along with upper tertile. But the average age was decreased in upper tertile. SGLT2i SU 0.08 (0.06, 0.11) † 0.08 (0.04, 0.13) † In addition to reducing LDL cholesterol, PIT treatment may provide a benefi t in preventing NOD in lean Japanese subjects with IGT. GLP1 SU No data at 52 weeks DPP4i SU 0.09 (0.08, 0.12) † 0.09 (0.06, 0.14) † TZD SU 0.09 (0.03, 0.24) † 0.09 (0.02, 0.33) † Absolute risk of hypoglycaemia at 52 weeks SU 26.5% (20.2%, 33.9%) 26.5% (20.17%, 34.0%) SGLT2i 2.9% (1.9%, 4.4%) 2.7% (1.45%, 4.9%) GLP1 No data at 52 weeks DPP4i 3.3% (2.2%, 4.9%) 3.2% (1.78%, 5.5%) TZD 3.3% (0.9%, 8.6%) 3.2% (0.71%, 11.1%) † statistically signifi cant result based on the 95% credible interval (CrI).

1201-P Breadth of DPP-4i Cardiovascular Outcomes Trials Enrollment Cri- teria to the Whole Type 2 Diabetes Population in the U.S. ANNE L. PETERS, JOANNA P. MACEWAN, JOHN SHEEHAN, JACQUELINE VANDERPUYE-ORGLE, IFTEKHAR KALSEKAR, ANUP MALANI, Los Angeles, CA, Fort Washington, PA, Chicago, IL In 2008, FDA asked that sponsors establish the cardiovascular (CV) safety of new antidiabetic pharmacotherapy for type 2 diabetes mellitus (T2DM). Supported By: Waksman Foundation of Japan, Inc.; Kowa Pharmaceutical POSTERS Dipeptidyl-peptidase-4 inhibitors (DPP-4i) makers designed CV outcome tri- Therapeutics Europe Co. Ltd. als (CVOTs) to assess CV safety. Each CVOT enrollment criteria varied. This Clinical Diabetes/ retrospective study examined the share of adult T2DM patients in the U.S. 1200-P who met the eligibility criteria for 5 different CVOTs. Network Meta-analysis of Diabetes Drug Classes as Add-on to This study used patient characteristics, prescriptions, exam, and lab re- Metformin for T2D sults from the representative 2009-2012 National Health and Nutrition Ex- MICHELLE E. ORME, KELLY BELL, PRAVEEN DHANKHAR, Swindon, United Kingdom, amination Surveys to identify patients who met the criteria for enrollment Fort Washington, PA in: SAVOR (saxagliptin), CARMELINA (linagliptin), CAROLINA (linagliptin), We conducted a network meta-analysis to compare antidiabetes drug TECOS (sitagliptin), and EXAMINE (alogliptin). classes in type 2 diabetes (T2D) patients inadequately controlled on metformin Patients who met the criteria for at least 1 of the CVOTs were older (p<0.001), monotherapy. We updated a published systematic review to identify recent more likely to be in Medicare (p<0.001), and had more comorbidities (e.g., hyper- randomized controlled trials (up to Sept 2014) for dipeptidyl peptidase-4 inhibi- tension (0.001), high cholesterol (0.023), stroke (0.010)) compared to the average tors (DPP4i), glucagon-like peptide-1 (GLP1) receptor agonists, thiazolidinediones American with T2DM. Overall, 28% of the T2DM population met the criteria for (TZD), sulfonylureas (SU) and sodium glucose co-transporter-2 inhibitors (SGLT2i). at least one of the 5 CVOTs. Of those who met any of the 5 CVOT criteria, 60% Across the studies the average patient age was 57 years, duration of diabetes only met the criteria for 1 of the 5 CVOTs, and no patients met the criteria for all 5. 6.1 years, baseline HbA1c 7.9%, weight 88kg and 46% were female. Twelve stud- Approximately 21%, 9%, 5%, 4%, and 0.2% of patients with T2DM met the cri- ies qualifi ed for the basecase at 52 weeks of follow-up. Based on the random- teria for SAVOR, CARMELINA, CAROLINA, TECOS, and EXAMINE, respectively. effects model, SGLT2i, TZD and DPP4i have a similar reduction in HbA1c as SU: The estimated share of patients meeting eligibility criteria differed signifi cantly HbA1c control with GLP1 is signifi cantly better than SU. SGLT2i, DPP4i and GLP1 between all CVOTs (p<0.005), except TECOS and CAROLINA (p=0.86), based on result in signifi cant weight loss. SGLT2i results in signifi cantly lower systolic t-tests for equal means. In the two most inclusive CVOTs, 38% of patients with blood pressure (SBP). SGLT2i, TZD and DPP4i result in signifi cantly lower odds T2DM eligible for a CVOT were eligible for SAVOR only, 12% for CARMELINA of hypoglycemia compared to SU. The results indicate that the SGLT2i class pro- only, and 17% for both SAVOR and CARMELINA. vides good glycemic control, a reduced risk of hypoglycemia, with the biggest This study indicates that among DPP-4i CVOTs, the share of adults in the impact in terms of lowering blood pressure and weight loss. U.S. with T2DM who would meet enrollment criteria varies substantially and Table. Results from 52 Week Basecase Network Meta-analysis (NMA). that SAVOR’s enrollment criteria are the most inclusive of the general T2DM population. Class Compared to Fixed-Effect NMA Random-Effects NMA Supported By: AstraZeneca Difference in HbA1c% after 52 weeks SGLT2i SU -0.05 (-0.11, 0.00) -0.05 (-0.17, 0.08) 1202-P GLP1 SU -0.44 (-0.61, -0.26)† -0.44 (-0.70, -0.18)† Pharmacokinetics (PK) and Pharmacodynamics (PD) of PF-06291874 DPP4i SU 0.08 (0.05, 0.12) 0.08 (-0.01, 0.17) (PF), a Glucagon Receptor Antagonist, in Subjects with T2DM DAVID J. KAZIERAD, ARTHUR BERGMAN, BEESAN TAN, VEENA SOMAYAJI, TZD SU 0.02 (-0.14, 0.18) 0.02 (-0.24, 0.28) DOUGLAS S. LEE, TIMOTHY ROLPH, Cambridge, MA SU Placebo -0.63 (-0.85, -0.41)† -0.64 (-0.94, -0.33)† The purpose of this study was to investigate PK, PD, and safety follow- Difference in weight (kg) after 52 weeks ing oral doses of PF in subjects with T2DM. This was a 2-part, randomized, SGLT2i SU -4.71 (-4.94, -4.48) † -4.68 (-5.18, -4.16) † double-blind, placebo-controlled trial. PF was administered once daily for 2 weeks on a background of metformin (MET) [Part A] or MET and a sulfony- GLP1 SU -4.05 (-4.81, -3.28) † -4.07 (-5.16, -2.99)† lurea (SU) [Part B]. PF Cmax and AUC increased proportionally with dose. Tmax DPP4i SU -1.98 (-2.14, -1.81) † -2.00 (-2.39, -1.63) † occurred 4-6 hours post dose and the mean terminal t½ ranged from 19.7 to TZD SU 0.10 (-0.54, 0.74) 0.10 (-0.92, 1.13) 22.7 hours. Dose-dependent reductions in day 14 mean daily glucose (MDG) SU Placebo 1.93 (1.13, 2.73) † 1.90 (0.75, 3.04) † and fasting plasma glucose (FPG) were observed (table below). Following MMTT, dose-dependent increases in glucagon and total GLP-1 were ob- Difference in systolic blood pressure (mmHg) after 52 weeks served, although there were no meaningful changes in insulin, C-peptide or SGLT2i SU -5.01 (-5.96, -4.06) † -4.97 (-6.89, -2.97) † active GLP-1. Dose-dependent increases topping at 12%, 56% and 46% over GLP1 SU -3.89 (-7.04, -0.73) † -3.75 (-8.64, 1.40) baseline were observed in plasma LDL-C, ALT and AST, respectively. There DPP4i SU -2.89 (-4.93, -0.87) † -2.88 (-6.47, 0.72) was no difference in frequency of hypoglycemia in Part A, and only a slight increase over placebo was noted for the 30 mg dose in Part B. In conclusion, TZD SU No data at 52 weeks PF was safe and well tolerated, with robust reductions in plasma glucose SU Placebo 2.01 (-1.56, 5.55) 1.94 (-2.70, 6.59) following 2 weeks of dosing in subjects on background MET ± an SU.

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Table. therefore investigated the frequency and characteristics of hypersensitivity Dose Background PF-06291874 AEs pooled across 21 phase 2/3 comparator-controlled DAPA trials, includ- (mg) Treatment PD Effects ing a subanalysis of Asian pts. In the total population, AEs and serious AEs (SAEs) of hypersensitivity were infrequent and reported in a similar propor- N CFB‡ MDG CFB* FPG % CFB in LDL-C* tion of pts with DAPA or comparator (Table); the most common events were (mg/dL) (mg/dL) [Mean±ΣΔ] [LSMean(90% CI)] [Mean±ΣΔ] rash, eczema, dermatitis, and urticaria. Few pts discontinued as a result of hypersensitivity AEs. In pts of Asian descent, a lower frequency of hypersen- 0A18-11.5 -14.8 ± 30.0 -9.6 ± 12.6 sitivity AEs was observed with DAPA vs. comparator. In the placebo (PBO)- (-20.3, -2.8) controlled pools hypersensitivity AEs were slightly more frequent with DAPA 5A12**-14.3 -19.2 ± 21.5 -9.4 ± 10.8 vs. PBO across the overall population and less frequent with DAPA vs. PBO in (-25.5, -3.2) Asian pts. In conclusion, hypersensitivity events with DAPA were infrequent 15 A 12 -33.2 -39.8 ± 34.1 -6.4 ± 16.7 across the clinical program and were similar between PBO and compara- (-44.0, -22.4) tor. These events rarely led to discontinuation of DAPA and were not more 50 A 12 -38.1 -42.4 ± 29.6 2.0 ± 17.9 frequent in Asian pts. (-48.8, -27.4) 1Suzuki Y, et al. Diabetes Res Clin Pract. 2014;106(Supp 1):S265. 100 A 14 -43.9 -37.7 ± 19.5 -0.4 ± 12.2 Table. Hypersensitivity Events*. (-53.9, -33.8) DAPA COMPARATOR 150 A 12 -53.9 -49.1 ± 18.3 12.0 ± 18.3 (-64.7, -43.1) Study Pool: Total DAPA All control All phase 2b and 3 N=5936 N=3403 0B12-31.3 -31.0 ± 35.0 -5.5 ± 15.6 (-42.1, -20.5) Total AEs, n (%) 270 (4.5) 148 (4.3) AEs in Asian pts, n/N (%) 21/1050 (2.0) 23/513 (4.5) 15 B 10 -20.9 -35.3 ± 18.3 1.5 ± 21.5 SAEs, n(%) 11 (0.2) 3 (0.1) (-32.6, -9.2) Discontinuations, n (%) 9 (0.2) 5 (0.1) 30 B 14 -50.7 -45.3 ± 32.4 -7.5 ± 14.2 Most common events (≥ 0.5% in any group), n (%) – – (-60.6, -40.7) Rash 63 (1.1) 36 (1.1)

Eczema 38 (0.6) 26 (0.8) POSTERS

‡ Therapeutics CFB=Change From Baseline; Baseline was Day -1 value; *Baseline was the Dermatitis 29 (0.5) 13 (0.4) average of Day - 1 and Day 0 values. Urticaria 27 (0.5) 6 (0.2) Clinical Diabetes/ **N=11 for MDG; LSMean=Least Square mean adjusted for baseline; PBO-controlled DAPA 10 mg PBO SD=Standard Deviation; CI=Confi dence Interval. A=MET; B=MET + SU. Short-term PBO N=2360 N=2295 Total AEs, n (%) 61 (2.6) 50 (2.2) AEs in Asian pts, n/N (%) 2/209 (1.0) 7/206 (3.4) 1203-P SAEs, n (%) 2 (0.1) 2 (0.1) Effi cacy and Safety of Ipraglifl ozin in Japanese Type 2 Diabetic Discontinuations, n (%) 4 (0.2) 3 (0.1) Patients Short-term plus Long-term PBO N=2026 N=1956 MASAHIRO TAKIHATA, YASUO TERAUCHI, Miura, Japan, Yokohama, Japan Total AEs, n(%) 96 (4.7) 75 (3.8) There were few studies which investigated the effi cacy and safety of AEs in Asian pts, n (%) 2/131 (1.5) 6/120 (5.0) sodium-glucose transporter 2 inhibitors in Asian patients including Japa- SAEs, n (%) 3 (0.1) 2 (0.1) nese. The aim of this study was to investigate effi cacy and safety of ip- Discontinuations, n (%) 3 (0.1) 4 (0.2) raglifl ozin for diabetes and its complications in Japanese type 2 diabetic *Categorized using the Medical Dictionary for Regulatory Activities (Med- patients. Subjects whose HbA1c level had been over 6.0% were eligible for DRA) 17.0 preferred terms and using the standardized MedDRA queries recruitment with conventional therapy. Of the 281 patients who were added (SMQ) hypersensitivity narrow terms. ipraglifl ozin 50 mg/day, 229 patients who completed the 12 weeks follow up Supported By: AstraZeneca were analyzed in the levels of HbA1c, body weight, and markers of lipids, uric acid, liver function and renal function. At 12 weeks, the mean HbA1c level, 1205-P the body weight, systolic blood pressure, diastolic blood pressure, uric acid, A Novel Tricyclic Pyrone Compound TP70 Decreases Hyperglyce- and urine albumin-to-creatinine ratio (UACR) improved from 7.53 ± 1.21% to mia in Diabetic NOD/Shiltj Mice and High-Fat Diet-induced Diabe- 6.98 ± 0.80% (P<0.001), from 71.1 ± 12.8 kg to 68.9 ± 12.7 kg (P<0.001), tes in Wild Type Mice from 143 ± 19 mmHg to 133 ± 18 mmHg (P<0.001), from 79 ± 12 mmHg to BENDE ZOU, CHRISTOPHER A. LIEU, CONRADO PASCUAL, SAHANI M. 75 ± 11 mmHg (P<0.001), from 5.29 ± 1.35 mg/dl to 4.95 ± 1.33 mg/dl (P<0.001), WEERASEKARA, ALEX MEIER, DUY H. HUA, XINMIN (SIMON) XIE, Redwood City, and from 174 ± 599 mg/gCr to 102 ± 308 mg/gCr (P<0.001). Aspartate amin- CA, Manhattan, KS otransaminase, alanine aminotransferase, and gamma-glutamyl transpepti- A novel class of tricyclic pyrone compounds, particularly the lead TP70 dase levels also improved signifi cantly. However, creatinine level, estimated has been shown to inhibit activity of acyl CoA-cholesterol acyltransferase. glomerular fi ltration rate, and high-density lipoprotein cholesterol level were The present study was undertaken to investigate effects of TP70 on diabetic exacerbated from 0.74 ± 0.23 mg/dl to 0.78 ± 0.25 mg/dl (P<0.001), from models. Diabetes NOD/ShiLtJ mice (Jackson Laboratory) exhibit hyperglyce- 79.2 ± 21.7 mL/min to 75.5 ± 20.1 mL/min (P<0.001), and from 50 ± 14 mg/dl mia with hypoinsulinemia, modeling Type 1 insulin-dependent diabetes. NOD/ to 48 ± 15 mg/dl (P<0.001), respectively. There were signifi cant correlations ShiLtJ female mice under normal diet spontaneously developed hyperglycemia between the changes in body weight and those in the blood pressure and the by age of 4 months old, when the treatment began. TP70 dissolved in water markers of liver function, but not between the changes in body weight and (0.12 mg/ml with 5% propylene glycol as vehicle) was administrated via drink- those in the changes in HbA1c, uric acid, and UACR. Hypoglycaemia (12 pa- ing (daily TP70 intake between 22 - 28 mg/kg). Blood glucose level was mea- tients [5.2%]), rash (6 patients [2.6%]), and constipation (27 patients [11.8%]) sured using TRUEtrack glucose meter. Following two months of treatment, the were observed during 12 weeks. In conclusion, ipraglifl ozin improved not non-fasting glucose levels of the vehicle group increased to 409.3 ± 110.5 mg/ only HbA1c level but also body weight, blood pressure, liver function, uric dl from a pre-diabetic level of 91.3 ± 2.9 mg/dl (n = 4), whereas the treatment acid, and UACR in Japanese type 2 diabetic patients. group increased to 124.8 ± 22.1 mg/dl from 88.4 ± 6.4 mg/dl (n = 5). To confi rm the drug action, a high fat diet-induced diabetes in male C57BL/6 1204-P mice was used to mimic type 2 noninsulin-dependent diabetes. High fat diet Hypersensitivity Events with Dapaglifl ozin: A Pooled Analysis and TP70 treatment began simultaneously at ages around 3-month-old. After ANNIKA MELLANDER, MARTIN BILLGER, JENNIFER SUGG, KRISTINA JOHNS- 4 weeks, glucose in the vehicle group increased to 178.5 ± 7.8 mg/dl from a SON, EVA JOHNSSON, Mölndal, Sweden, Gaithersburg, MD baseline of 108.6 ± 4.1 mg/dl (n = 8), whereas in the TP70 group (daily intake In patients (pts) with type 2 diabetes mellitus dapaglifl ozin (DAPA) im- of 20 - 28 mg/kg via drinking) was 148 ± 6.4 mg/dl (baseline 110.6 ± 5.0 mg/ proves glycemic control, is generally well tolerated, and has an adverse dl, n = 8). The reduction of glucose level is signifi cant and persistent through- event (AE) profi le typically related to its mechanism of action. Hypersensitiv- out the treatment (> 2 months). TP70 at the same therapeutic doses did not ity events have been reported in some pts with sodium-glucose cotrans- affect the body weight, locomotion (traveling distance and speed), rearing porter 2 inhibitors, including a report of dermatological AEs in Japan1. We activity and rotarod performance assessed using the SmartCage system

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(AfaSci, Inc.). These preliminary in vivo study results have demonstrated that all well tolerated. Increased effi cacy with QD vs. BID dosing and markedly TP70 could be a new effective and safe therapeutic for the treatment and reduced exposure with MetDR strongly support a major role for Met bowel prevention of diabetes by a reduction of hyperglycemia. accumulation to mediate Met’s glucose lowering effects. Restricting Met to Supported By: National Institutes of Health (R43AG043203, R44NS086343) the lower bowel may be a better alternative for patients with renal impair- ment to avoid met plasma accumulation associated with lactic acidosis. 1206-P Initial Triple Drug Combination and Subsequent Maintenance by 1208-P Metformin/Pioglitazone Combo Gives Good Long-Term Glycemic Dual Treatment with Saxagliptin + Dapaglifl ozin Provides a Similar Control in Asian Indian Type 2 Diabetes Patients (T2DM) Increase in Urinary Glucose Excretion with Fewer Genitourinary VIJAY PANIKAR, SHASHANK JOSHI, NIKHIL NASSIKAR, BHAVIK SAGLANI, Infections Compared with Dapaglifl ozin CHANDNI JAIN, REMIA MACHADO, NARAYAN DEOGAONKAR, Mumbai, India, KATJA ROHWEDDER, ELLA ELKHOLM, WILLIAM COOK, HUNGTA CHEN, NAYYAR Nashik, India IQBAL, LARS HANSEN, BOAZ HIRSHBERG, Wedel, Germany, Mölndal, Sweden, This study assessed the effi cacy of initial triple drug combination (TDC) of Gaithersburg, MD, Princeton, NJ Gliclazide 80 mg, and a fi xed dose combination (FDC) of metformin SR 500 + SGLT2 and DPP-4 inhibitors have complementary mechanisms of action pioglitazone 7.5 mg (Met/Pio) given twice a day in newly diagnosed T2DM to improve glycemic control with a low risk of hypoglycemia and the added patients followed by only the FDC in maintaining long-term glycemic control. benefi t of SGLT2 inhibitor-induced weight loss. Patients with T2DM are pre- All newly diagnosed (<1 year duration) T2DM patients treated with a disposed to genital (GIs) and urinary tract infections (UTIs) due to several TDC were followed up for a period of 4 years. Those controlled only on the factors, including glucosuria. Pharmacologically induced glucosuria with FDC were designated as “responders” and those needing additional drugs SGLT2 inhibitors raises the risk of developing GIs and, to a relatively lesser as “nonresponders”. The primary effi cacy end-points were: 1. Time taken to extent, UTIs. In a recently published add-on on to metformin study, we re- discontinue Gliclazide. 2. Duration of control only on Met/Pio combo. 3. Cor- ported an increased frequency of GIs in the dapaglifl ozin (DAPA) but not in relation with age, sex, BMI, waist circumference (WC), lipid abnormalities. the saxagliptin (SAXA) or SAXA+DAPA add-on arms (5.6% vs. 0.6% vs. 0%, 1522 newly diagnosed T2DM patients, 962 (males) and 560 (females) were respectively). UTIs were reported in 3.9% of patients in the DAPA arm com- analysed. Time taken to discontinue Gliclazide was 2.83 ± 3.77 months in pared with 5.1% in the SAXA and 0.6% in the SAXA+DAPA arms. We evalu- 1272 (83.6%) patients (responders) where as 250 (16.4%) patients continued ated if the reduced risk of GIs and UTIs with the combination of SAXA+DAPA

POSTERS to need gliclazide (nonresponders). was related to differences in urinary glucose excretion (UGE). Spot urine Therapeutics data suggest that patients in the DAPA and SAXA+DAPA arms have clini- Clinical Diabetes/ Table. Profi le of Responders as per Duration. cally similiar increases in UGE and urinary glucose/creatinine ratios after 24 Duration Total Responders Responders Responders Non weeks of treatment (Table). In conclusion, UGE was increased similarly with of followup pts. only on Met/Pio only on Met/Pio only on Met/Pio Responders in yrs But not completed studied No % No % SAXA+DAPA and DAPA alone suggesting that the reduced occurrence of GIs the duration and UTIs observed with the combination of SAXA+DAPA in this study does not appear to be associated with UGE differences. ≤ 1 1522 1272 83.6 0250 16.4 Table. 2 1272 360 912 0830 91.0 0082 09.0 3 830 290 540 0464 85.9 0076 14.1 4 464 205 259 0206 79.5 0053 20.5 Patients with higher BMI, higher WC and Triglyceride/HDL ratio ≥ 3 re- sponded better. All responders maintained HbA1c below 7% throughout the 4 year period. In this study we have found that we could achieve long term glycemic control of T2DM patients using initial TDC for a few months and then main- taining the glycemic control with Met/Pio for many years. Supported By: AstraZeneca 1207-P The Primary Glucose-Lowering Effect of Metformin Resides in the 1209-P Gut Not the Circulation—Results from 7-Day and 12-Week Studies Changes in the Lymphocyte Count with Saxagliptin and Its Associa- MARK FINEMAN, JOHN B. BUSE, RALPH A. DEFRONZO, JULIO ROSENSTOCK, tion with Clinical Outcomes in the SAVOR Trial TERRI KIM, COLLEEN BURNS, SHARON SKARE, ALAIN BARON, San Diego, CA, AVIVIT CAHN, OFRI MOSENZON, BOAZ HIRSHBERG, CHRISTINA A.M. STAHRE, Chapel Hill, NC, San Antonio, TX, Dallas, TX LEON E. LITWAK, BASIL S. LEWIS, KRZYSZTOF STROJEK, MARINA V. SHESTA- The intestine is a major site of metformin (Met) accumulation (300-1000X KOVA, ANGELO AVOGARO, CHERYL WEI, ITAMAR RAZ, Jerusalem, Israel, Gaith- plasma), however its impact on glucose homeostasis is unknown. Met ersburg, MD, Gothenburg, Sweden, Buenos Aires, Argentina, Haifa, Israel, Zabrze, delayed-release (MetDR) is formulated to deliver Met to the lower bowel Poland, Moscow, Russian Federation, Padova, Italy where bioavailability is 1/5th that of the upper bowel. MetDR was explored Concerns regarding an increased risk of infection with use of DPP-4 inhibi- in two studies in subjects with T2D not on Met ≥2 wks prior to dosing. Study tors have been raised as DPP-4 (CD26) is found on immune cells and lym- I compared 1000 mg MetDR QD vs. 500 mg MetDR BID in a 7 day crossover phopenia has been reported with DPP-4 inhibitors. design (n=26, mean FPG 168 mg/dl). In the SAVOR trial 16,492 patients with type 2 diabetes were randomized Results: 1000 mg QD resulted in a 29% decrease in exposure vs. 500 mg to saxagliptin (SAXA) or placebo and followed for a median of 2.1 years. A BID (p <0.05). 1000 mg QD dosing resulted in a 9% reduction in 24 hr plasma decrease in the lymphocyte count to <0.5 × 109 cells/L was an adverse event glucose from baseline (p <0.05) and 5% reduction for 500 mg BID (p=0.099). of special interest and was not increased with SAXA vs. placebo [0.6% vs. Study II assessed the effect of 600 mg and 1000 mg MetDR QD on FPG over 0.5% HR 1.27 (0.84, 1.94)]. 12 wk in a randomized blinded study. Met extended release (MetXR) 1000 There was a reduction in the lymphocyte count from baseline to end of mg was included as a non-blinded reference (n=~40/group, mean FPG=173 trial in the SAXA arm vs. an increase in the placebo arm (-0.064 vs. +0.014, mg/dl, mean HbA1c=7.4%, mean Met dose prior to washout=1438 mg). p<0.001), yet there was no increased risk of severe infections with SAXA vs. Results: Mean 4-12 wk change in FPG from baseline was reduced for placebo (585 vs. 567 [HR 1.03 (0.91, 1.15)]). MetDR: -13.5 mg and -18.0 mg/dl for 600 mg and 1000 mg vs. -1.2 mg/dl for Reduction in lymphocytes has been reported to be associated with adverse PBO (all p<0.05). The mean 4-12 wk FPG reduction for 1000 mg MetXR (-13.3 cardiovascular (CV) outcomes. In the overall population, an increased risk for mg/dl, p<0.05 vs. PBO) was similar to 600 mg MetDR with an apparent 40% the primary and secondary endpoints and for hospitalization for heart failure increase in potency of MetDR vs. MetXR. The increased potency is more was observed in the tertile of subjects whose lymphocyte count decreased evident when considering that fasting Met plasma exposure was reduced (Table). Cox proportional hazard model was used to assess the difference be- by almost 90% with MetDR vs. Met XR (median plasma Met: 56 vs. 515 ng/ tween treatment arms by lymphocyte change categories. SAXA did not modify ml for 600 mg MetDR vs. 1000 mg MetXR). The mean HbA1c differences the interaction between lymphocyte changes and outcomes (p >0.1). from placebo at 12 weeks were 0.36%, and -0.27% for 600 mg and 1000 We conclude that the mild lymphocyte reduction observed with SAXA did mg MetDR respectively and -0.22% for 1000 mg MetXR. Treatments were not increase the risk for severe infections or CV events.

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Table. T2DM duration ~14 yrs, HbA1c 8.2%, ~50% with NYHA class ≥2 HF). Patients receiving DAPA experienced clinically meaningful PBO-adjusted declines in HbA1c (−0.55%; 95% CI −0.80, −0.30), weight (−2.67 kg; 95% CI −3.88, −1.47) and systolic BP (−2.1 mmHg; 95% CI −5.68, 1.57) over 52 weeks; there was no change in heart rate in either group. The rates of orthostatic hypotension, syn- cope and hypoglycemia were similar between the two groups. More patients on DAPA vs. PBO had a decrease in creatinine clearance (11 [6.4%] vs. 2 [1.3%]) and increase in creatinine (7 [4.1%] vs. 2 [1.3%]); however, absolute difference in eGFR from baseline to 50 weeks was minimal (−1.4 vs. −2.6 mL/min/1.73 m2 with PBO vs. DAPA). In summary, treatment with DAPA 10 mg vs. PBO produced clinically meaningful reductions in HbA1c, weight and systolic BP in patients Supported By: AstraZeneca with T2DM and HF, and was well tolerated. The weight and BP effects of DAPA may lead to improvement in HF related symptoms in this patient population, 1210-P which should be further investigated in prospective studies. Achievement of HbA1c Goal and Body Weight and Systolic Blood Supported By: AstraZeneca Pressure Reduction When Treated with Dapaglifl ozin in Patients with Type 2 Diabetes Stratifi ed by Disease Duration HELEN YEH, ARIE KATZ, JASON MORAN, Fort Washington, PA 1212-P Approximately 60% of individuals with type 2 diabetes (T2D) are obese, Changes in Insulin: Glucose, Glucagon: Glucose, and Insulin: Glu- 70% have hypertension, and 48% have both comorbidities. Few patients cagon Ratios Correlate with Glycemic Response in Patients with reach all treatment goals for all conditions over time. In this post hoc analy- Type 2 Diabetes Treated with Saxagliptin Plus Dapaglifl ozin Add- sis, we assessed the proportion of patients who achieved HbA1c <7%, a body on to Metformin Therapy weight (BW) reduction of ≥3%, and a systolic blood pressure (SBP) decrease LARS HANSEN, NAYYAR IQBAL, ELLA ELKHOLM, HUNGTA CHEN, WILLIAM of ≥3 mmHg without hypoglycemia after treatment with dapaglifl ozin (DAPA) COOK, BOAZ HIRSHBERG, Princeton, NJ, Mölndal, Sweden, Gaithersburg, MD 5 mg/d (n=763) or 10 mg/d (n=2224) or placebo (PBO, n=2153) for 24 weeks. Adults with A1C 8.0%-12.0% were randomized to add-on therapy to met- End points were assessed in patients pooled from 10 DAPA monotherapy and formin XR ≥1500 mg/d with saxagliptin (SAXA) 5 mg/d plus dapaglifl ozin

(DAPA) 10 mg/d (SAXA+DAPA+MET; n=160), SAXA 5 mg/d and placebo POSTERS combination therapy clinical trials, and results were stratifi ed by duration of Therapeutics (SAXA+MET; n=154), or DAPA 10 mg/d and placebo (DAPA+MET; n=152). We T2D of <7 and ≥7 years. The proportion of patients with T2D for <7 years who Clinical Diabetes/ achieved HbA1c <7% and all associated composite end points was signifi - analyzed changes in insulin: glucose, glucagon: glucose, and insulin: glucagon cantly greater with DAPA 5 and 10 mg/d vs. PBO (Table). In patients with T2D ratios and ratios of the area under the curve (AUC) from 0-180 minutes during for ≥7 years, a greater proportion of patients consistently met HbA1c <7%, a meal test at baseline and wk 24 of blinded treatment and their relation to the BW, and SBP end points with DAPA vs. PBO, particularly with DAPA 10 mg. glycemic response. Similar increases in insulin: glucose ratios were observed DAPA when used as monotherapy or as combination therapy improved goal across treatment groups, whereas glucagon: glucose ratios increased more achievement for HbA1c and was associated with BW and SBP reductions with SAXA+DAPA+MET and DAPA+MET than with SAXA+MET (Table). In con- without hypoglycemia, and across the disease duration spectrum. Effects trast, insulin: glucagon ratios increased with SAXA+MET but decreased with appeared greater when DAPA was used earlier in the course of T2D. SAXA+DAPA+MET and DAPA+MET. Correlation of changes in A1C with chang- es in the AUC ratios was assessed using linear regression with A1C change Table. as dependent and AUC ratios and treatment groups as independent variables (Table). Despite a differential treatment effect on AUC ratios and A1C across treatment groups, changes in insulin: glucose, glucagon: glucose, and insulin: glucagon ratios were correlated with changes in A1C, with the insulin: glucose ratio being associated with the greatest changes in A1C. Table.

Supported By: AstraZeneca Supported By: AstraZeneca 1211-P 1213-P Effi cacy and Safety of Dapaglifl ozin in Patients with Type 2 Diabetes Empaglifl ozin (EMPA) Reduces HbA1c with Lower Insulin Doses Mellitus (T2DM) and Concomitant Heart Failure in Patients with Type 1 Diabetes (T1DM): A 4-Week Placebo-Con- MIKHAIL KOSIBOROD, INGRID AMI GAUSE-NILSSON, CHRISTIAN SONESSON, trolled Trial (EASE-1) JENNIFER E. SUGG, EVA JOHNSSON, Kansas City, MO, Mölndal, Sweden, Gaith- THOMAS R. PIEBER, SUSANNE FAMULLA, JENS EILBRACHT, JESSICA CES- ersburg, MD CUTTI, NIMA SOLEYMANLOU, ODD ERIK JOHANSEN, HANS J. WOERLE, ULI C. Over 40% of patients with heart failure (HF) have T2DM; a number that is BROEDL, STEFAN KASPERS, Graz, Austria, Neuss, Germany, Biberach, Germany, expected to increase due to rising prevalence of both conditions. Yet, remark- Reims, France, Burlington, VT, Asker, Norway, Ingelheim, Germany ably little is known about the optimal glycemic management in this patient In a Phase II double-blind trial, patients with T1DM were randomized to group. Dapaglifl ozin (DAPA), a sodium-glucose co-transporter 2 (SGLT2) inhibi- placebo (PBO; n=19), EMPA 2.5 mg (n=19), EMPA 10 mg (n=19) or EMPA 25 mg tor, promotes renal glucose excretion, causing osmotic diuresis, weight loss (n=18) as adjunct to insulin (multiple daily injections) for 28 days. Insulin dose and decreased blood pressure (BP). These effects may provide a unique benefi t was to be kept as stable as possible for 7 days and was freely adjustable to patients with coexisting T2DM and HF, but have not been formally evalu- thereafter. The primary exploratory endpoint was change from baseline in ated in this group. We pooled data from 5 clinical trials, selecting patients 24-h urinary glucose excretion (UGE) at day 7. randomized to DAPA 10 mg or placebo (PBO), that had a documented history of EMPA signifi cantly increased 24-h UGE vs. PBO at days 7 and 28. At day HF. Using longitudinal repeated-measures models, we examined the effects of 28, EMPA signifi cantly reduced HbA1c vs. PBO, with reductions in fasting DAPA vs. PBO on HbA1c, weight and BP for up to 1 year in patients with T2DM plasma glucose, and a signifi cant reduction in recorded total daily insulin and HF. Safety was also assessed. In total, 171 patients received DAPA 10 use. EMPA signifi cantly reduced weight vs. PBO at day 28. Adverse events mg and 149 patients received placebo (PBO) across the 5 studies (age 64 yrs, (AEs) were reported in 94.7%, 89.5%, 78.9% and 100.0% of patients on PBO,

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EMPA 2.5 mg, 10 mg and 25 mg, respectively. AEs consistent with urinary to fi nd out glucagon dysregulation is related to those receptors expression in tract infection were reported in one patient (on EMPA 25 mg). No AEs con- hyperglycemia and the effect of GLP-1 agonist about that. sistent with genital infection were reported. In PBO, EMPA 2.5 mg, 10 mg Alpha-TC cell was cultured in hyperglycemia with or without GLP-1 ago- and 25 mg groups, respectively, 19, 8, 10, and 13 symptomatic hypoglycemic nist for 72hours. SGLT2 mRNA and protein, GLUT2 mRNA and protein were episodes with glucose ≤54 mg/dL not requiring assistance were reported. measured. Glucagon mRNA and secretion were also measured. One hypoglycemic episode requiring assistance was reported (on PBO). In hyperglycemia, SGLT2 mRNA and protein was decreased in pancreatic In conclusion, in patients with T1DM, EMPA for 28 days as adjunct to in- alpha cell. GLUT2 mRNA and protein was also decreased. Glucagon mRNA sulin increased UGE, improved HbA1c and reduced weight with lower insulin was increased in alpha cell under hyperglycemia. GLP-1 agonist treatment doses vs. PBO and was well tolerated. increased SGLT2 mRNA and GLUT2 mRNA and decreased glucagon mRNA. Table. GLP-1 agonist increased glucose uptake related genes and proteins in pancreatic alpha cell. Increased glucagon in hyperglycemia was decreased with GLP-1 agonist treatment.

1216-P Safety and Effi cacy of Dapaglifl ozin in Patients with T2DM and Car- diovascular Disease Receiving Loop Diuretics WILLIAM T. CEFALU, LAWRENCE LEITER, EVA JOHNSSON, JENNIFER SUGG, IN- GRID GAUSE-NILSSON, Baton Rouge, LA, Toronto, ON, Canada, Mölndal, Sweden, Gaithersburg, MD We present the results of a post hoc safety and effi cacy subanalysis of dapagli- fl ozin (DAPA) 10 mg (N=942) or placebo (PBO) (N=945) in patients (pts) with T2DM and cardiovascular disease +/- loop diuretics (LDs) across 2 trials (NCT01031680; mean age 63 yrs, NCT01042977; mean age 64 yrs). AEs and SAEs were more common in pts with LDs (Table). Over 24 weeks there were few events of volume depletion and hypotension, and no difference between DAPA or PBO +/- LDs.

POSTERS There was a similar reduction in eGFR and increase in hematocrit with DAPA +/- Therapeutics LDs. Baseline mean eGFR mL/min/1.73 m2 was lower in pts on LDs (DAPA 67.2, Clinical Diabetes/ PBO 70.1) vs. without LDs (78.5 both groups), and may explain why renal impair- ment was more commonly reported with LDs. These events were more frequent with DAPA + LDs. Hypoglycemia was more frequent with DAPA +/- LDs (no major Supported By: Boehringer Ingelheim/Eli Lilly and Company episodes). One pt on DAPA without LDs discontinued due to hypoglycemia. No clinically relevant changes in serum sodium or potassium were observed. PBO- 1214-P adjusted effects of DAPA on HbA1c reduction were similar +/- LDs (-0.36% and Teneligliptin Scavenges Hydroxyl Radical: Electron-Spin-Reso- -0.45% respectively). SBP decreased in pts taking DAPA vs. PBO without LDs. nance Study and Administration Study of Teneligliptin Using DPP-4 Similar decreases in body weight with DAPA vs. PBO were observed +/- LDs. In Defi cient Rats conclusion, with some exceptions (hypoglycemia and renal laboratory param- SHINICHIRO KIMURA, TOYOSHI INOGUCHI, TOSHIHIDE YAMASAKI, MAYUMI eters) the safety profi le for T2DM pts treated with DAPA was similar +/- LDs and YAMATO, MAKOTO IDE, NORIYUKI SONODA, KENICHI YAMADA, RYOICHI TA- signifi cant reductions in HbA1c and body weight were observed. KAYANAGI, Fukuoka, Japan Table. Recently various dipeptidyl peptidase 4 (DPP-4) inhibitors have emerged PBO DAPA because of their high effectiveness and safety. In spite of their common ef- Safety Loop diuretics No loop diuretics Loop diuretics No loop diuretics fect of DPP-4 inhibition, the chemical structures are diverse, which may induce (N=182) (N=763) (N=182) (N=760) benefi cial effects. Recent studies have revealed the role of reactive oxygen species in diabetic complications and the effectiveness of antioxidants. There- ≥ 1 AE, n (%) 110 (60.4) 421 (55.2) 112 (61.5) 434 (57.1) fore we investigated radical-scavenging activity for hydroxyl radical (·OH) and ≥ 1 SAE, n (%) 19 (10.4) 53 (6.9) 17 (9.3) 51 (6.7) superoxide (O2-) using electron spin resonance spectroscopy in vitro and found Volume depletion*, n (%) 3 (1.6) 8 (1.0) 3 (1.6) 12 (1.6) that teneligliptin, the novel DPP-4 inhibitor from Japan, scavenged ·OH. The ·OH Hypotension, n (%) 1 (0.5) 2 (0.3) 2 (1.1) 6 (0.8) scavenging activity of teneligliptin was greater than that of glutathione. Fur- Renal impairment/failure*, n (%) 10 (5.5) 19 (2.5) 18 (9.9) 37 (4.9) thermore, we identifi ed the metabolite produced by reaction of teneligliptin and AE term> 1% in any group, n (%) - - - - ·OH using thin-layer chromatography. Mass spectrometry analysis showed that Decrease in creatinine clearance 3 (1.6) 11 (1.4) 7 (3.8) 13 (1.7) the structure of product was an oxygen-atom added. This structure was found Renal impairment 4 (2.2) 5 (0.7) 6 (3.3) 11 (1.4) the same as the most abundant metabolite of teneligliptin in human plasma Increase blood creatinine 2 (1.1) 3 (0.4) 4 (2.2) 2 (0.3) reported in the previous study, supporting that teneligliptin reacts with ·OH in ≥ 1 incidence of hypoglycemia, vivo. In this study, we further confi rmed this effect of teneligliptin in vivo using n (%) 33 (18.1) 135 (17.7) 45 (24.7) 145 (19.1) DPP-4 defi cient rats. Streptozotocin-induced diabetes caused increased excre- Change from baseline eGFR, tion of urinary 8-hydroxy-2-deoxyguanosine (8-OHdG) in both DPP-4 defi cient mL/min/1.73 m2, mean (SE) -1.4 (0.89) -1.6 (0.43) -2.6 (0.95) -3.2 (0.43) rats and control rats. Administration of teneligliptin did not affect blood glucose Change from baseline hematocrit, levels in diabetic DPP-4 defi cient rats, while it signifi cantly inhibited urinary ex- %, mean (SE) -0.62 (0.24) -0.22 (0.09) 2.54 (0.22) 2.43 (0.10) cretion of 8-OHdG. These fi ndings suggest that teneligliptin has an anti-oxidant effect, independently of its DPP-4 inhibition and blood glucose lowering effect. Change from baseline Na+, mEq/L, mean (SE) -1.6 (0.28) -1.2 (0.12) -1.5 (0.24) -0.6 (0.13) This might be useful in the prevention of diabetic complications. Change from baseline K+, mEq/L, mean (SE) -0.04 (0.04) -0.02 (0.02) -0.13 (0.03) -0.05 (0.02) 1215-P Effi cacy# (N=179) (N=762) (N=180) (N=755) GLP-1 Agonist Treatment and SGLT2 and GLUT2 Expressions in Pan- creatic Alpha Cell Change from baseline HbA1c, %, MI-KYUNG KIM, HYE SOOK JUNG, EUN JU LEE, TAE KYOON KIM, TAE NYUN mean (95% CI) 0.16 (0.01, 0.31) 0.08 (0.01, 0.14) -0.20 (-0.36, -0.05) -0.37 (-0.44, -0.31) KIM, MIN JEONG KWON, SOON HEE LEE, BYUNG DOO RHEE, JEONG HYUN Change from baseline seated SBP, PARK, Busan, Republic of Korea mm Hg, mean (95% CI) 1.44 (-1.16, 4.04) -0.61 (-1.67, 0.45) 0.19 (-2.48, 2.86) -3.35 (-4.41, -2.28) Dysregulation of glucagon secretion is an important pathophysiology of Change in body weight, kg, type 2 diabetes. Glucagon is not suppressed at high glucose which exag- mean (95% CI) -0.42 (-1.07, 0.25) -0.45 (-0.71, -0.20) -2.46 (-3.12, -1.79) -2.56 (-2.81, -2.31) gerates hyperglycemia and is inadequate at low glucose which can develop *Based on a predefi ned list of events. fatal hypoglycemia. The mechanism of dysregulation in diabetes is not clear # Excluding data after rescue for change in HbA1c and SBP, and including yet. Recently, one study reported SGLT2 is expressed in alpha cell. SGLT2 data after rescue for change in body weight. and GLUT2 are important to glucose sensing in alpha cell. Therefore, we try Supported By: AstraZeneca

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1217-P Effi cacy and Safety of Dapaglifl ozin in Patients with Type 2 Diabe- tes: Outcomes by Race and Ethnicity JASON MORAN, HELEN YEH, ARIE KATZ, Fort Washington, PA The prevalence of diagnosed diabetes in Hispanic and black adults in the U.S. is nearly double that of white adults, underscoring the need for effec- tive, well-tolerated treatments in these populations. Among U.S. patients enrolled in dapaglifl ozin (DAPA) phase 3 clinical trials, 12% were black and 34% were Hispanic. Using data pooled from placebo (PBO)-controlled stud- ies of DAPA as monotherapy or add-on therapy to other antidiabetes drugs, we conducted a post-hoc analysis in U.S. patients with type 2 diabetes (T2D) assessing the effi cacy (24-week, 10-study pool) and safety of DAPA 5 and 10 mg in subgroups by race (white vs. black) and ethnicity (Hispanic vs. non- Hispanic). At week 24, DAPA 5 and 10 mg signifi cantly reduced HbA1c from baseline vs. PBO in whites (both P<0.0001), blacks (P=0.0009 and P=0.0002), Hispanics (P=0.0014 and P<0.0001), and non-Hispanics (P=0.0001 and P<0.0001), respectively. Similar proportions of patients achieved HbA1c <7% and reductions in body weight and systolic blood pressure with DAPA. Geni- Supported By: Boehringer Ingelheim tal infections and in most cases urinary tract infections were more frequent with DAPA vs. PBO across groups. Hypoglycemia rates were similar for DAPA and PBO within groups; no major hypoglycemia was reported. These data 1219-P support DAPA as an effective and well-tolerated treatment option for black Inhibition of Serotonin Receptor 2A Improves Glucose Homeostasis and Hispanic patients with T2D. in High-Fat Diet-fed Mice ABUDUKADIER ABULIZI, JOÃO-PAULO G. CAMPOREZ, MAX C. PETERSEN, MI- Table. CHAEL J. JURCZAK, GERALD I. SHULMAN, New Haven, CT In this study we examined the effects of ketanserin, a selective inhibi- POSTERS

tor of serotonin receptor 2A, on basal and insulin-stimulated rates of whole Therapeutics

body glucose metabolism in mice fed either a regular chow (RC) or high fat Clinical Diabetes/ diet (HFD). Ketanserin treatment (1 mg/kg x 4 weeks) had no effect on body weight, plasma glucose or insulin concentrations in RC-fed mice. Interest- ingly, ketanserin-treated mice gained less weight and fat mass during HFD feeding compared to controls. Fasting plasma glucose concentrations were reduced by ~40% (P<0.01) and glucose tolerance was signifi cantly improved (AUC 314±17 vs. 170±30 (mg-min)/dl, P<0.001). Plasma insulin excursions dur- ing the glucose tolerance test were also decreased in ketanserin treated mice, indicating protection from HFD-induced whole body insulin resistance. In order to further examine the mechanism by which ketanserin protected mice from HFD induced insulin resistance we performed hyperinsulinemic- euglycemic clamp studies and found that ketanserin improved whole-body insulin sensitivity compared with control HFD mice (glucose infusion rate: 24.1±2.5 vs. 36.6±3.4 mg/(kg-min), P=0.001). Differences in whole-body insulin sensitivity were largely accounted for by improved suppression of endogenous glucose production (97±9 vs. 52±7%, P<0.01) and improved insu- lin-stimulated peripheral glucose uptake (28.7±2.7 vs. 37.3±3.2 mg/(kg-min), P=0.06) in ketanserin treated mice. Adipose tissue insulin sensitivity was Supported By: AstraZeneca also improved as refl ected by a 30% (P<0.01) increase in insulin suppression of plasma fatty acid levels. Ketanserin treatment also increased the ratio 1218-P of high molecular weight adiponectin to total adiponectin concentrations Effi cacy and Safety of Linagliptin/Metformin Fixed-Dose Combina- (0.21±0.01 vs. 0.16±0.01, P<0.001). In conclusion, these data suggest that tion (FDC) as Initial Therapy in Asian Patients with Type 2 Diabetes ketanserin treatment protects mice from high fat diet-induced insulin resis- (T2D) and Severe Hyperglycemia tance and that serotonin receptor 2A inhibition is a potential novel therapeu- YIMING MU, CHANGYU PAN, BEI FAN, UWE HEHNKE, YAN GONG, Beijing, China, tic target for reversing insulin resistance and type 2 diabetes. Shanghai, China, Ingelheim, Germany Supported By: Kato Asao International Scholarship Foundation Oral antidiabetes therapy is generally not considered as initial treatment in T2D pts with severe hyperglycemia. In a large, randomized trial investi- 1220-P gating linagliptin/metformin FDC (NCT01708902), drug-naïve Asian pts with Relationship between Diabetes Duration and Real-World Effective- HbA1c ≥11% were studied separately. Pts were randomized to linagliptin ness of Second-Line Dual OAD Therapy 2.5 mg/metformin 1000 mg BID (L2.5/M; n=72) or linagliptin 5 mg QD (L5; HELMUT BRATH, PÄIVI M. PALDÁNIUS, GIOVANNI BADER, CHANTAL MATHIEU, n=71) for 24 wks. Pts in the L5 group switched to the L2.5/M group at wk Vienna, Austria, Basel, Switzerland, Leuven, Belgium 12 if HbA1c was >8%. Primary endpoint was HbA1c change from baseline Type 2 diabetes mellitus (T2DM) is a chronic disease requiring progres- to wk 12. Baseline mean (SD) age, BMI, HbA1c and FPG were 49.7 (11.6) yrs, sive intensifi cation of oral antidiabetic (OAD) therapy, mainly due to declin- 25.5 (3.9) kg/m2, 11.9 (1.0)%, and 223.9 (58.7) mg/dL, respectively. At wk ing β-cell function. Sulfonylureas (SU) or DPP-4 inhibitors (DPP-4i) are the 12, adjusted mean (SE) changes from baseline in HbA1c were −3.46 (0.22)% most widely used second-line OADs after metformin. We used data from an and −4.71 (0.22)% in the L5 and L2.5/M groups; difference −1.25% (95% CI, observational study, EDGE, in which the effectiveness of second-line OADs −1.87 to −0.63; p=0.0001). Unadjusted mean HbA1c changes over time to wk was studied over 12 months, to assess the impact of diabetes duration on the 24 and effi cacy response of HbA1c <7% are shown in the table. At wks 12 glucose-lowering effect of SU vs. a DPP-4i, vildagliptin. We extracted two and 24, adverse events were generally of mild or moderate intensity. At wk cohorts, treated with SU (n=11,446) or vildagliptin (n=24,721) dual regimens. 12, rates of hypoglycemia (1.4%, both groups) and of premature treatment At baseline, mean T2DM duration (±SD) was 5.4±5.0 vs. 5.5±5.4 years and discontinuation (4.2% with L5; 6.9% with L2.5/M) were low. In conclusion, HbA1c 8.2±1.3% vs. 8.1±1.4% for SU vs. vildagliptin, respectively. In a linear initiating L/M FDC therapy in drug-naïve Asian pts with severe hyperglyce- regression model (adjusted r2=0.52, p<0.0001), HbA1c change from baseline mia may reduce blood glucose more rapidly and effectively than switching was inversely proportional to T2DM duration (0.01 per year, 95% CI 0.001, to the FDC after failure of monotherapy. 0.013) and BMI (0.008 per unit, 95% CI 0.006, 0.0102), and proportional to baseline HbA1c (-0.68 per unit, 95% CI -0.696, -0.681) (all p<0.0001). The adjusted mean difference between groups was -0.21 (95% CI -0.232, -0.191, p<0.0001), with loss of effect being 5 times greater in the SU group (adjusted

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marginal difference 0.10, 95% CI -0.121, -0.092) (Figure). Duration of T2DM of antiglycemic drugs is important for developing individualized treatment negatively impacts the glucose-lowering capacity of OAD dual regimens, recommendations for people with diabetes. with a more pronounced effect in SU- vs. vildagliptin-treated patients.

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1221-P POSTERS Therapeutics WITHDRAWN Clinical Diabetes/ 1223-P Combined Treatment with Saxagliptin + Dapaglifl ozin Improves β-Cell Function and Reduces Insulin Levels by Increased Insulin Clearance ELLA ELKHOLM, LARS HANSEN, NAYYAR IQBAL, BJÖRN CARLSSON, HUNGTA CHEN, BOAZ HIRSHBERG, Mölndal, Sweden, Princeton, NJ, Gaithersburg, MD Dapaglifl ozin (DAPA) alone and in combination with saxagliptin (SAXA+DAPA) reduced while SAXA increased insulin levels during a meal tolerance test (MTT). We asked if this was driven by increased insulin clear- ance. C-peptide/insulin ratio was used as a marker for insulin clearance during an MTT and β-cell function was assessed by HOMA-2 in a study testing SAXA 5 mg+DAPA 10 mg vs. SAXA and DAPA alone in T2D patients poorly controlled with metformin (NCT01606007). At wk 24, SAXA+DAPA and SAXA increased mean (95% CI) C-peptide AUC from baseline, whereas no change was observed for DAPA (SAXA+DAPA: 40.2 [9.2, 71.3 ng/mL]; SAXA: 95.4 [63.4, 127.4] ng/mL; DAPA: 14.5 [-17.6, 46.8] ng/mL). In contrast, change from baseline in insulin AUC was reduced with SAXA+DAPA (-1120.4 [-1633.9, -606.9] µU/mL), and DAPA (-1018.6 (-1550.5, -486.8), but increased with SAXA (661.2 [131.1, 1191.3] µU/mL). Curves for C-peptide/insulin at baseline were similar between the 3 treatment groups. At 24 wk, C-peptide/ insulin was unaltered by SAXA but increased similarly after SAXA+DAPA and DAPA (Figure), mainly due to decreased insulin AUC with DAPA. All treatments improved β-cell function compared with baseline (SAXA+DAPA: 20.6% [16.5, 24.8]; DAPA: 17.0% [12.7, 21.4]; SAXA: 11.0% [6.6, 15.5]). The 1222-P data suggest that at 24 wk, SAXA+DAPA and DAPA improved β-cell function Effi cacy of Saxagliptin in Patients with Type 2 Diabetes: Subgroup and increased insulin clearance. Analysis by Sex and Age JUDITH G. REGENSTEINER, DANIELLE DAY, GENEVIEVE WORTZMAN-SHOW, GI- ANMARIA MINERVINI, YUCHEN BARRETT, CHERYL WEI, HENRY WU, JANE E.B. REUSCH, Aurora, CO, Fort Washington, PA Diabetes increases CV disease burden more in women than men and age accentuates diabetes-related problems in both sexes. Still little is known about sex or age differences in response to antiglycemic agents. We tested the hypotheses that age and sex would impact saxagliptin (SAXA) effi cacy on A1C changes at 24 wk of treatment using data from 9 placebo-controlled randomized clinical trials. Age subgroups (<45 yrs, 45-57 yrs & ≥58 yrs) were used as surrogate categories for menopausal status in women. SAXA treat- ment signifi cantly lowered A1C vs. placebo across all age groups in women and men. There was no treatment-by-sex interaction (p =0.560) but A1C re- duction tended to be greater for men than women for the 2.5-mg dose (-0.6 ±0.98 vs. -0.5±1.01, p=0.06), and the difference reached signifi cance with the 5-mg dose (-0.8 ±0.94 vs. -0.7±0.92, p=0.002). SAXA effects on A1C dif- fered amongst age groups in women, but not men (Table). Both SAXA doses demonstrated greater effi cacy on A1C and fasting plasma glucose in women >58 yrs compared with women <45 yrs. Further investigation is warranted to determine whether these small signifi cant differences persist in prospec- Supported By: AstraZeneca tive studies designed to evaluate sex and age differences. These preliminary fi ndings suggest that understanding sex and age differences on the effects

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1224-P Table. Effi cacy and Safety of Dapaglifl ozin in Patients with Type 2 Diabetes on Insulin ± Metformin Regimens ARIE KATZ, HELEN YEH, Fort Washington, PA In this post hoc analysis of a placebo (PBO) controlled trial evaluating the effi cacy and safety of dapaglifl ozin (DAPA) in patients with type 2 diabetes (T2D) inadequately controlled with high doses of insulin (INS) ± up to 2 oral antidiabetes agents, 587 patients were stratifi ed by INS regimen (basal, sliding scale, or basal/sliding scale) and metformin (MET) use. Mean T2D duration was >10 y and baseline HbA1c was 8.4-8.8% across groups. With each of the 3 INS regimens, DAPA 5 and 10 mg/d signifi cantly reduced HbA1c (all P<0.001 vs. PBO) and body weight (BW, all P<0.01, except DAPA 5 mg/d + Supported By: AstraZeneca basal INS) from baseline at week 24. DAPA reduced HbA1c and BW with MET (all P<0.0001 vs. PBO) or without MET (HbA1c, all P<0.0001; BW, P=0.0439 1226-P and <0.0001 for DAPA 5 and 10 mg/d, respectively), but reductions were Insulin-Sensitizing Effects of Methylsulfonylmethane (MSM), an numerically larger with MET and signifi cantly more patients receiving MET Organosulfur Compound, in Diet-induced Obese Mice had HbA1c <7% at 24 weeks (P<0.01 vs. PBO). Genital and urinary tract infec- INES LIMA, SIN YOUNG PARK, JI A. SEO, MICHELLE CHUNG, LEANDRO MAURA, tions were more frequent with DAPA than PBO. Hypoglycemia was more PAULA MACEDO, SEUNG-HOON LEE, YOUNG-BUM KIM, Boston, MA, Lisbon, Por- common with DAPA (45%, 48%) than PBO (42%); 1 major hypoglycemia event tugal, Seoul, Republic of Korea occurred in each DAPA dose group and 2 in the PBO group. In patients with Methysulfonlymethane (MSM) is an organosulfur compound naturally T2D, including those with progressive disease (inadequately controlled on found in plants. MSM has been used as a dietary supplement that can im- INS, T2D duration >10 y), DAPA was effective and well tolerated with each prove various metabolic-related diseases, including joint infl ammation, os- INS regimen, with no increase in major hypoglycemia. The effects of DAPA teoarthritis, rheumatoid arthritis, osteoporosis, musculoskeletal pain, and appeared greater in patients receiving MET in addition to INS. chronic pain. However, the effects of MSM treatment on obesity-linked Table. metabolic disorders remain unclear. To determine the therapeutic effects

of MSM treatment on diet-induced obesity and insulin resistance, male C57 POSTERS mice (5 weeks of age) fed a high-fat diet (HFD) were treated with MSM (2.5- Therapeutics 5% m/v) by drinking water for 10 weeks. After 10 weeks of MSM treatment, Clinical Diabetes/ serum insulin levels were greatly decreased from 10.9±1.9 mg/dl (before treatment) to 3.3 ± 1.2 mg/dl (after treatment) in mice fed a HFD. Consistent with this, a HFD fed mice treated with MSM displayed hypersensitivity to in- sulin, suggesting that MSM exerts insulin-sensitizing effect. The molecular mechanism for this regulation is most likely due to increased insulin signal- ing in insulin-target tissues. However, MSM treatment had no effect on glu- cose tolerance and serum lipid profi les. Histological analysis indicated that hepatic steatosis was decreased in HFD mice treated with MSM. This was associated with a signifi cant reduction in lipogenic gene expression of FAS and ACC. In addition, gene expression of key molecules involved in hepatic infl ammation, including MCP1, TNF-alpha, and IL-6, was greatly suppressed by MSM therapy. Importantly, FACS analysis revealed that MSM treatment markedly increased B220+ cells and decreased Gr-1+ myloid cells in periph- eral blood and in bone marrow. These data suggest that MSM has benefi cial effects on hyperinsulinemia, insulin resistance, and infl ammation, which are often found in type 2 diabetes. Thus, MSM could be the therapeutic option for the treatment of metabolic disorders such as insulin resistance.

1227-P Supported By: AstraZeneca Saxagliptin Effect on Liver Enzymes in the SAVOR Trial ITAMAR RAZ, AVIVIT CAHN, FREDDY G. ELIASCHEWITZ, BOAZ HIRSHBERG, JAI- 1225-P ME E. VILLENA, CHRISTINA A.M. STAHRE, CARLOS A. AGUILAR-SALINAS, ILAN Cystatin C and Creatinine-based Estimates of GFR in Dapaglifl ozin YANUV, ALIZA ROZENBERG, JOOST HOEKSTRA, CHERYL WEI, OFRI MOSENZON, Phase 3 Clinical Trials Jerusalem, Israel, São Paulo, Brazil, Gaithersburg, MD, Lima, Peru, Gothenburg, Swe- CHRISTIAN MENDE, ARIE KATZ, La Jolla, CA, Fort Washington, PA den, Mexico City, Mexico, Amsterdam, Netherlands SGLT2 inhibitor effi cacy depends on the kidneys’ ability to fi lter glucose While some DPP-4 Inhibitors have been shown to be related to increased and declines with lower glomerular fi ltration rate (GFR). Estimates of GFR liver enzymes, more recent data suggest a protective effect of the drug class based on creatinine (eGFRcr) are routinely used but are affected by factors, in liver steatosis. In the SAVOR trial liver enzyme abnormalities were pre- such as muscle mass and diet, and may be inaccurate under certain con- defi ned adverse events of special interest (AEOSI). We analyzed the liver ditions. Estimates based on cystatin C (eGFRcys) appear to correlate better enzymes data collected from the 16,492 type 2 diabetes (T2D) patients dur- with morbidity and mortality than eGFRcr. KDIGO guidelines suggest measur- ing the 2.1 years median follow-up. 2 ing eGFRcys when eGFRcr is 45-59 ml/min/1.73 m with no evidence of kidney Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and damage and/or when eGFRcr may be unreliable. We used both eGFRcr and total bilirubin (TB) were measured at baseline, 1 year, 2 years and end of eGFRcys to determine the proportion of type 2 diabetes (T2D) patients with study (EOS). Predefi ned liver AEOSI included ALT or AST >3 × upper limit of eGFR <60 mL/min/1.73 m2 pooled from 9 dapaglifl ozin (DAPA) phase 3 trials. normal (ULN) and total bilirubin >2 × ULN. 2 The correlation between eGFRcr and eGFRcys was poor; r =0.25. At least 60% Liver AEOSI was found in 11 (0.1%) subjects “on treatment” and in 13 of patients who had moderate renal impairment (eGFR 30-<60) at baseline (0.2%) subjects overall in the saxagliptin (SAXA) arm, and in 18 (0.2%) and based on eGFRcr had an eGFRcys ≥60. Among patients with eGFRcr ≥60, ≥95% 22 (0.3%) in the placebo arm respectively. On-treatment fatal AEs of liver remained ≥60 with eGFRcys. Decreases in HbA1c, body weight, and systolic abnormalities were 4 [<0.1%] in the SAXA arm and 7 [<0.1%] in the placebo blood pressure with DAPA were similar in patient subgroups defi ned by ei- arm. Investigator reported adverse events of increased liver enzymes were ther eGFR estimate, and statistically signifi cant and clinically meaningful 55 (0.7%) and 65 (0.8%) in the SAXA and placebo arms respectively. Multi- with DAPA 10 mg in most subgroups. The data suggest that in patients with variable adjusted association of demographic and clinical parameters (of the T2D, renal function as assessed by eGFRcr may be underestimated, rendering entire study population) with liver enzymes is shown (Table). such patients ineligible to receive medications limited by renal function (eg, We conclude that SAXA had no effect on liver enzymes in a large popula- metformin, SGLT2 inhibitors). tion of high cardiovascular risk T2D patients supporting the overall hepatic safety of SAXA.

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Table. mellitus (T2DM). A multiple-ascending dose (MAD) study (1.25-100 mg QD for 10 days) in 48 healthy subjects and a MAD study (5-20 mg QD for 7 days) in 30 T2DM subjects were conducted. Most of the adverse events were mild and no hypoglycaemia was reported, no serious adverse events were observed and no subjects discontinued due to adverse events occurred in either study. In healthy subjects, Henaglifl ozin was rapidly absorbed (Tmax, 1.25-2.25 h), the ac- cumulation (defi ned as the geometric mean ratio of AUC0-24h at day10 to AUC0-24h at day 1) after multiple dosing was minimal (1.08-1.14 fold), and the elimina- tion half-life was 9.48 to 14.8 h, and 3.05-5.13% of Henaglifl ozin was excreted unchanged in urine. Systemic exposure and maximum plasma concentration of Henaglifl ozin was proportional to dose. At steady state (day 10), Urinary glucose excretion over 24 h was characterized by an inhibitory-effect PD model with Emax of 61.0 g and ED50 of 3.9 mg, respectively. Henaglifl ozin didn’t signifi - cantly change the plasma glucose in healthy subjects. After 7 days of dosing, the T2DM subjects showed similar steady-state pharmacokinetic profi le with healthy subjects. No dose-related increase in the amount of glucose excreted in the urine over 24 h was found in T2DM subjects over the dose of 5mg to 20mg, which might result from the limited sample size. Henaglifl ozin demon- strated signifi cant glycemic improvements versus placebo, with dose-related decreases in plasma glucose parameters (ΔFPG -18.0 to -52.0 mg/dl vs. ΔFPG 16.4 mg/dl, ΔMPG -8.8 to -24.7 mg/dl vs. 34.9 mg/dl) in subjects with T2DM. Supported By: AstraZeneca Henaglifl ozin was well tolerated and showed predictable dose-proportional PK and PD parameters in both healthy and T2DM Chinese subjects. These results 1228-P support further study of Henaglifl ozin. Quality Measure Thresholds with Saxagliptin (SAXA) + Dapagli- 1230-P

POSTERS fl ozin (DAPA) Dual Therapy vs. Individual Components as Add-on to Therapeutics Metformin (MET) Effects of Vildagliptin vs. Saxagliptin on Daily Acute Glucose Fluc- Clinical Diabetes/ tuation in Chinese Type 2 Diabetics Inadequately Controlled with LAWRENCE BLONDE, JOHN J. SHEEHAN, RICARDO GARCIA-SANCHEZ, YU Dual Combination of Metformin and Sulphonylurea CHEN BARRETT, New Orleans, LA, Fort Washington, PA, Gaithersburg, MD There is a continued need to monitor and improve quality of care for pa- XIAOYAN CHEN, JING WANG, XIAOCHUN HUANG, YUYU TAN, SHUNYOU DENG, tients with diabetes. In a phase 3, randomized, double-blind trial (N=534), YINGYU FU, Guangzhou, China dual add-on SAXA 5 mg + DAPA 10 mg in patients with type 2 diabetes The aim of this study was to compare the effects of vildagliptin (Galvus) inadequately controlled with MET signifi cantly improved HbA1c at week 24 and saxagliptin (Onglyza) on 24-hour acute glucose fl uctuations in Chinese from baseline (primary end point) vs. add-on of SAXA or DAPA alone. Qual- type 2 diabetics. ity measure treatment outcomes were assessed at 24 weeks. Evaluation A prospective, randomized, open-label study was designed. 73 Chinese included the National Quality Forum-endorsed measures of Comprehensive type 2 diabetics adequately controlled with stable dosage of metformin plus Diabetes Care (patients with HbA1c <7%, <8%, or >9%, systolic/diastolic gliclazide for more than 3 months (HbA1c 7.0 ~10.0%), were randomized to blood pressure [SBP/DBP] <140/90 mmHg or <140/80 mmHg, and low den- vildagliptin 50mg bid (n=37) or saxagliptin 5mg qd (n=36) for 24 week. Mean sity lipoprotein cholesterol [LDL-C] <100 mg/dL) and Optimal Diabetes Care amplitude of glycemic excursions (MAGE), HbA1c, FPG, and 2HPPG were (HbA1c <8%, SBP/DBP <140/90 mmHg, and LDL-C <100 mg/dL). Analysis evaluated at baseline and the study endpoint. showed signifi cantly more patients had HbA1c <7% or <8% with SAXA + 73 patients with a mean age of 62.9±6.55 years, and a mean disease dura- DAPA vs. SAXA or DAPA alone, and less had HbA1c >9% vs. SAXA (Table). tion of 7.0 ±2.33 years, a mean HbA1c of 8.35±0.68% were enrolled. Each BP threshold was achieved by a similar proportion of patients in SAXA Mean change in MAGE (ΔMAGE), from the baseline to endpoint, on + DAPA and DAPA groups, with slightly lower proportions in the SAXA group. vildagliptin group were signifi cantly greater than that on saxagliptin No signifi cant difference was observed in the proportion of patients with group [1.74±0.48 mmol/L (from 5.81±1.16 mmol/L to 4.06±0.86 mmol/L) vs. LDL-C <100 mg/dL in the SAXA + DAPA group vs. SAXA or DAPA alone. These 0.87±0.40 mmol/L (from 5.66±1.14 mmol/L to 4.79±1.25 mmol/L) (P=0.000)]. fi ndings show more patients treated with SAXA + DAPA as add-on to MET Mean change in HbA1c (ΔHbA1c) on vildagliptin group was 1.22±0.40%, reach quality measures, particularly those related to HbA1c, than patients and ΔHbA1c on saxagliptin group was 1.07±0.36%, with no difference be- treated with SAXA or DAPA as add-on alone. tween the two groups (P=0.091). Change of FPG from the baseline to end- point was 1.37±0.31mmol/L on vildagliptin group, was signifi cantly greater Table. than that on saxagliptin group 0.90±0.30 mmol/L (P =0.000). A similar ef- fect was observed in 2HPPG change [3.50±1.52 on vildagliptin group and 3.20±1.66 mmol/L on saxagliptin group respectively (P=0.172)]. The overall safety and tolerability of vildagliptin and saxagliptin were similar. Adverse events were infrequent and mild in both treatment groups. Vildagliptin produced a signifi cantly greater reduction in 24-hour acute glu- cose fl uctuations compared with saxagliptin when added to dual combination of metformin and sulphonylurea in Chinese patients with type 2 diabetes.

1231-P Omarigliptin Improves Glycemic Control and Is Well Tolerated as Add-on Therapy to Oral Antihyperglycemic Agents in Japanese Pa- tients with Type 2 Diabetes IRA GANTZ, TARO OKAMOTO, ASAKO SATO, KOTOBA OKUYAMA, ESENG LAI, Supported By: AstraZeneca SAMUEL S. ENGEL, Whitehouse Station, NJ, Tokyo, Japan Omarigliptin (OMARI) is a once-weekly (q.w.) DPP-4 inhibitor in devel- opment for the treatment of T2DM. Previously completed studies have 1229-P demonstrated the effi cacy and safety of OMARI as monotherapy. In this Pharmacokinetics and Pharmacodynamics of Henaglifl ozin, a Nov- randomized, double-blind, parallel-group, placebo (PBO)-controlled study, el Selective Inhibitor of Sodium-Glucose Co-transporter Type 2, in the safety and effi cacy of OMARI was assessed in Japanese patients with Healthy and T2DM Chinese Subjects T2DM as add-on therapy to oral antihyperglycemic agents (AHA) including HAIYAN LIU, YANMEI LIU, XIAOLAN YONG, CHENGYU GUAN, YING CHEN, MIN- sulfonylureas (SU), glinides (GL), biguanide (BG), thiazolidinedione (TZD), and QUAN WANG, HUAQIONG SHEN, Shanghai, China α-glucosidase inhibitors (AGI). Henaglifl ozin, a selective, orally active, renal sodium glucose cotransporter Five hundred sixty-eight patients with inadequate glycemic control on a 2 (SGLT2) inhibitor, is under investigation as a treatment of type 2 diabetes single AHA were stratifi ed by background medication (BM) and randomized

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A318 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS in a 2:1 ratio to OMARI 25 mg q.w. or PBO. At Week 24, OMARI signifi cantly 1233-P reduced HbA1c and fasting plasma glucose from baseline in all BM strata, Evaluation Series on Safety and Effi cacy of Nutritional Supplements compared to PBO. There were no notable differences in the incidences of ad- (ESSENS) in Newly Diagnosed Hyperglycemia verse events between OMARI and PBO in the overall study population or in HEMANT P. THACKER, SUNIL M. JAIN, GANAPATHI M. BANTWAL, BANSHI D. any BM stratum. The incidences (%) of symptomatic hypoglycemia (OMARI SABOO, SHAILAJA KALE, JUGAL B. GUPTA, SANJAY KALRA, Karnal, India, Indore, vs. PBO) were generally low: SU 6/126 (4.8) vs. 2/63 (3.2); GL 1/65 (1.5) vs. India, Bengaluru, India, Mumbai, India, Ahmedabad, India, Pune, India, Jaipur, India 0/34 (0.0); BG 2/66 (3.0) vs. 0/33 (0.0); TZD 0/65 (0.0) vs. 0/34 (0.0) and AGI Diabetes is endemic in society. Beyond lifestyle modifi cation (often short 0/67 (0.0) vs. 0/32 (0.0). lived) and metformin, which while effective has gastrointestinal side ef- In conclusion, in this study OMARI improved glycemic control and was well fects, other available pharmacological options are challenging to implement tolerated as add-on therapy to oral AHAs in Japanese patients with T2DM. across populations of newly diagnosed patients. The recent position state- Table. ment by ADA/EASD calls for patient-centered individualized therapies to suit patients’ needs. Glucose-lowering nutritional supplements may be an Background Treatment N HbA1c (%) Fasting Plasma Glucose Medication groups (mg/dL) effective and safe option for newly diagnosed hyperglycemia. Heretofore (BM) their safety and effi cacy have not been systematically evaluated in random- Baseline LS mean LS mean Baseline LS mean LS mean ized clinical trials. change difference change difference from from In this 12-week, investigator-initiated, six-center, randomized, double- baseline baseline blind, placebo-controlled, phase 3 trial, newly diagnosed subjects (N=232) with FPG>100 mg/dL received PreCrea (a proprietary nutritional supplement Sulfonylureas (SU) OMARI 126 8.1 -0.84 -0.93† 165.4 -24.37 -17.58† containing standardized plant extracts and dietary elements) or placebo PBO 63 8.1 0.09 – 170.5 -6.79 – one capsule twice daily along with lifestyle modifi cation. Primary endpoint Glinides (GL) OMARI 65 8.0 -0.68 -0.98† 163.5 -19.29 -21.33‡ was the change from baseline HbA1c at week 12. Secondary endpoint was PBO 34 8.0 0.30 – 164.4 2.04 – change from baseline in FPG. At week 12, HbA1c was signifi cantly reduced from baseline with PreCrea Biguanide (BG) OMARI 66 7.8 -0.94 -0.92† 155.8 -29.00 -14.60‡ compared to placebo (−0.91 vs. +0.08%); p < 0.001). Reductions in FPG in the PBO 33 8.0 -0.02 – 157.6 -14.40 – PreCrea group compared to placebo (p 0.0428) (-23.1 mg/dL vs. -7.2 mg/dL at † † week 12), with no hypoglycemia, no weight gain and no adverse effects and Thiazolidinedione OMARI 65 8.2 -0.88 -1.16 163.4 -28.39 -23.87 POSTERS Therapeutics (TZD) PBO 34 7.9 0.28 – 152.4 -4.52 – no difference in safety parameters. Clinical Diabetes/ † ‡ PreCrea provided clinically important and statistically signifi cant improve- α-Glucosidase OMARI 67 7.9 -0.74 -0.80 157.7 -20.38 -12.12 ments in glycemic control compared to placebo. The effi cacy (nearly 1% inhibitors (AGI) PBO 32 7.9 0.06 – 159.8 -8.26 – reduction in HbA1c), safety and tolerability profi le of PreCrea highlights its †p<0.001, ‡p<0.05. potential as an initial therapy choice in newly diagnosed hyperglycemia and LS Mean = Least Squares Mean. in patients intolerant or reluctant to take metformin. Longer head-to-head Based on a constrained Longitudinal Data Analysis model with terms for comparative studies would be required to evaluate effi cacy with PreCrea treatment, BM (SU/GL/BG/TZD/AGI), prior AHA therapy status (except for over other oral hypoglycemia agents in such patients. BM); yes/no, time, and the interaction of time by treatment, time by BM, time by prior AHA therapy status, BM by time by treatment, BM by time by prior AHA therapy status and BM by time by treatment by prior AHA ther- 1234-P apy status with the restriction of a common baseline mean between two treatment groups. WITHDRAWN Supported By: Merck & Co., Inc.

1232-P Low β-Cell Function at Baseline Is Associated with Higher Rates of Hypoglycemia in Response to Treatment with Glimepiride in El- derly Patients with Type 2 Diabetes Inadequately Controlled with Metformin SHIRA PERL, WILLIAM COOK, CHERYL WEI, PETER OHMAN, BOAZ HIRSHBERG, Gaithersburg, MD Elderly patients with type 2 diabetes (T2D) pose a challenge for manage- ment of glycemia owing to excess fragility and risk of adverse outcomes during hypoglycemic episodes. We therefore sought to identify risk factors for the development of hypoglycemia (any reported symptomatic event and events of plasma glucose concentration <54 mg/dL regardless of symptoms) in elderly patients when saxagliptin (SAXA) or glimepiride (GLIM) is added to metformin. A post hoc analysis of data from the GENERATION trial (NCT01006603) that enrolled 720 patients aged ≥65 years was conducted. β-cell function was as- sessed using HOMA-2%β. The proportion of patients experiencing any hypo- glycemic event was lower with SAXA vs. GLIM (5.8% vs. 34.8%). Regardless of treatment, patients with baseline HOMA-2%β ≤median value of 39.1% had a higher event rate of hypoglycemia of 1.27 events/patient year compared with patients with baseline HOMA-2%β >median, 0.82 events/patient year (RR = 1.300 [95% CI, 1.084, 1.560]). In the GLIM-treated patients, the hypogly- cemia event rate in patients with baseline HOMA-2%β ≤median was higher (2.29 events/patient year) compared with patients with baseline HOMA-2%β >median (1.60 events/patient year; RR = 1.278 [95% CI, 1.057, 1.545]); corre- sponding SAXA hypoglycemia event rates were too low to draw meaningful 1235-P conclusions at 0.16 vs. 0.09 events/patient year (RR = 1.446 [0.687, 3.043]), The SGLT2 Inhibitor Dapaglifl ozin Decreases Body Weight by Induc- respectively. The association between lower β-cell function at baseline and ing Visceral Fat Tissue Loss in the Early Stage of Treatment increased incidence of hypoglycemia was particularly strong for patients ≥75 KEIICHIRO NAKAMAE, IZURU MASUDA, HIDEKI HIGE, BUN CHIN, ARATA IWA- years (RR = 2.572 [95% CI: 1.787–3.701], P<0.001). In patients with lower β-cell SAKI, KATSUYO TODA, MASARU IMAI, SEIJI KUROSE, NOBUYUKI AZUMA, function, the addition of a sulfonylurea is associated with increased risk of HIDESHI KUZUYA, Kyoto, Japan hypoglycemia compared with patients with higher β-cell function. These fi nd- Dapaglifl ozin (DAPA) exhibits potent antihyperglycemic and antiobesity ings are especially relevant to the elderly patients, in whom hypoglycemia as- effects, but the underlying mechanisms, in particular during the early phase sociated morbidity is higher. of treatment has not been clarifi ed. The DUALSCAN, the world’s fi rst device Supported By: AstraZeneca for measuring visceral and subcutaneous fat areas (VFA, SFA) based on dual

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bioelectrical impedance analysis, has recently become available in Japan. 1237-P We reported a close correlation between VFA determined by DUALSCAN Leucine-Metformin Synergy Activates the AMPK/Sirt1 Pathway to and that determined by CT imaging. In the present study, we used DUALS- Increase Insulin Sensitivity in Skeletal Muscle and Glucose and CAN to assess the changes in body composition in people with type 2 dia- Lipid Metabolism and Lifespan in C. elegans betes (T2D) receiving DAPA. The 33 Japanese T2D patients (age 59±9 years, MICHAEL B. ZEMEL, ANTJE BRUCKBAUER, Knoxville, TN HbA1c 7.6±0.9%, BMI 28.8±5.3 kg/m2) were treated with 5 mg/d DAPA for We have previously shown leucine (Leu) to activate Sirt1 by lowering its 12 wk. An adverse event (urinary tract infection) occurred in one subject in Km for NAD+, thereby amplifying the effects of other sirtuin activators and wk 4. DAPA treatment reduced glycoalbumin (GA) levels and body weight improving insulin sensitivity. Metformin (Met) converges on this pathway (BW) forə2wk, VFAə4wk, and SFAə8wk from the baseline, respectively (Fig). both indirectly (via AMPK) and by direct activation of Sirt1, and we recently Multiple regression analysis indicated that reduced VFA (β=0.43 p=0.01) and found Leu to synergize with Met to improve insulin sensitivity and glycemic increased hematocrit (β=-0.50 p < 0.01) were independent predictors of re- control while achieving ~80% dose-reduction in diet-induced obese mice. duced BW in 2 wk. These results suggest that the rapid antihyperglycemic Accordingly, we sought here to defi ne the mechanism of this interaction. and antiobesity effects of DAPA are caused in part by increased lipolysis in Leu (0.5 mM) + Met (50-100 µM) synergistically activated Sirt1 (p<0.001) at visceral adipose tissue in addition to osmotic diuresis. low (<100 µM) NAD+ levels while Met exerted no independent effect. This was associated with an increase in AMPK and IRS1 phosphorylation and in insulin-independent glucose disposal in myotubes (~50%, p<0.002) evident within 30 minutes as well as a 60% reduction in insulin EC50. We utilized C. elegans to assess the metabolic consequences of this interaction. Exposure to high glucose impaired glucose utilization and shortened lifespan by ~25%, while addition of Leu + Met to high glucose-treated worms increased me- dian and maximal lifespan by 29 and 15%, respectively (p=0.023), restored normal glucose utilization and increased fat oxidation ~two-fold (p<0.005), while metformin exerted no independent effect at any concentration (0.1 - 2.0 mM). Thus, Leu and Met synergize to enable Sirt1 activation at low NAD+ concentrations (typical of energy replete states), resulting in improvements in energy metabolism and insulin sensitivity. POSTERS Therapeutics Clinical Diabetes/ 1238-P Bile Acid Resins Correct HDL-microRNA Intercellular Communica- tion Associated with Type 2 Diabetes LESLIE A. ROTETA, QUANHU SHENG, YAN GUO, KASEY C. VICKERS, CARINE BEYSEN, SCOTT TURNER, Nashville, TN, Emeryville, CA Colesevelam is a bile acid resin clinically used to treat type 2 diabetic 1236-P (T2D) patients. Although its mechanism of action is not completely known, Factors Associated with the Effects of Ipraglifl ozin on the Diurnal clinical trials suggest increased secretion of gastric incretins, i.e. glucagon- Profi les of Plasma Glucose and 3-hydroxybutyrate in Patients with like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), may underlie its Type 2 Diabetes glucose-lowering properties. Nevertheless, our recent work suggests that HITOMI NAKAYAMA, SATOKO YOSHINOBU, SEIKO KAWANO, MUNEHISA TSU- an incretin-independent mechanism contributes to colesevelam’s glycemic RUTA, MASAYUKI NOHARA, RIKA HASUO, SHOKO AKASU, ICHIRO TOKUBUCHI, effect. Using a rodent model, we treated Zucker Diabetic Fatty (ZDF) rats NOBUHIKO WADA, SAORI HIRAO, SHINPEI IWATA, HIROO KAKU, SHUICHI OTA- with colesevelam (2% in diet) for 8-weeks. Despite no apparent change BE, YUJI TAJIRI, KENTARO YAMADA, Kurume, Japan in GLP-1 secretion nor GIP levels, improvements in glucose tolerance and To assess the effects of SGLT2 inhibitor therapy on the pathophysiology insulin secretion were detected 1-week post treatment, suggesting other of type 2 diabetes, we analyzed the diurnal profi les of plasma glucose and non-incretin mechanisms are likely involved. microRNAs (miRNA) are power- 3-hydroxybutyrate (3HB) in diabetic patients treated with an SGLT2 inhibi- ful regulators of glucose metabolism and contribute to the pathogenesis of tor. We administered ipraglifl ozin to 19 inpatients with type 2 diabetes for T2D. We have previously reported that miRNAs are carried on high-density 7 days. Continuous glucose monitoring revealed that the 24-h glucose curve lipoproteins (HDL) and represent a novel intercellular communication path- was shifted downward without hypoglycemia by the administration of ip- way. Therefore, we performed small RNA sequencing on total RNA isolated raglifl ozin. The average glucose level was reduced from 189±53 mg/dl to from islets, HDL and livers of ZDF rats treated with colesevelam for 4-weeks. 144±33 mg/dl (p<0.0001). The magnitude of the reduction in the average Strikingly, we found 10% and 17% of miRNAs altered in diabetic islets and glucose concentration was highly correlated with the baseline average glu- liver, respectively, were corrected back to healthy levels with colesevelam cose level (p<0.0001). HOMA-IR was decreased from 3.46±1.86 to 1.98±1.22, treatments. On HDL, 16 miRNAs that were altered with T2D (vehicle) were and HOMA-β was increased from 34.2±26.3 to 45.7±27.8. Urinary glucose corrected back to healthy levels post treatment. To distinguish between gly- excretion was correlated with the average glucose level both on day 0 and cemic improvements and colesevelam-induced mechanisms, we analyzed on day 7, although the regression line was steeper and shifted leftward on HDL from rats treated with Metformin or Pioglitazone for 4-weeks and found day 7. The subjects lost 1.2±0.5 kg of body weight during the treatment. The 8 miRNAs responded to overall glycemic improvement. Strikingly, these 8 plasma levels of 3HB were increased with the most obvious elevations in the miRNAs are predicted or validated to regulate lipid and glucose metabolism pre-breakfast and pre-dinner 3HB levels. Patient age and body weight loss genes. However, only 2 miRNAs, let-7a-5p and miR-328b-3p, were specifi c to were negatively (pre-breakfast p=0.0006, pre-dinner p=0.02) and positively colesevelam only. As such, we propose that HDL-miRNA changes induced by (pre-breakfast p=0.002, pre-dinner p=0.03) correlated with the peak levels colesevelam treatment likely contribute to the drug’s mechanism of action. of 3HB on day 7, respectively, suggesting that younger individuals, rather than elderly persons, are susceptible to hyperketonemia when an SGLT2 in- 1239-P hibitor is administered. In conclusion, the ipraglifl ozin treatment improved Dapaglifl ozin Added to Metformin Plus a Sulfonylurea Is More Effec- the 24-h glucose curve without causing hypoglycemia. The improvements tive than Placebo in Achieving Combined Improvements in HbA1c, in -cell function and insulin sensitivity occurred within a week of initiating β Weight Blood Pressure, and Frequency of Hypoglycemic Events ipraglifl ozin treatment. Although mild to moderate ketosis may be harmless, KEITH BOWERING, CATARINA STERNHUFVUD, JAYANTI MUKHERJEE, JENNI- marked hyperketonemia with a risk of ketoacidosis should be avoided. It may FER E. SUGG, ELISABETH SÖRSTADIUS, DAVID SJÖSTRÖM, EVA JOHNSSON, be prudent to monitor ketone body levels in younger subjects and in patients Edmonton, AB, Canada, Mölndal, Sweden, Wallingford, CT, Gaithersburg, MD with a rapid weight loss. Type 2 diabetes (T2D) management must balance achieving glycemic con- trol, avoiding side effects such as weight gain and hypoglycemia, and reduc- ing associated risk factors such as raised blood pressure (BP). The SGLT2 inhibitor dapaglifl ozin (DAPA) increases glucosuria in an insulin-independent manner resulting in reductions in hyperglycemia, weight and BP with a low risk of hypoglycemia when given alone or with other low hypoglycemic risk agents. Key results from this 52-week study in patients with T2D (mean

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HbA1c 8.16%) on maximum tolerated doses of sulfonylurea (SU) and met- 1241-P formin (MET) randomized to receive add-on DAPA 10 mg (N=108) or placebo Empaglifl ozin (EMPA) Decreases Glucose Exposure and Variability (N=108) have been reported before. This post-hoc analysis assessed the in Patients with Type 1 Diabetes (T1DM): Continuous Glucose Moni- proportion of patients achieving composite outcomes, including combina- toring (CGM) Data (EASE-1) tions of clinically relevant diabetes related endpoints such as HbA1c <7% or SUSANNE FAMULLA, THOMAS R. PIEBER, JENS EILBRACHT, DIETMAR NEU- HbA1c reduction ≥0.5% and no hypoglycemic events together with moderate BACHER, NIMA SOLEYMANLOU, HANS J. WOERLE, ULI C. BROEDL, STEFAN reductions in body weight (≥3%) and systolic BP (≥3 mmHg). Although pa- KASPERS, Neuss, Germany, Graz, Austria, Biberach, Germany, Ingelheim, Germany, tient proportions achieving these composite outcomes (Table) were modest Burlington, VT in those receiving DAPA + SU + MET (8.3%-18.5%), they were consistently EMPA lowers blood glucose by reducing renal glucose reabsorption via a higher than in those receiving placebo + SU + MET (0%-1.9%). These data mechanism independent of the action of insulin. In this Phase II double-blind suggest that DAPA added to SU + MET can positively impact key treatment trial, patients with T1DM were randomized to placebo (PBO; n=19), EMPA parameters in patients with T2D. 2.5 mg (n=19), EMPA 10 mg (n=19) or EMPA 25 mg (n=18) as adjunct to insulin Table. Proportions of Patients Achieving Different Defi nitions of Composite for 4 weeks. Insulin dose was to be kept as stable as possible for the fi rst 7 Outcomes at 52 Weeks. days and was freely adjustable thereafter. Markers of glucose exposure and Composite outcome PBO + MET + SU DAPA 10 mg + MET + SU variability were assessed from 7-day blinded CGM periods. (N=108) (N=108) At week 1, all EMPA doses decreased total glucose exposure (AUC) and increased time in the glucose range of >70 mg/dL to 180 mg/dL vs. PBO; HbA1c ≤ results were sustained to week 4 with EMPA 25 mg (Table). A similar pat- Body weight loss ≥3% AND SBP reduction ≥3 mmHg 0 / 108 (0.0%) 11 / 108 (10.2%) tern was observed in nocturnal glucose exposure (00:00-05:59h). Hours/day with glucose ≤70 mg/dL increased with EMPA 10 mg and 25 mg vs. PBO at …Difference vs. PBO+MET+SU (95% CI) 10.2% (5.6%, 17.6%) week 1 but there were no signifi cant differences with EMPA vs. PBO at week HbA1c 4. Hours/day with glucose ≤54 mg/dL were not increased with EMPA vs. Body weight loss ≥3% AND PBO. All EMPA doses signifi cantly reduced glucose variability, as measured No major/minor hypoglycemia* 2 / 108 (1.9%) 9 / 108 (8.3%) by interquartile range (IQR [Table]; ambulatory glucose profi ling) and mean …Difference vs. PBO+MET+SU (95% CI) 6.5% (0.7%, 13.7%) amplitude of glucose excursions (MAGE), vs. PBO at weeks 1 and 4. These CGM data show that EMPA as adjunct to insulin therapy decreased HbA1c reduction ≥0.5% AND POSTERS Body weight loss ≥3% AND glucose exposure and variability and increased time in glucose target range Therapeutics SBP reduction ≥3 mmHg 0 / 108 (0.0%) 20 / 108 (18.5%) over 4 weeks in patients with T1DM. Clinical Diabetes/ …Difference vs. PBO+MET+SU (95% CI) 18.5% (12.0%, 27.3%) Table. N is the number of patients in the full analysis set. Percentages reported are based on the total number of patients with non-missing baseline val- ues. Patients discontinued, rescued or with missed measurements at the time point were considered as not having achieved a response. Confi dence intervals (CI) were calculated using an exact method. HbA1c reduction of ≥0.5% was defi ned as change from baseline to Week 52 greater or equal to 0.5%. Body weight reduction of ≥3% was defi ned as the percent change from baseline to Week 52 greater or equal to 3%. SBP reduction of ≥3 mmHg was defi ned as change from baseline to Week 52 greater or equal to 3 mmHg. *Includes major or minor hypoglycemic events with onset on or after the fi rst date/time of double-blind treatment and on or prior to the last day of treatment plus 4 days. MET, metformin; PBO, placebo; SU, sulfonylurea; SBP, systolic blood pressure. Supported By: Bristol-Myers Squibb

1240-P Evaluation of the Antidiabetic Effect of Novel, Selective Glucocorti- Supported By: Boehringer Ingelheim/Eli Lilly and Company coid Antagonists in a Model of Cortisone-induced Diabetes HAZEL J. HUNT, ROBERT B. JONES, STEVE P. VICKERS, KEITH DICKINSON, SHA- 1242-P RON C. CHEETHAM, Menlo Park, CA, Nottingham, United Kingdom Identifi cation of a Potent, Selective, and Structurally Novel GPR120 The development of type 2 diabetes has been associated with the in- Agonist with Anti-infl ammatory Activity creased secretion of corticosterone. Selective inhibitors of glucocorticoid BYUNG GYU KIM, Daejeon, Republic of Korea receptors may therefore have a role in the treatment of diabetes. In this Omega-3, the natural ligand of GPR120, is known to improve glucose study we have evaluated novel and selective inhibitors of the glucocorticoid tolerance and insulin resistance in animal diabetes models. Nonetheless, receptor in a sub-chronic model of glucocorticoid-induced insulin resistance. it showed not only very low potency for GPR120, also redundant activity for Male Sprague Dawley rats were purchased from Charles River (UK). After a other receptors such as GPR40 and PPARs. Therefore, it is strongly required 3-day baseline run-in period during which animals were dosed with vehicle, to develop more selective and potent GPR120 agonist to evaluate GPR120 as rats were administered cortisone (30 mg/kg sc qd) or vehicle for 6 days. Body a therapeutic target for the type II diabetes. Here, we identifi ed LGLS120-A weights were measured daily and at termination (Day 7) a blood sample was with a low- nanomolar potency and analyzed its in vitro activities in compari- collected (tail vein) for determination of plasma glucose and insulin in fed son with several structurally different GPR120 agonists. First, LGLS120-A rats. Novel glucocorticoid receptor antagonists were evaluated initially at exhibited 10-fold more potent than other GPR120 agonists in the both cal- 30 mg/kg po bid and compared to the non-selective glucocorticoid /proges- cium mobilization and beta-arrestin assays for GPR120. Moreover, LGLS120- togen receptor antagonist mifepristone (30 mg/kg po qd) which was used A was analyzed for its selectivity for GPR120 versus GPR40, as both of them as a positive control in this test system. Vehicle treated control rats gained are long chain free fatty acid receptors. Intriguingly, we observed that a weight steadily over the study period body weight increasing from approx few GPR120 agonists had high activity for mouse GPR40 but not for human 300g (Day 1) to 370g (Day 7). Cortisone caused an average reduction in body GPR40, showing species difference. However, LGLS120-A was found to be weight gain of 20.1% (p<0.001), and caused plasma insulin to increase ap- 1000-fold more selective for GPR120 without cross-activity for human and proximately 4-fold compared to-vehicle treated controls. Mifepristone par- mouse GPR40. Finally, anti-infl ammatory effect of LGLS120-A was examined tially reversed (by 68%) cortisone-induced weight loss but fully reversed because infl ammation is considered to be one of the key factors to cause the insulin resistance caused by cortisone. The selective glucocorticoid insulin resistance in type II diabetes. Micromolar concentration of LGLS120- antagonist CORT A (30mg/kg po) was observed to be equally effective as A was enough to inhibit infl ammatory signaling pathways and cytokine pro- mifepristone in reversing glucocorticoid induced weight loss and inhibiting duction in both RAW264.7 cells and mouse primary macrophages stimulated the development of insulin resistance. Selective glucocorticoid antagonists with LPS. Furthermore, it was confi rmed that anti-infl ammatory effect of are therefore effective in ameliorating the insulin resistance induced by ex- LGLS120-A is mediated through GPR120 by analyzing macrophages isolated ogenous cortisone administration. from GPR120-knockout mouse. Taken together, various in vitro assessments

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strongly suggest that LGLS120-A is the most selective and potent GPR120 1245-P agonist with anti-infl ammatory effect. Effi cacy and Safety of the DPP-4 Inhibitor Combined with Insulin Therapy in Patients with Type 2 Diabetes: A Systematic Review and 1243-P Meta-analysis Dapaglifl ozin May Attenuate Adipose Tissue Infl ammation and Ar- SE HEE MIN, YEONG G.I. KIM, SEOKYUNG HAHN, TAE JUNG OH, EUN K.Y. terial Stiffness in Type 2 Diabetes KIM, CHANG HO AHN, LEE-KYUNG KIM, SOO HEON KWAK, KYONG SOO PARK, STAMATIS EFSTATHIOU, IRINI SKEVA, THEODORE MOUNTOKALAKIS, Athens, YOUNG MIN CHO, Seoul, Republic of Korea Greece In this study, we conducted a systematic review and meta-analysis to Adipose tissue infl ammation impairs arterial compliance at early stages compare the effi cacy and safety of the addition of a dipeptidyl peptidase-4 of type 2 diabetes mellitus (T2DM). This study aimed to assess the impact of (DPP-4) inhibitor or a placebo in patients with type 2 diabetes inadequately dapaglifl ozin (DPG) as compared to saxagliptin (SXG) on aortic stiffness and controlled with insulin. serum adiponectin (ADPN), an adipocytokine with insulin-sensitizing, anti- We searched MEDLINE, EMBASE, LILACS, Cochrane library and Clinical- infl ammatory and anti-atherogenic properties, in T2DM. In this 24-week, Trials.gov databases up to October 2014. Randomized controlled trials were prospective, pilot, randomized, open, parallel-group, active-comparator selected if they had at least 12 weeks of treatment duration, compared controlled trial, 66 Caucasian diabetics with inadequate glycemic control on addition of a DPP-4 inhibitor to insulin therapy (INS/DPP4i) with addition metformin monotherapy (≥1500 mg daily) were randomly assigned to receive of a placebo to insulin therapy (INS/PCB) in patients with type 2 diabetes 10 mg DPG (n=34) or 5 mg SXG (n=32) orally once daily. Arterial stiffness was mellitus, and described in English. The primary outcome was the change in assessed as carotid-femoral pulse wave velocity (PWV) measured via an au- hemoglobin A1c (HbA1c) from baseline. The secondary outcomes included tomatic computerized technique (Complior; Artech Medical, Pantin, France), the changes in fasting plasma glucose (FPG) levels, body weight, and daily whereas a sandwich enzyme-linked immunosorbent assay was employed insulin doses and the risk of hypoglycaemia. for ADPN measurement. In the entire study population, mean age was 54.6 Of 3105 potentially relevant published articles and 206 registered trials, 9 years, diabetes duration 6.5 years, baseline HbA1c 7.7%, fasting plasma glu- studies met the inclusion criteria. Compared to INS/PCB, INS/DPP4i therapy cose [FPG] 164 mg/dl, body mass index [BMI] 31.6±4.8 kg/m2, GFR 88.5 mL/ exhibited a greater reduction in HbA1c (weighted mean difference [WMD] min/1.73m2, PWV 13.0±2.5 m/s and ADPN 6.0±1.9 µg/ml. After 24 weeks -0.58%, 95% confi dence interval [CI] -0.70 to -0.46) and FPG (WMD -0.59 signifi cant changes were observed in HbA1c and FPG with both DPG (-0.72% mmol/L, 95% CI -0.79 to -0.40). Despite better glycemic control, INS/DPP4i exhibited insulin sparing effect compared to INS/PCB therapy (WMD -1.86 POSTERS and -24.2 mg/dl, respectively) and SXG (-0.70% and -22.1 mg/dl, respective- Therapeutics ly; p<0.001 for all comparisons, the between-group differences being non- IU, 95% CI -3.27 to -0.45) and did not elicit weight gain (WMD -0.04 kg, 95% Clinical Diabetes/ signifi cant), whereas hypoglycemia rates were comparable (3% with DPG CI -0.25 to 0.16). The risk of hypoglycemia was similar between INS/DPP4i and 2.8% with SXG; p=0.218). Body weight declined by 3.6 kg (p<0.001) with and INS/PCB therapy (the risk ratio in favor of INS/PCB was 0.94, 95% CI DPG and 0.5 kg (p=0.084) with SXG (p<0.001 for between-group difference). 0.84 to 1.05). PWV decreased (-2.9±0.9 [p<0.001] with DPG and -1.4±0.5 m/s [p<0.05] with In conclusion, combined DPP-4 inhibitor and insulin therapy signifi cantly SXG) and ADPN increased (3.2±0.9 [p<0.001] with DPG and 1.5±0.5 mg/L improved glycemic control without increasing the risk of hypoglycemia and [p<0.05] with SXG), the differences being greater with DPG (p<0.01 for both weight gain and exhibited an insulin sparing effect in patients with type 2 comparisons). Addition of DPG to metformin may attenuate adipose tissue diabetes. Therefore, adding a DPP-4 inhibitor to insulin therapy would be a infl ammation and arterial stiffness to a greater extent than SXG in patients good treatment option for poorly controlled type 2 diabetes. with T2DM. 1246-P 1244-P Safety and Effi cacy of Linagliptin in Patients with Type 2 Diabetes Linagliptin Enhances Beta-Cell Function Independent of Enteric (T2D) and Coronary Artery Disease (CAD): Analysis of Pooled Inci- Glucose in a Mouse Model of Type 2 Diabetes dent Investigator Reported Events from Phase 3 Clinical Trials BENJAMIN J. LAMONT, MATTHEW F. WATERS, CHRISTOS N. JOANNIDES, MICHAEL LEHRKE, LAWRENCE A. LEITER, UWE HEHNKE, SANDRA THIEMANN, THOMAS KLEIN, SOF ANDRIKOPOULOS, Melbourne, Australia, Biberach, Germany ODD-ERIK JOHANSEN, AMIT BHANDARI, SANJAY PATEL, HANS-JUERGEN WO- Dipeptidyl peptidase-4 inhibitors (DPP4i) act to preserve the levels of in- ERLE, Aachen, Germany, Toronto, ON, Canada, Ingelheim, Germany, Asker, Norway, tact glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic Ridgefi eld, CT, Bracknell, United Kingdom peptide (GIP). An increase in these gut-derived incretin hormones following Patients (pts) with T2D continue to have increased CAD morbidity and nutrient ingestion is thought to be the predominant mechanism of action for mortality. We examined patient-level safety and effi cacy data of the DPP-4 this class of drugs. However recent studies have shown that DPP4i can also inhibitor linagliptin 5 mg (LINA) in pts with CAD (identifi ed using standard- directly enhance insulin secretion from pancreatic islets ex vivo. Therefore ized MedDRA query “embolic and thrombotic events” using data pooled we wanted to test whether enteric glucose was required for a DPP4i (lina- from randomized placebo (PBO)-controlled trials. The safety set included pts gliptin) to enhance insulin secretion in a model of type 2 diabetes (T2D). The with ≥12 wks of treatment (19 trials; LINA, n=451; PBO, n=272). The effi cacy polygenic New Zealand Obese (NZO) mouse is obese and insulin resistant, set included pts with ≥24 wks of treatment (12 trials: LINA, n=328; PBO, and develops hyperglycemia as a result insuffi cient insulin secretion. In this n=198). In the safety set, baseline mean ± SD age, BMI and HbA1c were model we found that both acute (3 mg/kg body weight via oral gavage) and 64.7 ± 9.2 yrs, 30.6 ± 4.9 kg/m2 and 8.1 ± 0.9%, respectively. Baseline car- sub-chronic (0.08 mg/kg mixed in the food for 6 weeks) administration of diovascular (CV) risk factors/history were well matched between groups linagliptin reduced the blood glucose excursion (AUCglucose: 2610±156 vs. (Table), as were vital signs and concomitant use of CV drugs. Hypoglyce- 2970 ± 150 mM x min) and increased plasma insulin levels (2.2 ± 0.6 vs. 1.3 ± mia occurred in 20.8% of LINA pts and 24.6% of PBO pts. Overall, adverse 0.3 ng/ml at 10 min) following an oral glucose challenge (1 g/kg). Moreover events (AE) and serious AEs with LINA vs. PBO were not increased; cardiac linagliptin-treated NZO mice also displayed elevated insulin levels when AEs were reported by 9.1% of LINA pts and 9.2% of PBO pts (Table). In the glucose (1 g/kg) was administered via either an intraperitoneal injection effi cacy set (baseline mean ± SD HbA1c = 8.2 ± 0.9%), PBO-adjusted mean (plasma insulin: 2.1±0.3 vs. 1.2±0.3 ng/ml at 10 min) or intravascular bolus HbA1c change from baseline at wk 24 was -0.57% (95% CI -0.70, -0.43; (AUCinsulin: 96.7 ± 7.7 vs. 27.7 ± 5.7 ng/ml x min). These enhancements in p < 0.0001). Pts were more likely to achieve HbA1c <7% with LINA vs. PBO glucose stimulated insulin levels were not associated with an increase in (OR 3.70; p < 0.0001). LINA was well tolerated and effi cacious in patients beta cell mass following linagliptin treatment. We conclude that DPP4i medi- with known risk factors for CAD. ated improvements in beta cell function do not require enteric glucose, and suggest that direct effects of DPP4i on pancreatic islets may contribute to their action in this model of T2D. Supported By: Boehringer Ingelheim

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Table. POSTERS Therapeutics Clinical Diabetes/

Supported By: Boehringer Ingelheim Supported By: Boehringer Ingelheim 1248-P Effi cacy and Safety of Saxagliptin in Patients with Type 2 Diabetes: 1247-P Outcomes by Race and Ethnicity Effi cacy and Safety of Linagliptin/Metformin Fixed-Dose Combina- YU CHEN BARRETT, GIANMARIA MINERVINI, HUNGTA CHEN, AMEEN GHAN- tion (FDC) as Initial Therapy in Drug-Naïve Asian Patients with Type NAM, Fort Washington, PA, Gaithersburg, MD 2 Diabetes (T2D) Diabetes affl icts 387 million people worldwide, and the number of people CHANGYU PAN, YIMING MU, BEI FAN, UWE HEHNKE, YAN GONG, Beijing, China, with type 2 diabetes (T2D) is increasing in every country, suggesting the ur- Shanghai, China, Ingelheim, Germany gent need for effective, well-tolerated treatment options across patient popu- A 24-wk study investigated the effi cacy and safety of initial fi xed-dose lations. Using data pooled from 9, phase 3, randomized, placebo (PBO)-con- combination (FDC) therapy with linagliptin (L) and metformin (M) immediate trolled studies of saxagliptin (SAXA) 2.5 and 5 mg/d as monotherapy or add-on release in drug-naïve pts from Asia (83.4% from China) with T2D and inad- to oral antidiabetes medications or insulin ± metformin in patients with T2D, equate glycemic control. In total 733 pts (initial HbA1c [%] ≥7.5-<11) were we conducted a post-hoc analysis assessing the 24-week effi cacy and safety randomized to 1 of 5 regimens (L5 QD, M500 BID, M1000 BID, L2.5/M500 of SAXA in subgroups by race (white, black, Asian) and ethnicity (Hispanic). BID, L2.5/M1000 BID). Primary endpoint was HbA1c change from baseline Duration of T2D was similar in white, black, and Hispanic patients (mean 4.9- (BL) to wk 24. Overall mean BL (SD) age, BMI, HbA1c and FPG were 51.3 (10.0) 7.2 y) but was shorter in Asian patients (mean 3.2-3.9 y). At week 24, SAXA 2.5 2 yrs, 26.0 (3.6) kg/m , 8.7 (1.0) % and 169.0 (39.5) mg/dL, respectively. At and 5 mg/d signifi cantly reduced HbA1c from baseline vs. PBO in white, black, wk 24, the FDCs showed clinically meaningful reductions from BL in HbA1c Asian, and Hispanic patients (all P<0.001), with signifi cant proportions of white and FPG (Table). The fi rst test of the primary HbA1c analysis (L2.5/M1000 (both doses P<0.001), black (P=0.029 for SAXA 2.5 mg/d), and Asian (P=0.003 BID vs. M1000 BID) was borderline non-signifi cant; however, all but 1 pre- and P<0.001, SAXA 2.5 and 5 mg/d, respectively) patients achieving HbA1c defi ned sensitivity analysis showed that the FDCs had signifi cantly greater <7%. Signifi cant reductions in fasting plasma glucose and 2-hour postprandial reductions in HbA1c from BL vs. their respective monotherapy components. glucose were observed at week 24 across the groups (Table). Adverse event This was also shown for a pre-defi ned subgroup analysis in Chinese pts. occurrence, including hypoglycemia, was similar for SAXA and PBO within Target HbA1c (<7%, wk 24) was reached in 44-77% of pts (Table). Adverse subgroups. These data support SAXA as an effective and well-tolerated treat- event (AE) rates were similar across groups except for a small but expected ment option for various patient populations with T2D. increase in gastrointestinal AEs with M and FDCs particularly with M1000. Hypoglycemic AEs were low across groups. In conclusion, FDCs signifi cantly Table. improved glycemic control and were well tolerated. NCT01708902

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1249-P Table. Dapaglifl ozin Decreases Postprandial Glucose without an Increase in C-Peptide or Insulin THOMAS FORST, KATJA ROHWEDDER, JENNIFER SUGG, EVA JOHNSSON, Mainz, Germany, Wedel, Germany, Gaithersburg, MD, Mölndal, Sweden Control of postprandial glucose (PPG) is important for type 2 diabetes mellitus (T2DM) management and risk reduction. The combination of PPG, insulin and C-peptide are measures of β-cell function, insulin resistance and success of glycemic control. In a small subgroup of patients from a 4-year, phase 3 trial of dapaglifl ozin (DAPA, ≤ 10 mg/d) vs. glipizide (GLIP, ≤ 20 mg/d) as add-on to metformin (MET) in patients with T2DM (NCT00660907), PPG was assessed by oral glucose tolerance test at 52 and 104 weeks. At 52 weeks, mean area under the curve (AUC0-180mins) for PPG was reduced from baseline in both groups, but was more pronounced with DAPA compared with GLIP (-11467.3 [1376.4] mg/dL/min vs. -7176.8 [1489.6] mg/dL/min, respec- tively). Reductions were sustained at 104 weeks (DAPA, -9317.5 [1890.6] mg/ dL/min; GLIP, -7290 [1928] mg/dL/min). At both time points, DAPA-mediated re- ductions in PPG were not associated with an increase in AUC for circulating in- sulin; this fi nding was the opposite for GLIP. In addition, increases in C-peptide AUC were greater with GLIP than DAPA at both time points (Table). Compared with GLIP, DAPA is associated with a sustained reduction in PPG and improvement in glycemic control without an increase in C-peptide or insulin over 2 years, suggestive of a potential protective effect of β-cell function and alleviation of β-cell stress and insulin resistance. Table. AUC Change from Baseline. POSTERS

Therapeutics 52 weeks 104 weeks

Clinical Diabetes/ DAPA GLIP DAPA GLIP (N = 400) (N = 401) (N = 400) (N = 401) Glucose (mg/dL/min) n 34 29 24 23 Mean –11467.3 –7176.8 –9317.5 –7290 95% CI (–14219.5, –8715.0) (–10155.5, –4198.1) (–13125.4, –5509.6) (–11173.2, –3406.8) Diff vs. GLIP –4290.5 – –2027.5 – 95% CI (–8352.2, –228.7) – (–7478.3, 3423.3) – 1251-P Insulin (µU/L/min) Teneligliptin Decreases the Uric Acids Levels by Reducing Xanthine n 35 29 24 23 Oxidoreductase Expression in 3T3-L1 Adipocytes Mean –333.7 1860.3 –346.1 1828.5 CHIHIRO MORIYA TSUKAGOSHI, TSUYOSHI WATANABE, HIROAKI SATOH, Fu- 95% CI (–1055.0, 387.7) (1068.2, 2652.4) (–1438.5, 746.2) (713.9, 2943.1) kushima, Japan Diff vs. GLIP –2194.0 – –2174.7 – Teneligliptin, a novel dipeptidyl peptidase-4 (DPP-4) inhibitor, exhibits a 95% CI (–3266.9, –1121.0) – (–3739.1, –610.3) – unique structure characterized by fi ve consecutive rings, which produce a C-peptide (ng/mL/min) potent and long-lasting effect. Previously, we have reported that teneliglip- n 35 24 tin improves not only glycemic control but lipid and uric acids metabolism in Mean 35.2 29 85.0 23 type 2 diabetic patients. Uric acid is also one of risk factor in the cardiovascu- 95% CI (–70.1, 140.4) 294.5 (–53.2, 223.1) 347.6 lar diseases. Recently it has reported adipose tissue produces and secretes Diff vs. GLIP –259.3 (178.9, 410.1) –262.7 (206.6, 488.6) uric acid through xanthine oxidoreductase (XOR) and that the production is 95% CI (–415.8, –102.9) (–460.1, –65.2) enhanced in obesity. Adipose tissue is one of major organs that has abun- Data are adjusted mean changes from baseline derived from longitudinal dant expression and activities of XOR. However, the molecular mechanisms repeated measures analyses. by which teneligliptin is decreased serum uric acid are not understood. In Supported By: AstraZeneca this study, we investigated the mechanism of the effects of teneligliptin on the uric acids metabolism in 3T3-L1 adipocytes. 1250-P We fi rst examined the effect of teneligliptin treatment for 3 hours on Xor DPP-4 Inhibitor and Risk of Infection: A Meta-analysis of Random- mRNA expression in 3T3-L1 adipocytes. Teneligliptin signifi cantly decreased ized Controlled Trials Xor mRNA expression by 45% (p < 0.01), 35% (p < 0.01), and 34% (p < 0.01) at WENJIA YANG, XIAOLING CAI, XUEYAO HAN, LINONG JI, Beijing, China 1, 5, and 10 µM concentration, respectively, in 3T3-L1 adipocytes. The treat- Aims: To evaluate the risk of infections in the treatment of type 2 diabetes ment of DPP-4 (200 ng/ml), which was a novel adipokine that impaired insu- patients with DPP-4 inhibitors. lin sensitivity in an autocrine and paracrine fashion, signifi cantly increased Methods: A literature search was conducted through electronic data- Xor mRNA expression by 49% (p < 0.01) in 3T3-L1 adipocytes. Under condi- bases MEDLINE®, EMBASE®, CENTRAL. The inclusion criteria in our meta- tion with pretreatment of DPP-4 (200 ng/ml) for 12 hours, 10 µM teneligliptin analysis included study duration of no less than 12 weeks developed in type signifi cantly decreased Xor mRNA expression by 38% (p < 0.01). These re- 2 diabetes patients, the use of a randomized control group receiving DPP-4 sults suggest the possibility of the mechanism that teneligliptin decreases inhibitor, and the availability of outcome data for infections. Data abstrac- serum uric acid. tion was completed by two independent investigators. Out of 1,421 studies, In conclusion, teneligliptin may decrease uric acid levels by reducing Xor 70 studies were fi nally included. mRNA expression. Teneligliptin is more effective in patients with type 2 dia- Results: Compared with placebo treatment, odds ratio (OR) of infections in betes combined with hyperuricemia. DPP-4 inhibitors treatment was 0.99 [95% confi dence interval (CI), 0.93 to 1.06, P=0.83]. Compared with metformin treatment, OR of infections in DPP-4 inhibi- 1252-P tors treatment was 1.24 (95% CI, 0.99 to 1.55, P=0.06). Compared with sulpho- Sitagliptin, a DPP-4 Inhibitor, Alters the Number and Proportion of the nylurea treatment, OR of infections in DPP-4 inhibitors treatment was 0.98 (95% Subsets of Circulating CD4+ T Cells in Patients with Type 2 Diabetes CI, 0.76 to 1.25, P=0.86). Compared with thiazolidinediones treatment, OR of YOSHIMASA ASO, MASAAKI SAGARA, KUNIHIRO SUZUKI, TERUO JOJIMA, infections in DPP-4 inhibitors treatment was 0.86 (95% CI, 0.65 to 1.14, P=0.29). TOSHIE IIJIMA, TOSHIHIKO INUKAI, Mibu, Japan, Koshigaya, Japan Compared with alpha glucosidase inhibitor treatment, OR of infections in DPP-4 Objective: CD26/DPP-4 is highly expressed on the surface of T cells, es- inhibitors treatment was 1.03 (95% CI, 0.33 to 3.22, P=0.96). pecially CD4+ T cells (T helper cell; Th) and may regulate the development, Conclusions: The overall risk of infections of DPP-4 inhibitor was not increased maturation, or differentiation of CD4+ T cells. We investigated effects of compared with control groups.

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A324 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS sitagliptin, a DPP-4 inhibitor, on the absolute counts of the subsets of cir- 1254-P culating CD4+ T cells and the percentage of each subset among all CD4+ T Bioequivalence (BE) of Saxagliptin (SAXA)/Dapaglifl ozin (DAPA) cells in patients with type 2 diabetes. Fixed Dose Combination (FDC) Tablets Compared with Coadminis- Methods: We studied 30 consecutive patients with type 2 diabetes (16 tration of the Individual Tablets women and 14 men). This study is a prospective, randomized, open label, BLISSE VAKKALAGADDA, MARION VETTER, JIGNASA RANA, CHARLES H. blinded endpoint design. Eligible participants were randomly assigned in a SMITH, JIAN HAUNG, JENNIFER KARKAS, DAVID W. BOULTON, FRANK LACRE- 2:1 ratio to one of two groups, either a sitagliptin (50 mg/d) group or an ac- TA, Pennington, NJ, Princeton, NJ, Plainsboro, NJ, Richmond, VA, Morrisville, NC tive placebo group. Each patient was followed for 12 weeks with review ev- This was an open-label, randomized, single-dose crossover study to dem- ery month. Peripheral blood mononuclear cells of all subjects were examined onstrate the BE of SAXA/DAPA 2.5/5 mg and 5/10 mg FDC tablets compared by fl ow cytometry for intracellular cytokines (IFN-γ for Th1; IL-4 for Th2: IL-17 to coadministration of individual tablets. Food effect on bioavailability and for Th17) and expression of CD4, CD25 and Foxp3 (regulatory T cells [Treg]). safety were also assessed. Healthy subjects were randomly assigned to a Results: Both groups showed similar improvements in glycemic control. treatment sequence with either SAXA 2.5 mg + DAPA 5 mg fasted; 2.5/5 mg The number of total CD4+ T cells was decreased after treatment with sita- FDC fasted; 2.5/5 mg FDC fed (Cohort 1) or SAXA 5 mg + DAPA 10 mg fasted; gliptin, while it did not change in the active placebo group. The number and 5/10 mg FDC fasted; 5/10 mg FDC fed (Cohort 2). There was a 6-day washout percentage of Th17 cells and Treg cells were decreased signifi cantly in the between doses. Blood samples were obtained pre- and ≤60 h post-dose. BE sitagliptin group, but not the active placebo group. We found a signifi cant of FDC tablets vs. individual components was concluded if the 90% CIs for positive correlation between changes in the percentage of Th17 cells and test to reference ratios of the geometric means were between 0.80-1.25. A those in the percentage of Treg cells after treatment with sitagliptin. total of 72 subjects were randomized; 71 completed the study. SAXA/DAPA Conclusions: Treatment with sitagliptin for 12 weeks reduced the num- 2.5/5 mg and 5/10 mg FDC tablets were BE to the individual component tab- ber of circulating CD4+ T cells, especially Th17 and Tregs cells in patients lets administered concomitantly (Table). Food had no clinically meaningful with type 2 diabetes. effect on SAXA or DAPA total drug exposure. Adverse events (AEs) were reported for 22 (30.5%) subjects (nausea was most common); most events 1253-P were mild and none were considered serious. No AEs led to discontinuation. Effect of Sex and Age on HbA1c, Body Weight, and Systolic Blood These data demonstrate the BE of SAXA/DAPA FDC tablets to the coadmin- Pressure Reduction with Dapaglifl ozin istration of individual components in healthy subjects under fasted condi- tions. Food had no effect on bioavailability; treatment was well tolerated. JANE E.B. REUSCH, DANIELLE DAY, GENEVIEVE WORTZMAN-SHOW, ARIE KATZ, POSTERS Therapeutics JUDITH G. REGENSTEINER, Denver, CO, Fort Washington, PA, Aurora, CO Table. In the U.S., over 10.9 million people over age 65 and 13.5 million women Clinical Diabetes/ of all ages suffer from diabetes. Clinical trials have not consistently evalu- ated effects of antidiabetes agents on women or older individuals. In this post-hoc analysis, we examined whether sex or age would impact treatment effect of dapaglifl ozin (DAPA) on HbA1c, body weight (BW) and systolic blood pressure (SBP) using pooled data from 10, 24-wk placebo-controlled phase 3 trials of DAPA as monotherapy or combination therapy. DAPA signifi cantly reduced HbA1c, BW, and SBP in women and men, with no apparent sex dif- ference (Table). Data were analyzed in 3 age groups used as surrogate cate- gories for menopausal hormone status in women (<45 years, 45-57 years and ≥58 years); data for men in the same age groups were analyzed for primary Supported By: AstraZeneca age effects. HbA1c reductions were signifi cantly greater for all groups on DAPA vs. placebo, and both women and men demonstrated a signifi cant age 1255-P interaction (effi cacy appeared to decline with age, see Table). There were no Initial Combination Therapy with Dapaglifl ozin (DAPA) + Metformin age interactions for BW or SBP. Further investigation is warranted to deter- Extended-Release (MET XR) Impacts Quality Measures Relevant to mine which factors (e.g, baseline HbA1c, eGFR, duration of diabetes) may ac- Diabetes Care count for the reduction in HbA1c effi cacy with advancing age. DAPA reduced KELLY BELL, ARIE KATZ, JOHN J. SHEEHAN, Fort Washington, PA HbA1c, BW, and SBP in both sexes and across age ranges corresponding Diabetes measures are designed to improve the quality, safety, and af- with pre-, peri- and postmenopause in women, but the effect on HbA1c ap- fordability of healthcare for patients with type 2 diabetes mellitus (T2DM). peared to diminish with age in both sexes. In 2 phase 3 trials in treatment-naive patients with T2DM, DAPA 5 or 10 mg as initial combination therapy with MET XR signifi cantly reduced HbA1c from baseline at 24 weeks vs. DAPA or MET alone. A pooled analysis of data from these studies (N=814) was performed to determine the effect of DAPA 5 or 10 mg + MET XR vs. PBO + MET XR treatment on U.S. diabetes quality measures. Among all measures, the most stringent HbA1c, systolic/diastolic blood pressure (SBP/DBP) and low-density lipoprotein cholesterol (LDL-C) thresholds were: HbA1c <7%, SBP/DBP <130/80 mmHg, and LDL-C<100 mg/ dL. The proportion of patients with baseline body mass index >25 kg/m2 who lost ≥4.5 kg was also assessed. Outcomes showed signifi cantly more pa- tients in the DAPA 5 or 10 mg groups achieved HbA1c <7% vs. PBO (Table, P<0.02 for each dose). The difference from PBO in the proportion of patients with SBP/DBP <130/80 mmHg was statistically signifi cant with DAPA 5 mg, although not with 10 mg. A similar proportion of patients had LDL-C <100 mg/dL among groups. Signifi cantly more patients lost ≥4.5 kg with DAPA vs. PBO. These data suggest that initial combination therapy with DAPA 5 or 10 mg + MET XR improves quality measures relevant to clinical outcomes and diabetes care.

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1256-P Lack of Pharmacokinetic Interaction between Saxagliptin and Da- 1258-P paglifl ozin in Healthy Subjects The Effi cacy and Safety of Dipeptidyl Peptidase-4 Inhibitors vs. BLISSE VAKKALAGADDA, SUSAN LUBIN, LAURIE REYNOLDS, DAN LIANG, ALAN Sulphonylurea in Patients with Type 2 Diabetes: A Meta-analysis of S. MARION, DAVID BOULTON, FRANK LECRETA, Princeton, NJ, Portland, OR, West Randomized Clinical Trials Windsor, NJ, Gretna, NE JIAN-BO ZHOU, JIN-KUI YANG, Beijing, China This single-dose, open-label, 3-period, 3-treatment crossover drug-drug Objective: To assess the effi cacy and safety of dipeptidyl peptidase-4 (DPP- interaction study was conducted to evaluate any differences in the pharma- 4) inhibitors compared with sulphonylurea as monotherapy, or with a metform- cokinetics of saxagliptin (SAXA) + dapaglifl ozin (DAPA) when coadministered. in combined with sulphonylurea, in patients with type 2 diabetes (T2D). Healthy subjects (N=42) received the following 3 treatments in a random Design Meta-analysis of Randomised Controlled Trials: Data sources order: SAXA 5 mg alone; DAPA 10 mg alone; and SAXA 5 mg + DAPA 10 mg Medline/Pubmed, EMBASE, SCOPUS, CINAHL, Google Scholar, conference, POSTERS Therapeutics coadministered with a washout period of ≥6 days between treatments. Se- proceedings, trial registers, and drug manufacturers’ websites.

Clinical Diabetes/ rial blood samples for determining SAXA and DAPA plasma concentrations Results: Fifteen studies including 6121 patients randomized to a DPP-4 in- were collected predose and up to 60 hours postdose. No interaction was to hibitor and 5355 patients randomized to sulphonylurea were eligible for the be concluded if the 90% confi dence intervals for the geometric mean ratios meta-analysis. Compared with sulphonylurea, DPP-4 inhibitors were associ- of the combination compared with each drug given alone for both Cmax and ated with a smaller decline in HbA1c (WMD 0.275, 95% CI: 0.009 to 0.541, AUCinf were within 0.8 to 1.25.The results showed that DAPA had no effect P=0.043), and resulted in weight loss of 1.945kg (95% CI: -2.237 to -1.653, on the pharmacokinetics of SAXA and vice versa. The 90% CIs for Cmax and p<0.0001). The effect of DPP4 inhibitors lowering FBG was inferior to that of AUCinf for both comparisons were contained entirely within the 0.80 to 1.25 sulfonylureas (WMD, 0.268, 95% CI, 0.151 to 0.385, p<0.0001), and similar in equivalence intervals (Table). No differences were observed in the apparent reducing PBG (WMD, 0.084, 95% CI, -0.701 to 0.869, p=0.833). DPP-4 inhibi- oral clearance or half life of SAXA or DAPA when administered alone or when tors had a favorable insulin resistance compared with sulfonylurea (WMD, coadministered. No safety or tolerability fi ndings of concern were observed −0.673, 95% CI, −1.248 to −0.097,p=0.022). The incidence of hypoglycaemia during the study. All adverse events were mild, and no serious adverse events was lower with DPP4 inhibitors (RR, 0.24, 95% CI, 0.21 to 0.27, p<0.000). In- were reported. These data show that coadministration of SAXA and DAPA cidence of discontinuation rate (RR, 0.775, 95% CI, 0.656 to 0.934, p=0.003), exhibits no pharmacokinetic interaction and is well tolerated. asthenia (RR, 0.426, 95% CI, 0.334 to 0.542, p=0.000), dizziness (RR, 0.520, Table. 95% CI, 0.432 to 0.626, p=0.000), Drug-related AE (RR, 0.475, 95% CI, 0.436 to 0.517, p=0.000) was higher in patients receiving sulphonylurea than in those receiving DPP4 inhibitor. Conclusion: Patients with type 2 diabetes who receive DPP4 inhibitors could achieve the almost similar glycaemic targets with sulphonylureas, with favour effects on body weight and lower incidence of hypoglycaemia.

1259-P Safety and Tolerability of Combinations of Empaglifl ozin/Linaglip- tin (EMPA/LINA) for 52 Weeks in Subjects with Type 2 Diabetes (T2DM) SANJAY PATEL, RALPH A. DEFRONZO, ANDREW LEWIN, DACHENG LIU, RENEE KASTE, SVEN KOHLER, HANS J. WOERLE, ULI C. BROEDL, Bracknell, United King- dom, San Antonio, TX, Los Angeles, CA, Ridgefi eld, CT, Ingelheim, Germany Two 52-week Phase III studies evaluated the effi cacy and safety of once daily combinations of EMPA/LINA as monotherapy or add-on to metformin in Supported By: Bristol-Myers Squibb/AstraZeneca subjects with T2DM. Using pooled data from these trials, we assessed the safety and tolerability of EMPA/LINA in 1363 subjects treated with EMPA 25 mg/LINA 5 mg (n=273), EMPA 10 mg/LINA 5 mg (n=272), EMPA 25 mg 1257-P (n=276), EMPA 10 mg (n=275), or LINA 5 mg (n=267). Adverse events (AEs) were assessed descriptively in subjects who took ≥1 dose of study drug. WITHDRAWN Total exposure was 251, 255, 256, 249, and 243 patient-years in the EMPA 25 mg/LINA 5 mg, EMPA 10 mg/LINA 5 mg, EMPA 25 mg, EMPA 10 mg, and LINA 5 mg groups, respectively. The percentage of subjects with any AE(s) was similar across groups (Table). The percentage of subjects with confi rmed hypoglycemic AEs (plasma glucose ≤70 mg/dL and/or requiring assistance) was low in all groups (1.1%-2.2%); none required assistance. Events consis- tent with urinary tract infection were reported in similar percentages of sub- jects in all groups. Events consistent with genital infection were reported in higher percentages of subjects on EMPA/LINA or EMPA than LINA 5 mg, and in a greater proportion of female than male subjects. EMPA/LINA as monotherapy or add-on to metformin for 52 weeks was well tolerated in subjects with T2DM, with safety profi les similar to indi- vidual components, including a low risk of hypoglycemia.

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1261-P Abnormal Fat Tissue Distribution Contributes to Glucose Dysme- tabolism in Werner Syndrome Patients and Cockayne Syndrome Patient with Diabetes AIKO HAYASHI, MINORU TAKEMOTO, TAKUMI KITAMOTO, KAZUKI KOBAYASHI, KOUTARO YOKOTE, Chiba, Japan Werner syndrome (WS) and Cockayne syndrome (CS) are classifi ed as progeroid syndrome which premature aging symptoms develop chronologi- cally. Although WS is often complicated with diabetes, few CS patients

present diabetes. Since we experienced a CS patient with diabetes, we POSTERS Therapeutics analyzed glucose metabolism in detail and compared with WS patients with Clinical Diabetes/ diabetes. Changes in hormone levels were analyzed after consumption of a test meal in 3 WS patients with diabetes (mean age 57 years, all females, A1c Supported By: Boehringer Ingelheim/Eli Lilly and Company mean 7.6%). The meal was Calorie Mate (500 g; calorifi c level: carbohydrate: fat: protein = 60:26:14). A 75-g glucose tolerance test (GTT) was performed 1260-P to one CS patient with diabetes (age 24 years, male, A1c 8.6%). Subcutane- Evolution of Pharmacotherapy in Type 2 Diabetes Patients over the ous and visceral fat areas were evaluated by computed tomography (CT). Course of the Disease—ARETAEUS2-Market Study Results The effects of sitagliptin, a dipeptidyl Peptidase-4 inhibitor, on glycemic LESZEK CZUPRYNIAK, EWA PLACZKIEWICZ-JANKOWSKA, WIKTORIA LESNIAK, control were also examined in all cases. MALGORZATA M. BALA, ROMAN TOPOR-MADRY, ELEKTRA SZYMANSKA-GAR- Both WS and CS patients showed high insulin resistance (IR; mean HOMA- BACZ, PAWEL BIJOS, JERZY LOBA, Łód´z, Poland, Kraków, Poland, Warsaw, Poland IR: 7.6 for WS; HOMA-IR: 5.4 for CS). The meal test and GTT revealed that Type 2 diabetes (DM2) is a progressive disease and its pharmacotherapy post hyperglycemia with the paradoxical pattern of postprandial glucagon requires constant intensifi cation. Patients are also treated for hypertension secretion was present in both syndromes. WS showed the accumulation of or dyslipidemia, and these therapies are rarely seen as requiring step up visceral fat (mean 142 cm2), whereas CS showed fewer subcutaneous and approach over time. In 2012 a cross-sectional nationwide study assessing visceral fat areas (54.4 and 13.7 cm2), respectively. Sitagliptin effectively DM2 treatment effi cacy was conducted. Patients with DM2 (n=15,643) were ameliorated postprandial hyperglycemia in WS, but did not work effectively enrolled at general practice (68%) and diabetologic or cardiolologic (32%) in CS. CS needed the addition of pioglitazone to increase fat tissue and ame- outpatient clinics, and were analysed in three groups according to diabetes liorate blood glucose metabolism. duration: <2, 2-10, and >10 years. The patients with longer DM2 duration Patients with WS are reportedly insulin-resistant due to the accumulation received more intensifi ed treatment, with almost 50% taking insulin after 10 of visceral fat. Paradoxical pattern of postprandial glucagon secretion also years of diabetes (table). In the whole group HbA1c <7% was not achieved in contribute to the development diabetes in WS, whereas lipodystrophic-like 30% of those treated with oral monotherapy, in 46% - on dual oral therapy, conditions contribute to IR and glucose dysmetabolism in CS. Nevertheless, in 62% - on insulin only and in 69% - on metformin + insulin. Among cardio- abnormal fat tissue distribution seemed contributing to development of dia- vascular risk related therapies only statins and ACE inhibitors were used betes in both progeroid syndromes. with increased frequency over time. Less than 10% of all patients achieved three main therapeutic targets (HbA1c <7%, LDL cholesterol <100 mg or 70 1262-P mg/dl in patients with CVD, blood pressure <140/90 mmHg), while 20-25% Lifelong, Partial Reduction of Insulin-Degrading Enzyme Activity failed to achieve any of them. In conclusion, despite widely accepted need Signifi cantly Improves Glucose Tolerance In Vivo for progressive and multifactorial treatment of DM2, still many patients are CAROLINE R. THOMPSON, SARAH NAINAR, YU JIANG, MALCOLM A. LEIS- not treated intensively enough, even with older and inexpensive therapies. SRING, Irvine, CA Table. Following secretion from the pancreas, the metabolic fate of insulin is entirely controlled by catabolism, which, in turn, is principally mediated by insulin-degrading enzyme (IDE). Our group recently demonstrated that phar- macological inhibitors of IDE exhibit multiple anti-diabetic properties in vivo (Maianti et al., Nature 2014; 511:94-8). However, studies in IDE knockout (KO) mice have yielded paradoxical results, with a diabetic phenotype emerging in an age-dependent manner in mice with complete deletion of IDE throughout life (Abdul-Hay et al., PLoS ONE 2011; 6:e20818). To address these confl ict- ing fi ndings, we investigated the long-term consequences of partial (as op- posed to complete) reduction of IDE on glucose tolerance, using mice lacking a single copy of IDE (HET), which were compared to KO and wild-type (WT) mice. HET mice exhibited signifi cantly improved glucose tolerance relative to both WT and KO mice. Signifi cant reductions in blood glucose levels were observed 30, 60 and 90 mins post-injection (p<0.01), and the area under the curve (AUC) was signifi cantly reduced (8844 ± 1068 vs. 12395 ± 878 vs. 12559 ± 1517 for HET, WT and KO, respectively; p < 0.05). These results demon- strate that partial reduction of IDE activity, even life-long reduction, yields

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benefi cial effects on glucose tolerance in vivo, supporting the viability of IDE Table. inhibitors as novel antidiabetic agents.

Supported By: American Diabetes Association (7-11-CD-06 to M.L.)

1263-P Does the Gut Microbiota Potentially Contribute to the Antidiabetic and Additional Cardiovascular Benefi ts of Acarbose? XIUYING ZHANG, ZHIWEI FANG, CHUNFANG ZHANG, LINONG JI, Beijing, China, Shenzhen, China Background: Acarbose has been taken as an effi cacious monotherapy for the treatment and prevention of type 2 diabetes. However, a deeply inves- tigation of the response of gut microbiota to the administration of acarbose were required, as microbiota is thought to have a critical role in the develop-

POSTERS ment of metabolic diseases and acarbose is metabolized exclusively within Therapeutics the gastrointestinal tract. Clinical Diabetes/ Aims: To explore the changes of proportion and diversity of gut microbiota Supported By: AstraZeneca after treatment with acarbose in pre-diabetes. 1265-P Methods. We designed a randomized, double-blind and controlled crossover Changes in Liver Function Tests (LFTs) with Canaglifl ozin (CANA) vs. trial in which 52 pre-diabetes aged 30-60 years with BMI 18-35 kg/m2 by OGTT Sitagliptin (SITA) in Patients with Type 2 Diabetes Mellitus (T2DM) in China were randomly allocated to treatment with acarbose or placebo for Are Related to Changes in A1c and Body Weight (BW) 3 months. Gut microbiota characterizations were determined with 16S rDNA- LAWRENCE A. LEITER, THOMAS FORST, DAVID POLIDORI, DAINIUS BALIS, JOHN based high-throughput sequencing. The alpha diversity was estimated by Shan- XIE, SUE SHA, Toronto, ON, Canada, Mainz, Germany, San Diego, CA, Raritan, NJ non index, chao1 index and the beta diversity was estimated by PCA analysis. CANA, an SGLT2 inhibitor, has provided improvements in LFTs (eg, alanine Results: Based on the operational taxonomic units (OTUs) profi les, a total aminotransferase [ALT], aspartate aminotransferase) across Phase 3 studies. of 107 OTUs were found to change heavily after acarbose, with 76 (71%) be CANA improves glycemic control and lowers BW, both of which have been assigned to the order of Clostridiales. The decreased OTUs were basically of shown to improve LFTs. This analysis assessed the contributions of A1C and Ruminococcaceae (15 OTUs) and Lachnospiraceae (22 OTUs). Most of the 48 BW reductions to ALT reductions with CANA 300 mg and SITA 100 mg using increased OTUs were assigned to Lactobacillaceae (9, 8 Lactobacillus), Ru- pooled data from two 52-week, Phase 3 studies (N = 1,466; mean A1C = 8.0%; minococcaceae (11, 6 Faecalibacterium) and Veillonellaceae (15, 8 Dialister) BW = 88 kg; ALT = 29 U/L). Patients were divided into deciles by ΔA1C or ΔBW; and were found to be 12.8 times higher abundance after treatment with ac- median ΔALT, ΔA1C and ΔBW were calculated in each decile. ANCOVA was arbose. At genera level, 5 genera, especially Lactobacillus and Dialister were performed to assess the contributions of ΔA1C and ΔBW to ΔALT. Greater signifi cantly fl ourished after treatment with acarbose, while Butyricicoccus, reductions in all 3 measures were seen with CANA versus SITA (median Phascolarctobacterium and Ruminococcus were inhibited. ΔA1C = -0.9% vs. -0.7%; ΔBW = -3.1% vs. -0.4%; ΔALT = -11.1% vs. 0%; P Conclusions: This research supports that the antidiabetic and additional <0.0001 for each). For each treatment, greater ALT reductions were seen in pa- benefi ts of acarbose may correlated with the modulation of gut microbiota. tients with larger A1C and BW reductions. Even after adjusting for differences These results also indicate that the infl uence of acarbose on the composition in ΔA1C (Fig A) or ΔBW (Fig B), ALT reductions were greater with CANA than of gut microbiota may have some selectivity. with SITA (P <0.05 for each). However, a combined model including both ΔA1C and ΔBW as covariates suggested that the greater reductions in ALT seen with 1264-P CANA were fully explained by the combined greater ΔA1C and ΔBW seen with Impact of Saxagliptin Treatment on Glycemic Biomarkers and CANA (P = 0.87). In summary, CANA provided greater ALT reductions compared β-Cell Function in Patients with T2D with SITA that were related to changes in A1C and BW. YU CHEN BARRETT, SHIRA PERL, AMEEN GHANNAM, JOHN MONYAK, GIAN- MARIA MINERVINI, Fort Washington, PA, Gaithersburg, MD Type 2 diabetes (T2D) is a progressive disease as evidenced by deteriora- tion of glycemic control and declining β-cell function. DPP-4 inhibitors have been shown to improve insulin secretion and prevent β-cell stress in vitro and in preclinical models, but only limited data are available in patients with T2D. We conducted a post-hoc pooled analysis of 6, phase 3, randomized, placebo (PBO)-controlled clinical trials for up to 206 weeks as monotherapy or add-on to metformin in patients with T2D, assessing the impact of a DPP-4 inhibitor, saxagliptin (SAXA) 2.5 and 5 mg/d, on biomarkers of glu- cose homeostasis (glucose, insulin, C-peptide, glucagon) as well as calcula- tions of β-cell function and insulin sensitivity (HOMA-2β, HOMA2-IR, Insulin sensitivity index). Robust study data from the initial 50 weeks of treatment revealed that SAXA (both 2.5 and 5 mg/d) signifi cantly improved postpran- dial AUC 0-180 min for glucose, insulin, and C-peptide (P<0.01) with a numeri- cal reduction in glucagon and improvement in HOMA-2β (Table). No clear effects were observed on insulin sensitivity index, and HOMA2-IR. Initial signifi cant lowering of glucagon was observed with both doses. These data suggest that inhibition of DPP-4 with saxagliptin improves glycemic control via improvement of insulin secretion and may slow the natural progression of T2D, as demonstrated by improvement in β-cell function. Supported By: Janssen Research & Development, LLC

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1266-P with these conditions. These patterns should be accounted for in compara- Network Meta-analysis of Treatments for Type 2 Diabetes Mellitus tive effectiveness or safety studies of LINA. following Failure with Metformin + Sulfonylurea GRETA LOZANO-ORTEGA, SARAH GORING, HEATHER BENNETT, CATARINA 1268-P STERNHUFVUD, JAYANTI MUKHERJEE, KLAS BERGENHEIM, Vancouver, BC, Effi cacy and Safety of Oral Antidiabetic Drug Therapy in General Canada, Toronto, ON, Canada, Mölndal, Sweden, Wallingford, CT Hospitalized Population with Type 2 Diabetes The effi cacy of sodium-glucose linked transporters (SGLT-2) plus metform- FRANCISCO PASQUEL, MAYA FAYFMAN, PRIYATHAMA VELLANKI, SONYA HAW, in and a sulfonylurea (MET+SU) used in the treatment of T2DM in patients DAWN D. SMILEY, LIPING ZHAO, SHAILESH NAIR, JEFF WEAVER, GUILLERMO E. who fail to achieve glycemic control with MET+SU, was estimated relative UMPIERREZ, Atlanta, GA to other triple therapies licensed in the EU within a network meta-analysis Despite lack of safety and effi cacy data, many patients with type 2 diabe- (NMA). tes (T2D) are treated with oral antidiabetic drugs (OAD) in the hospital set- Of 2,236 abstracts identifi ed through a systematic literature review, 30 ting. This retrospective study aimed to determine the utilization, effi cacy and RCTs published between 2003 and 2013 were included. Eighteen RCTs in- safety of OAD in general hospitalized patients. We reviewed the medical volved a comparison between active treatments, and twelve were placebo- records of 5,848 patients with T2DM admitted to medical and surgical non- controlled. RCTs ranged from 12 to 52 weeks duration, included 28 to 1,274 ICU wards at 4 teaching medical centers between 2012 and 2013. A total of patients, were of parallel design, and most were open-label. Mean age of 1,350 patients (23.1%) were treated with OADs, 196 (3.4%) with OAD+basal patients ranged from 50.9 to 61.7 years and mean baseline HbA1c levels insulin (glargine or detemir), and 4,302 (73.6%) with basal insulin regimen. ranged from 7.4% to 11.3%. Random-effects models were used to estimate Among patients on OAD, 583 were treated with metformin (MET), 437 with relative effect sizes for absolute mean change in HbA1c, weight, SBP and sulfonylurea (SU), and 117 with MET/SU combination for an average of 2.8 risk of hypoglycemic event (Table 1). days. Patients treated with OADs had lower HbA1c and admission blood glu- SGLT-2 inhibitors demonstrated statistically signifi cant weight loss (-1.71; cose (BG) and continued to have lower BG during the hospital stay compared 95% Crl: -2.84, -0.57) and SBP lowering effects (-3.73; 95% Crl: -6.61, -0.57) to OAD+basal and basal. The rate of hypoglycemia, hospital complications when compared with other classes of antidiabetic agents, SGLT-2 inhibitors (lactic acidosis, myocardial infarction and acute kidney injury) and mortality also demonstrated comparable HbA1c control (-0.86; 95% Cl: -1.23, -0.50) were lower in the OAD group than in OAD+basal and basal insulin groups. and similar risk of hypoglycemia (3.12; 95% Crl: 1.33, 7.61) to other classes In conclusion, the inpatient use of OADs was not associated with in- of antidiabetic agents. creased risk of inpatient complications. Randomized controlled studies are POSTERS needed to determine the safety and effi cacy of OAD therapy in the general Therapeutics hospitalized population. Clinical Diabetes/ Table. OAD OAD + Basal Basal P-value # of patients, n (%) 1,350 196 4,302 Age, years 65.5±12.3 60.5±11.5 63.5±12.8 <0.0001 BMI, kg/m2 31.1±7 32.8±8 31.7±8 0.0034 Admit BG, mg/dl 153±53 210±77 199±78 <0.0001 HbA1c, % 6.9±1.5 8.5±2.2 8.1±2.2 <0.0001 Hospital daily BG, mg/dl 153±41 194±56 178±48 <0.0001 BG 80-180 mg/dl, n (%) 979 (81) 80 (46) 2384 (60) <0.0001 BG < 70 mg/dl, n (%) 103 (7.6) 18 (9.2) 479 (11.1) 0.0009 Length of stay, median days 5 (3 – 8) 5 (3 – 7) 5 (4 – 9) <0.0001 1267-P Mortality, n (%) 8 (0.6) 1 (0.5) 62 (1.4) 0.0301 Does Linagliptin Labeling Lead to Preferential Prescribing to Pa- Lactic acidosis, n (%) 46 (3.4) 6 (3.1) 271 (6.3) <0.0001 tients with Renal or Hepatic Impairment in Routine Care? Acute MI, n (%) 21 (1.6) 2 (1.0) 125 (2.9) 0.0088 ELISABETTA PATORNO, CHANDRASEKAR GOPALAKRISHNAN, OLESYA ZORINA, SEBASTIAN SCHNEEWEISS, DOROTHEE BARTELS, JUN LIU, JOHN SEEGER, Bos- AKI, n (%) 96 (8.6) 15 (9.1) 620 (15.8) <0.0001 ton, MA, Ingelheim, Germany Linagliptin (LINA) is a dipeptidyl peptidase-4 inhibitor (DPP-4i) recently approved in the U.S. for treatment of type 2 diabetes mellitus (T2DM). Dif- 1269-P ferently from other antidiabetic agents, LINA labeling does not indicate any Effi cacy and Safety of Gosogliptin as Monotherapy and in Combina- dose adjustment in patients with renal or hepatic impairment, suggesting tion with Metformin in Patients with Type 2 Diabetes Mellitus that it may be a preferred agent for such patients. We sought to determine JULIA TRAKHTENBERG, NATALIA VOSTOKOVA, OKSANA KARAVAEVA, VERA whether this labeling information might be refl ected in the characteristics of KREMINSKAYA, ALEXANDER AMETOV, Khimki, Russian Federation patients to whom LINA is prescribed. Gosogliptin (GOSO) is a novel DPP-4 inhibitor for treatment of type 2 dia- Within a large, nationwide U.S. health insurance database (Optum Clin- betes mellitus (DMT2). The aim of a phase 3 study was to demonstrate non- formatics), T2DM patients who initiated LINA or other non-insulin glucose inferiority of GOSO vs. vildagliptin as monotherapy and in combination with lowering agents between May 2011 and June 2012 are described in terms of metformin (MET) in drug-naïve patients with DMT2. medical characteristics at time of initiation. Separate descriptions are pro- The randomized, open-label study was conducted in 299 patients. The vided for patients who switched or augmented diabetes therapy and those primary endpoint was change in HbA1c from baseline; the secondary end- who were naive initiators. points: the proportion of patients who achieved HbA1c ≤ 7.0%, change in Of 155,345 T2DM patients who initiated a non-insulin diabetes agent, plasma glucose, and body weight. Safety endpoints included adverse events 2,820 (1.8%) did so with LINA. The percentage of patients with baseline and hypoglycemia. kidney disease initiating LINA (11.9%) was higher than among initiators of Subjects were randomized to GOSO 20 mg or vildagliptin 50 mg; the daily other DPP-4i (6.5%), sulfonylureas (6.9%), glitazones (6.8%) and metformin doses were titrated to 30 and 100 mg respectively in 4 weeks. After 12 (3.9%), with only meglitinide initiators (14.2%) having a higher percentage. weeks MET 1000 mg was added; the daily dose was titrated to 2000 mg in 4 LINA initiators also had more baseline chronic liver disease (3.0%) than other weeks; combination therapy continued for 24 weeks. DPP-4i (2.6%), metformin (2.5%), sulfonylurea (2.9%) and glitazones (2.6%). Non-inferiority of GOSO was demonstrated for mono and combination thera- These conditions and their associated comorbidities translate into a higher py (CI 97.5%, δ=0.4%): ΔHbA1c was -0.93% on GOSO vs. -1.03% on vildaglip- Charlson comorbidity score for LINA (1.68) and meglitinide initiators (1.79) tin (CI UB=0.34); -1.29% on GOSO+MET vs. -1.35% on vildagliptin+MET (CI than for any of the other diabetes drugs. Findings were similar among naive UB=0.30). The proportion of patients who achieved the target HbA1c had no initiators, and also in another U.S. insurance claims database (MarketScan). statistical difference between the groups: 41.0% vs. 44.5% (monotherapy) Patients initiating LINA exhibit a higher burden of comorbidities, including and 54.8% vs. 55.2% (combination). Other effi cacy and safety parameters renal and hepatic disease, suggesting preferential prescribing to patients were comparable in both groups. The study results allow concluding that GOSO is effective and safe DPP-4 inhibitor for treatment of DMT2.

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Supported By: AstraZeneca POSTERS Therapeutics 1271-P Clinical Diabetes/ TTP399, a Liver Selective Glucokinase Activator, Increases Effi cacy of Currently Marketed Therapies for Type 2 Diabetes CARMEN VALCARCE, TUNG M. FONG, High Point, NC, Somerset, NJ Glucokinase (GK) is an enzyme localized primarily in the liver and pancre- atic β-cells and acts as a glucose sensor to elicit glucose specifi c responses from the respective cell types. In the liver, GK is a major regulator of glucose metabolism. TTP399 is an oral, liver-selective GK activator (GKA) in clinical development for the treatment of type 2 diabetes mellitus (T2DM). At antici- pated therapeutic concentrations, TTP399 stimulates the liver to metabolize 1270-P glucose while inducing little or no insulin secretion, thus providing an attrac- Saxagliptin Effi cacy and Safety in Patients with Moderate Renal tive safety profi le by greatly reducing the risk of hypoglycemia. Impairment To determine if TTP399 can provide added benefi t to currently marketed SHIRA PERL, WILLIAM COOK, CHERYL WEI, NAYYAR IQBAL, BOAZ HIRSHBERG, therapies, suboptimal doses of TTP399 and current therapies were combined in Gaithersburg, MD, Princeton, NJ subchronic in vivo models of diabetes. Results from these studies demonstrate Type 2 diabetes (T2D) is the leading cause of chronic kidney disease (CKD) that combining TTP399 with metformin, sitagliptin, or exenatide shows additive in the U.S. with estimates suggesting that ~40% of individuals with T2D have and/or synergistic effects on reducing postprandial glucose, increasing insulin some evidence of CKD. A recent analysis of the NHANES (1999-2012) database sensitivity and/or reducing body weight without causing hypoglycemia. All com- reported that 12.9% of T2D patients had estimated glomerular fi ltration rates binations studies were safe and well tolerated indicating that TTP399 is ideal for (eGFR) in the upper range of moderate CKD (>45 and <60 mL/min/1.73 m2). The combination with currently-marketed therapies for type 2 diabetes. recommended dose of saxagliptin (SAXA) is 2.5 mg in patients with moderate Table. or severe renal impairment. In this post hoc analysis, we assessed the effect of SAXA 2.5 and 5 mg vs. control on glycemic measures in patients with T2D and Combination Animal Model Main Results eGFR 45-60mL/min/1.73m2 as measured by MDRD. Effi cacy data were pooled TTP399 + metformin ob/ob mice ·Additive in reducing postprandial glucose from 9, 24-week, randomized, placebo-controlled clinical trials, and safety was ·Synergistic in increasing insulin sensitivity assessed in a pool of 20 randomized trials with data from 4-206 weeks. The ma- ·Synergistic in reducing body weight jority of patients were women aged <65 years; half of the patients had a T2D du- TTP399 + sitagliptin DIO rats · Synergistic effect in reducing body weight ration ≥5 years (Table). Adjusted mean change from baseline in A1C was reduced TTP399 + exenatide ob/ob mice ·Additive in reducing glucose to a signifi cantly greater extent with SAXA 2.5 and 5 mg vs. control (Table). There ·Synergistic in increasing insulin sensitivity were numerically greater reductions in 2-hour postprandial glucose (PPG) and · Additive in reducing body weight fasting plasma glucose (FPG) and a greater proportion of patients achieved A1C <7% with SAXA 2.5 and 5 mg vs. control. Incidence of hypoglycemia was similar across treatment groups. These results suggest that SAXA improves glycemic 1272-P control and is generally well tolerated in patients with T2D and moderate CKD. Which Should Be a First-Line Medication, Metformin or DPP-4 Table. Inhibitor in Japanese Diabetic Patients? Comparison of the Two Medications in Terms of Glycemic Control and Treatment Duration as a Monotherapy TAKESHI HORII, YUSUKE KABEYA, MASUOMI TOMITA, TAKESHI KATSUKI, YO- ICHI OIKAWA, JYUNICHI SHIMIZU, AKIRA SHIMADA, Tokyo, Japan Metformin (MET) has been stated as a fi rst-line drug for the treatment of type 2 diabetes in the ADA/EASD guidelines. However, nowadays, DPP- 4 inhibitors are widely used as a fi rst-line drug in Japan. The aim of the study was to compare patients who started MET or sitagliptin (SITA) as a fi rst-line drug in terms of glycemic control and duration of treatment as a monotherapy in Japanese diabetic patients. We recruited type 2 diabetic patients who started MET (MET group n=791) or SITA (SITA group n=251) as a fi rst-line drug between January 2008 and November 2012. They were followed for up to 96 weeks. Differences in treatment duration of monotherapy between the SITA and MET groups

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A330 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS were assessed using Kaplan-Meier curves. To estimate the hazard ratio (HR) patient; 3+: 1 patient; 4+: 8 patients). Furthermore, Klebsiella pneumoniae (K. of treatment failure as a monotherapy among the SITA group in relation to pneumoniae) were seen in 3 patients before the administration. Six months the MET group, we constructed a Cox proportional hazard model, having after, K. pneumoniae were lower level of detection in 2 of whom whereas adjusting for age, gender, diabetes duration, BMI and baseline HbA1c levels. they thrived (4+) in 1 of whom. Besides, K. pneumoniae (4+) were found in At baseline, age, BMI and diabetes duration were signifi cantly different be- another patient at the end of the administration period. Although the ad- tween the two groups (MET vs. SITA age: 62.8 vs. 67.5 years, BMI: 25.6 vs. ministration of luseoglifl ozin was stopped temporarily in one patient for the 23.6 kg/m2, diabetes duration: 9.2 vs. 7.9 years). HbA1c levels were similar apparent infection of C. glabrata during this study, the administration was (MET vs. SITA 8.0±1.3 vs. 8.0±1.4%). At 24, 48, 72 and 96 weeks, the SITA continued because this infection was recovered with antibacterial agents. group had signifi cantly lower HbA1c levels as compared to MET group (MET These results suggest vigilance against intravaginal proliferation of Candida vs. SITA 24W 7.3±1.0 vs. 6.9±0.7%, 48W 7.4±1.0 vs. 7.0±0.7%, 72W 7.3±0.9 and E. coli in luseoglifl ozin-administered patients, whereas luseoglifl ozin has vs. 7.0±0.7%, 96W 7.4±1.0 vs. 7.0±0.8%). The treatment duration as a mono- benefi cial effects on glycemic control and body weight gain in the patients therapy in the SITA group was longer than the MET group (HR 0.71, 95% CI with type 2 diabetes. 0.55-0.93, log rank p<0.01). This study shows that SITA could achieve lower HbA1c levels and longer 1275-P duration of treatment as a monotherapy than MET when it was used as a Baseline Fasting Plasma Glucose May Predict Response to Dapa- fi rst-line medication in Japanese patients. We think that this data can be glifl ozin When Added to Metformin extended to other Asian diabetics who have lower insulin secretion capacity KATJA ROHWEDDER, EVA JOHNSSON, Wedel, Germany, Mölndal, Sweden as compared to Caucasian population. Dapaglifl ozin (DAPA) is a highly selective, orally active SGLT2 inhibitor that increases urinary glucose excretion and reduces hyperglycemia indepen- 1273-P dently of insulin. In a 52-week, double-blind, active-controlled, non-inferiori- Comparison of the Effi cacy on Glucose Control and β-Cell Function ty trial (NCT00660907), patients (pts) with T2DM inadequately controlled on between DPP-4 Inhibitors Treatment and AGI Treatment in Patients metformin were randomized to DAPA (≤ 10 mg/d; n=406) or glipizide (GLIP; with Type 2 Diabetes ≤ 20 mg/d; n=408). As previously reported, the response rate (reduction in XIAOLING CAI, XUEYAO HAN, WENJIA YANG, LINGLI ZHOU, LINONG JI, Beijing, HbA1c and body weight [BW] from baseline [BL] to 52 weeks) was signifi - China cantly higher in the DAPA group (66.9 vs. 21.3% [difference, 45.7%; 95% CI, 1

The aim of this study is to compare the effi cacy and safety of DPP-4 in- 39.3-51.6%]). We report the results of a post hoc analysis of BL factors, POSTERS hibitors treatment with AGI treatment in patients with type 2 diabetes by which may predict response to DAPA (C-peptide; fasting plasma glucose Therapeutics meta-analysis. [FPG]; C-peptide: FPG ratio; estimated glomerular fi ltration rate). In both Clinical Diabetes/ Studies were identifi ed by search of MEDLINE, EMBASE and CENTRAL un- arms, response rate increased as BL FPG increased (Table). Differences in til Dec 2014. The inclusion criteria were: 1) randomized controlled trial with response rate between BL FPG categories were signifi cant for DAPA catego- the aim of comparisons between DPP-4 inhibitors and AGI; 2) study length ries < 141 vs. ≥ 173 mg/dL (difference, 20.0%; P<0.001) and for ≥ 141-< 173 ≥12 weeks; 3) changes in HbA1c or fasting plasma glucose was assessed. vs. ≥ 173 mg/dL (difference, 11.8%; P=0.044) but not for any GLIP categories. 6 RCTs were appropriate for inclusion. Treatment with a DPP-4 inhibitor In both groups (full analysis set), greater HbA1c decreases occurred with was received by 1055 patients while an AGI treatment was received by 844 higher BL FPG. BW change showed no obvious pattern with BL FPG. These patients, with a comparable baseline BMI of 25.5±1.3 kg/m2and mean base- data suggest that BL FPG may predict the likelihood of combined HbA1c and line HbA1c 7.83±0.53%. When compared with AGIs, treatment with DPP-4 BW reduction in DAPA-treated T2DM pts. inhibitors led to a signifi cantly greater change from baseline in HbA1c levels 1 Rohwedder K, et al. Diabetes. 2013;62(Suppl 1):236-OR. (−0.35%; 95% CI, −0.54 to −0.15, p<0.0001) and FPG levels (−0.51 mmol/L; Table. 95% CI, −1.00 to −0.03, p=0.04), and it was associated with a signifi cantly greater increase in weight change (0.93 kg; 95% CI, 0.52 to 1.34, p<0.001). Baseline FPG DAPA GLIP (mg/dL) (N=400 ) (N=401 ) Treatment with DPP-4 inhibitors was associated with a signifi cantly greater increase in fasting insulin level (0.64 µU/mL; 95% CI, 0.40 to 0.89, p<0.0001) Outcome n Outcome n as well as an improvement of HOMA-β compared with AGI treatment (5.43; Response rate (%)* Response rate (%)* 95% CI, 1.01-9.85, p=0.02). HOMA-IR decrease from baseline was compa- < 141 57.5 127 17.3 133 rable with DPP-4 inhibitors and AGI treatment (0.05; 95% CI, −0.25 to 0.35, 141 to < 173 65.7 143 21.3 122 p=0.75). Compared with AGIs (813 participants), treatment with DPP-4 inhib- ≥ itors (1031 participants) was associated with a signifi cantly lower incidence ≥ 173 77.5 129 24.8 145 of drug-related AE (OR, 0.48; 95% CI, 0.36-0.64, p<0.0001). Change from BL in HbA1c, mean ± SD (%) This meta-analysis indicated the effi cacy on glucose control and the im- < 141 −0.26 ± 0.58 128 −0.20 ± 0.92 135 provement of β-cell function in DPP-4 inhibitors treatment were superior to 141 to < 173 −0.44 ± 0.70 142 −0.52 ± 0.94 122 those with AGI treatment, with lower incidence of drug-related AE. ≥ ≥ 173 −0.83 ± 0.82 129 −0.84 ± 1.08 143 1274-P Change from BL in weight, mean ± SD (kg) Effects of a Novel SGLT2 Inhibitor Luseoglifl ozin on Intravaginal < 141 −2.94 ± 3.87 128 1.57 ± 3.20 135 Bacteria and Fungi ≥ 141 to < 173 −2.89 ± 3.33 142 1.63 ± 3.11 122 MASATAKA KUSUNOKI, YUKIE NATSUME, DAISUKE SATO, YUKA YAMAGISHI, ≥ 173 −3.88 ± 3.76 129 1.18 ± 3.69 143 HIROYUKI SUEMATSU, HIDEYO TSUTSUI, YOSHIHARU OSHIDA, TAKAO NAKA- MURA, HIROSHIGE MIKAMO, Nagoya, Japan, Yamagata, Japan, Nagakute, Japan, SD, standard deviation; *proportion of patients with reduction in HbA1c Tokyo, Japan and BW from BL to 52 weeks. Sodium-glucose co-transporter-2 (SGLT2) inhibitor, which is known as a Supported By: AstraZeneca novel anti-diabetic agent, enhances glucose excretion in urine, and reduces blood glucose. However, the glucose-rich urine might cause urinary-tract 1276-P and genital infection. In the present study, we administered luseoglifl ozin Slope of Decline in HbA1c with Empaglifl ozin Appears to Be Greater (2.5 mg/day) to 26 Japanese female patients with type 2 diabetes (52 ± 13 than the Slope with Sitagliptin or Glimepiride in Patients with Type years old) for 6 months, and examined the intravaginal fl uid for bacteria and 2 Diabetes (T2DM) fungi. Six-month administration of luseoglifl ozin increased urinal glucose in RALPH A. DEFRONZO, ULRICH ELSASSER, SØREN S. LUND, THOMAS HACH, San all the patients, and signifi cantly reduced HbA1c level and body weight (P < Antonio, TX, Ingelheim, Germany 0.01, respectively). Before the administration, Candida (1+) were found in 3 The higher baseline HbA1c, the greater the reduction in HbA1c observed with patients. After the administration period, Candida proliferated in 9 patients antidiabetes agents. However, data on differences between agents are limited. (C. albicans in 6 patients [2+: 2 patients; 4+: 4 patients]; C. glabrata [4+] in 2 Two Phase III studies evaluated empaglifl ozin (EMPA) 10 mg and 25 mg as mono- patients; C. krusei [4+] in 1 patient). In addition, Escherichia coli (E. coli) were therapy compared with placebo or sitagliptin (SITA) 100 mg/day for 24 weeks and also seen in 5 patients (1+: 3 patients; 2+: 2 patients) before the administra- EMPA 25 mg compared with glimepiride (GLIM) 1-4 mg/day as add-on to met- tion. Although E. coli were not detectable level in 3 of whom 6 months later, formin for 104 weeks in patients with T2DM. We analyzed the effect of baseline they were found in 10 patients at the end of the administration period (2+: 1 HbA1c on the reduction in HbA1c with EMPA compared with SITA or GLIM.

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Steeper slopes of HbA1c decline were observed with EMPA 10 or 25 mg vs. 1278-P SITA monotherapy at week 24 (Figure). Regression analysis showed slopes Effi cacy and Safety of Dapaglifl ozin in Patients with T2DM Inad- of -0.59 (95% CI -0.70, -0.47), -0.49 (95% CI -0.62, -0.37) and -0.29 (95% CI equately Controlled on Metformin Plus Sulfonylureas According to -0.42, -0.15) for EMPA 10 mg, EMPA 25 mg and SITA, respectively (p<0.001 Background Sulfonylurea and p<0.05 for EMPA 10 mg and EMPA 25 mg, respectively, vs. SITA). Sim- STEPHAN MATTHAEI, KEITH BOWERING, KATJA ROHWEDDER, ANKE GROHL, ilarly, a steeper slope of HbA1c decline was observed with EMPA 25 mg EVA JOHNSSON, Quakenbrück, Germany, Edmonton, AB, Canada, Wedel, Germany, vs. GLIM as add-on to metformin at week 52 (Figure). Regression analysis Cologne, Germany, Mölndal, Sweden showed slopes of -0.52 (95% CI -0.59, -0.44) and -0.32 (95% CI -0.39, -0.25) Metformin (MET) and sulfonylureas (SUs) are commonly used in combina- for EMPA 25 mg and GLIM, respectively (p<0.001 for EMPA 25 mg vs. GLIM); tion therapies for type 2 diabetes mellitus (T2DM). Dapaglifl ozin (DAPA) is these results were consistent with those at week 104. a sodium glucose co-transporter 2 inhibitor that reduces hyperglycemia by In conclusion, incremental reductions in HbA1c with increasing baseline increasing urinary glucose excretion. A 24-week, Phase 3, double-blind study HbA1c appear to be greater with EMPA compared with SITA or GLIM in pa- previously evaluated the effi cacy and safety of DAPA 10 mg (N=108) vs. pla- tients with T2DM. cebo (PBO [N=108]) in patients with T2DM inadequately controlled with MET plus SU. In this post hoc analysis, we evaluated the effi cacy and safety of DAPA according to SU received (gliclazide [Glc], glimepiride [Glm], or gly- buride [Gly]; each of which has a distinct profi le). Baseline characteristics were balanced across SU groups. Signifi cant reductions in HbA1c and body weight were noted with DAPA vs. PBO with all SUs, with greater PBO-ad- justed reductions observed with Gly vs. other SUs (Table). DAPA signifi cantly reduced seated systolic blood pressure in the Glc subgroup only. Overall AEs and AEs of hypoglycemia were greater with Gly than with Glc or Glm. In sum- mary, although DAPA had a predictable effi cacy and safety profi le in patients with T2DM inadequately controlled with MET plus SU, this post hoc analysis in a small number of patients revealed some differences in HbA1c response and hypoglycemic AEs with Gly compared with the other SUs examined. POSTERS

Therapeutics Table. Safety and Effi cacy Outcomes after 24 Weeks.

Clinical Diabetes/ PBO + MET + SU DAPA 10 mg + MET + SU Glc (N=50) Glm (N=46) Gly (N=12) Glc (N=40) Glm (N=52) Gly (N=16) Baseline* Age, Yrs 60 (9.7) 61 (9.1) 64 (7.5) 62 (11.0) 61 (7.9) 61 (11.8) Diabetes duration, Yrs 9.2 (6.6) 9.7 (6.2) 11.2 (4.0) 9.2 (6.5) 8.9 (6.3) 10.6 (7.3) Fasting C-pep, mg/dL 2.4 (1.0) 2.7 (0.9) 2.8 (1.1) 2.7 (1.2) 2.4 (1.0) 2.5 (1.1) Safety data – – – – – – ≥1 AE, n/N (%) 27/51 (52.9) 21/46 (45.7) 8/12 (66.7) 20/41 (48.8) 22/52 (42.3) 11/16 (68.8) Supported By: Boehringer Ingelheim/Eli Lilly and Company ≥1 hypo, n/N (%) 1/51 (2.0) 1/46 (2.2) 2/12 (16.7) 5/41 (12.2) 5/52 (9.6) 4/16 (25.0) HbA1c, % – – – – – – 1277-P n 50 46 12 40 52 16 An Approach to Reporting Pooled HbA1c Reductions to Maximize BL mean (SD) 8.2 (0.9) 8.2 (0.9) 8.6 (0.7) 8.0 (1.0) 8.2 (0.9) 8.0 (0.8) the Accuracy of Between-Drug Comparisons: HbA1c Reductions PBO-corrected adj – – – −0.6 −0.7 −1.0 mean Δ BL – – – (−1.0, −0.3) (−0.9, −0.4) (−1.4, −0.5) with Vildagliptin Monotherapy (95%CI) – – – – – – MARC EVANS, ANJA SCHWEIZER, JAMES E. FOLEY, Cardiff, United Kingdom, Ba- sel, Switzerland, East Hanover, NJ Body weight, kg – – – – – – n 50 46 12 40 52 16 Several meta-analyses have compared the relative effi cacy of DPP-4 BL mean (SD) 88.8 (15.4) 91.7 (17.3) 89.2 (15.7) 87.2 (16.7) 90.5 (19.0) 85.7 (15.0) inhibitors by assessing HbA1c change (Δ) from baseline (BL). Such com- PBO-corrected adj – – – −2.3 −1.6 −2.5 parisons are limited by differences in BL HbA1c, potential interactions with mean Δ BL – – – (−3.2, −1.4) (−2.9, −0.4) (−4.9, −0.1) other oral antidiabetic agents (OADs), dosage, and treatment duration. Com- (95%CI) – – – – – – bined, these factors infl uence both the magnitude and variability of ΔHbA1c. SBP, mmHg – – – – – – We aimed to assess the effi cacy of vildagliptin monotherapy independent n 49 46 11 40 52 16 of these confounding factors. Data from 7 randomized controlled trials of BL mean (SD) 132.5 (13.6) 138.7 (14.5) 143.6 (12.5) 132.1 (14.2) 136.1 (12.1) 135.3 (9.0) vildagliptin monotherapy (50 mg bid) with HbA1c assessments at Week 24 PBO-corrected adj – – – −5.3 −2.9 −3.2 were pooled. The effect of BL HbA1c variability was reduced by stratify- mean Δ BL – – – (−10.1, −0.4) (−7.8, 2.1) (−12.3, 6.0) ing patients into ≤7%, >7-≤8%, >8-≤9%, >9-≤10% and >10% groups. Mean (95%CI) – – – – – – ΔHbA1c at Week 24 is reported. Data from 2079 patients (mean age 53.8 *Values are mean (SD). Effi cacy results exclude data after rescue; safety years; BMI 30.7 kg/m2; T2DM duration 2.1 years) were pooled. Mean ΔHbA1c results include data after rescue. Adj, adjusted; AE, adverse event; BL, was almost two-fold higher when the BL HbA1c was >10% vs. >8-≤9% baseline; Δ BL, change from baseline; CI, confi dence interval; DAPA, dapa- (-2.1 ± 0.1 vs. -1.2 ± 0.0%, respectively). From a BL >7-≤8%, at which mono- glifl ozin; Glc, gliclazide; Glm, glimepiride; Gly, glyburide; hypo, hypoglyce- mia; MET, metformin; n, number of patients; PBO, placebo; SBP, systolic therapy is often initiated, mean ΔHbA1c was -0.7% (Table). These data il- blood pressure; SD, standard deviation; Yrs, years. lustrate the importance of accounting for BL HbA1c when reporting HbA1c reductions. They also show, in a large sample size, that vildagliptin 50 mg bid Supported By: AstraZeneca has good effi cacy as an OAD monotherapy. Table. Effi cacy by Baseline HbA1c. 1279-P Urinary Glucose Excretion and Insulin to Carbohydrate Ratio to n Baseline HbA1c Mean baseline Mean HbA1c change range (%) HbA1c (%) from baseline (%) Assess Insulin Dose Adjustments in T1DM Subjects Treated with Dapaglifl ozin 28 ≤7 6.9 ± 0.0 -0.5 ± 0.2 LARS HANSEN, CHRISTIAN SONESSON, FREDRIK A.V. THORÉN, AGATA A. PTA- 711 >7-≤8 7.7 ± 0.0 -0.7 ± 0.0 SZYN SKA, NAYYAR IQBAL, EVA JOHNSSON, Princeton, NJ, Mölndal, Sweden 670 >8-≤9 8.5 ± 0.0 -1.2 ± 0.0 Dapaglifl ozin (DAPA) is a selective sodium-glucose co-transporter 2 inhibi- tor that lowers HbA1c, body weight and systolic blood pressure in subjects 469 >9-≤10 9.5 ± 0.0 -1.8 ± 0.1 with T2DM. DAPA has previously been shown to be safe and well tolerated 201 >10 10.6 ± 0.0 -2.1 ± 0.1 in a 14 day study (NCT01498185) in subjects with T1DM. We hypothesized Data are expressed as mean ± standard error. that carbohydrates (CHO) counted as 24h urinary glucose excretion (UGE) n, number of patients with assessments at both baseline and Week 24. after 7 days’ DAPA treatment in subjects with T1DM (NCT01498185) or as Supported By: Novartis UGE estimated from a DAPA dose-response model could be used to derive

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A332 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS an insulin to CHO ratio (I/C) to assess insulin dose adjustment in response function tests. Metformin was discontinued during hospitalization and patients to DAPA treatment in T1DM. Data on total daily insulin dose (TDD) were divided into two groups in a randomized controlled manner. Control group re- from study NCT01498185 or arbitrarily chosen to represent “low” or “high” ceived SC Insulin injections to control blood glucose values below 140 mg/dl or insulin dose. Insulin prediction factor 450 = TDD x I/C (for adults on short 180 mg/dl postprandial. Study group received SC Insulin and Vildagliptin with acting insulin) was applied to derive I/C. TDD adjustment was calculated the same target. GFR > 50 ml/min patients received Vildagliptin 50mg x 2/day; as UGE:I/C. Empirically, there was agreement between observed mean TDD GFR < 50 ml/min received 1/day. Creatinine values were measured and GFR adjustment (NCT01498185) and I/C-calculated mean TDD adjustment using calculated (MDRD GFR Equation) on admission (before cardiac catheterization), either observed mean UGE (NCT01498185) or estimated mean UGE from the on discharge and 30 days after discharge. Data were documented: creatinine DAPA dose-response model (Table). In conclusion, UGE and I/C can be used values, urea values, and calculated GFR. The two groups differed in GFR change to assess mean reduction in TDD upon initiation of DAPA. Further assess- between admission and discharge (F(1, 46)=3.16, p=0.08). The mean±SD val- ments are needed to evaluate the impact of subject characteristics such as ues of GFR in controls declined signifi cantly (t(22)=1.94, p=0.06) from admis- estimated GFR and average plasma glucose on individual TDD adjustment. sion 77.6±30.5 ml/min to discharge 70.9±23.8 ml/min vs. Study group, changed Table. (t(24)=0.53, p=0.60) from 69.72±20.6 ml/min to 71.4±27.3 ml/min. Administra- tion of Vildagliptin to diabetics hospitalized for ACS, even with cardiac catheter- Method of assessment Mean 24h Mean BL I/C = 450/ Mean daily INS ization, did not impair kidney function or lead to Acute Renal Failure (ARF). There UGE (g) TDD (IU) TDD (g/IU) dose red. (%) was no deterioration in kidney function 30 days after discharge. NCT01498185 observed Observed Supported By: Novartis DAPA 5 mg (n=14) 71.25 39.36 19 DAPA 10 mg (n=13) 88.02 55.14 17 NCT01498185 calculated Calculated 1282-P DAPA 5 mg (n=14) 71.25 39.36 11.43 16 Effect of Metformin on Thyroid Function in Type 2 Diabetic Patients DAPA 10 mg (n=13) 88.02 55.14 8.16 20 PENG LI, Nanjing, China Context: Metformin, an oral antidiabetic compound, is regarded as a fi rst- Model estimated UGE Modeled DAPA 10 mg 80.00 18 (low) 25.00 18 line drug for treatment of T2DM, and acts primarily by suppressing hepatic DAPA 10 mg 80.00 63 (high) 7.14 18 gluconeogenesis via activation of AMPK. In rat experiments, metformin levels in the pituitary gland are substantially increased. Recent studies suggest that BL, baseline; INS, insulin; red., reduction; TDD, total daily insulin dose; UGE,

metformin suppresses pituitary TSH secretion without signs of hyperthyroid- POSTERS urinary glucose excretion. Therapeutics ism or changes in FT4 and FT3 in patients with type 2 diabetes, but contrasting Supported By: AstraZeneca results are reported in different settings. Clinical Diabetes/ Objective: The aim of this retrospective study was to assess the effect of 1280-P metformin treatment on thyroid function in T2DM with or without thyroid dys- Acetyl-CoA Carboxylase Inhibition by ND-630 Reduces Hepatic function. Steatosis and Delays Diabetes Progression in ZDF Rats Research and Design Methods: We performed a retrospective cohort study GERALDINE HARRIMAN, JEREMY GREENWOOD, SATHESH BHAT, WILLIAM F. WEST- of 169 men and 176 women with type 2 diabetes treated with metformin alone LIN, ROSANA KAPELLER, H. JAMES HARWOOD, Cambridge, MA, New York, NY or combined with other antidiabetic drugs. Among them 36 patients in overt or Simultaneous inhibition of the acetyl-CoA carboxylase isozymes, ACC1&2, subclinical hypothyroidism, others were euthyroid patients. Peripheral blood results in concomitant inhibition of fatty acid synthesis (FASyn) and stimulation samples were collected and analyzed for the effects of metformin on thyroid of fatty acid oxidation (FAOxn) and may favorably affect obesity, diabetes, and axis hormones. fatty liver disease. We recently identifi ed a unique series of potent and effi - Results: After metformin treatment, a slight but signifi cant reduction in cacious allosteric ACC inhibitors, using state-of-the-art structure-based drug TSH levels was found in 21 patients with overt or subclinical hypothyroidism design with crystal structures of the human ACC biotin carboxylase domain, (P<0.01). The euthyroid patients not receiving L-T4, no changes in TSH levels that interacts within the subunit dimerization site of the enzyme to prevent were reported after treatment with metformin (P>0.05). No signifi cant chang- dimerization and inhibit enzymatic activity. We also previously reported that es in free T4 (FT4) and free T3 (FT3) were observed in any group (P>0.05). a representative analog of this series, ND-630, inhibits ACC dimerization, inhib- Conclusions: Metformin induces a reduction in TSH levels in overt or subclini- its the activity of human ACC1&2 (IC50 2.0nM), inhibits FASyn and stimulates cal hypothyroidism in patients with type 2 diabetes without change of FT4 and FAOxn in cultured cells, and inhibits rat liver FASyn (ED50 0.14mg/kg) and stimu- FT3. In contrast, no change in TSH levels is found in euthyroid patients. Future lates rat whole body FAOxn in vivo. ND-630 exhibits favorable drug-like proper- studies will be needed to reevaluation of thyroid function in these patients. ties and is highly effective in reducing hepatic steatosis, improving insulin sen- sitivity, and favorably affecting dislipidemia in both high-sucrose and high-fat 1283-P diet-induced obese rats. We now report that ND-630, administered orally twice Vildagliptin with Metformin: Results from a 1-Year Observational daily at doses of 0.5, 1.5 and 5 mg/kg to 8-wk old ZDF rats for 37 days as they Study in Real-Life Russian Clinical Settings progress from prediabetes to overt diabetes, dramatically and dose-depend- ALEXEY ZILOV, AIDA EMIROVA, Moscow, Russian Federation ently improved hepatic steatosis and delayed the onset of changes associated Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by with diabetes. In this regard, ND-630 treated, but not vehicle-treated animals hyperglycemia and insulin resistance. Metformin is an established fi rst-line had increased insulin secretion and reduced glucose excursion in response to a monotherapy, but treatment intensifi cation is required over time due to the glucose challenge, suggestive of beta-cell preservation. Finally, ND-630 did not progressive nature of the disease. exacerbate the hyperglycemia of overtly diabetic animals, as had been previ- The aim of this real-life, observational, non-interventional program was ously suggested from studies in ob/ob mice with the active-site proximal ACC to assess response, defi ned as the number of patients with T2DM achieving inhibitor, CP-640186. Together, these observations suggest that allosteric ACC HbA1c <7% without hypoglycemia or weight gain (>3% of baseline), when inhibitors may favorably affect obesity, diabetes, and fatty liver disease. adding vildagliptin to metformin, or using a fi xed-dose combination of vilda- gliptin + metformin. Patients had HbA1c >7% at baseline and were followed 1281-P up for 12 months. Renal Safety in ACS Patients with Galvus (Vildagliptin) Treatment 5231 patients were enrolled at 376 sites in Russia. 63% of patients were IDIT DOBRECKY-MERY, ADIR SOMER, HAMMOUD MAHMOD, EUGENY RADIZ- female and the mean age was 56.4 years. ISHEVSKY, ELENA RIVLIN, NADIA GOLDBERG, URI ROSENSCHEIN, Haifa, Israel Overall response rate was 56.5%. Mean HbA1c decreased from 8.2 to One-third of diabetic patients exhibit impaired kidney function and low Glom- 6.8%, and FBG from 8.5 to 6.3 mmol/L. BMI did not decrease signifi cantly. erular Filtration Rate (GFR). Diabetics hospitalized for ACS are likely to undergo Weight loss of >3%, >5% and >8% was reported in 46.6%, 26.7% and 10.3% cardiac catheterization using IV contrast. Contrast-induced acute kidney injury of patients, respectively. is defi ned by absolute (0.5 mg/dL) or relative increase (25%) in serum creati- Hypoglycemia was reported in only 0.8% of subjects. Adverse events nine (SCr) 48-72 hours after contrast administration. Cessation of Metformin (AEs) were reported infrequently (4.6% of patients); other than hypoglyce- is recommended 48 hours prior to catheterization, placing patients at risk for mia, the most common AEs were gastrointestinal in nature. Hyperglycemia. Vildagliptin, an oral anti-diabetic drug of the DPP-4 inhibitor This long-term observational study shows that vildagliptin added to met- class, provides glycemic control in patients with T2DM and CKD. We assessed formin provides effective and sustained glycemic control and is well-tolerat- Vildagliptin for glycemic control in 58 T2DM adult patients naïve to DPP4 In- ed over 12 months in the real-world setting in Russia. hibitors upon admission to ICCU with ACS diagnosis, while monitoring kidney Supported By: Novartis

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1284-P 1286-P LGLS120-A, a Potent, Selective, and Structurally Novel GPR120 Comparison of Vildagliptin and Glimepiride on Glycemic Variability Agonist, Provides Superior Glycemic Control to DPP-4 Inhibitor in and Cardiovascular Risk Factors Animal Model of Type 2 Diabetes KYEONG SEON PARK, MIN KYEONG KIM, LEE-KYUNG KIM, JI WON YOON, SOO BYUNG GYU KIM, Daejeon, Republic of Korea HEON KWAK, YOUNG MIN CHO, KYONG SOO PARK, SEONG YEON KIM, HYE GPR120 is the functional receptor for the free fatty acids. Several known SEUNG JUNG, Seoul, Republic of Korea GPR120 agonists have shown their activity on the glycemic control via in- DPP-4 inhibitors improve glycemic variability by inducing glucose-depen- sulinotropic action and improvement of insulin resistance. DPP-4 inhibitors dent insulin secretion and lowering postprandial glucose levels. Because are widely used as an oral glucose lowering agent, however, the combina- glycemic variability was suggested to be an independent risk factor for car- tion of these with other anti-diabetes drugs are strongly preferred due to diovascular disease (CVD) in diabetic patients, we aimed to evaluate the their limited effi cacy. Herein, we showed that LGLS120-A, a small molecule differences of glycemic variability between a DPP-4 inhibitor and a sulfony- agonist for GPR120, has superior effi cacy to a DPP-4 inhibitor, sitagliptin, in lurea, and various risk factors for CVD between the agents, and their rela- diet-induced obesity (DIO) mouse model of type 2 diabetes. LGLS120-A is a tionship with the glycemic indices. selective, potent and orally available GPR120 agonist with a low-nanomalar We designed a randomized, open-labeled, prospective, cross-over trial. EC50 value in CHO-GPR120 cell line. Obesity was induced in C57/BL6 mouse Thirteen patients with type 2 DM whose HbA1c was over 7% on metformin by feeding high-fat-diet for 16 weeks. After that, LGLS120-A or sitagliptin monotherapy were randomized to vildagliptin 50 mg twice a day or glimepir- was orally administered to DIO mice once a daily for 28 days. OGTT and ide 1 mg twice a day for 12 weeks, and then switched to the other drug for HbA1c measurement were performed on day 1 and day 28. As a result, both another 12 weeks. At the baseline and at each 12 week, glycemic variability LGLS120-A and sitagliptin treatment signifi cantly reduced glucose AUCs indices and CVD markers were measured and the CGMS was applied for 3 without any signifi cant difference between two groups. Despite the simi- days. lar levels of glucose AUC in OGTT, LGLS120-A treatment showed superior The subjects were 59 years old, having 6 years of DM duration and 26 effi cacy to sitagliptin in HbA1c level and reduced signifi cantly insulin level kg/m2 of BMI, under 1,334mg/day of metformin in average. After 12-week indicating the improvement of insulin resistance. Detailed analysis of infl am- treatment, both agents signifi cantly decreased HbA1c similarly. Vildagliptin mation profi le showed elevated mRNA expression and secretion of infl am- also decreased glycemic variability indices (MAGE, SD, and CONGA), while matory cytokine in liver and adipose tissues in LGLS120-A treatment group. glimepiride did not. As a result, CONGA and SD were different between the Taken together with its proved insulin secretion activity, it appears that the agents after 12-week treatment (p<0.05 and p=0.063, respectively), but the POSTERS Therapeutics overall superior glycemic control of LGLS120-A to sitagiptin over experimen- CVD risk factors such as hsCRP, BNP, LP(a) and PAI-1 were not different be- Clinical Diabetes/ tal period presumably results from its dual effects - insulinotropic effect and tween the agents. When we performed correlation analyses, decrease in improvement of insulin resistance. In conclusion, all these fi ndings suggests the glycemic variability was associated with reduced CVD markers, irrespec- that LGLS120-A could be a novel class of glucose-lowering agent that simul- tive of agents. Both agents increased body weight, and the weight changes taneously targets both insulin reistance and insulin defi ciency. were correlated with increment of PAI-1 and BNP. Weight gain could have interfered with any favorable effects of attenuated glycemic variability. 1285-P In conclusion, the difference in glycemic variability between vildagliptin Patient Characteristics of Sodium-Glucose Co-transporter 2 Inhibi- and glimepiride did not affect CVD markers during 12-week treatment, de- tors Initiators with Type 2 Diabetes Mellitus: A U.S. Claims Data- spite the improvements in glucose levels and glycemic variability. base Analysis SHENGSHENG YU, CHUN-PO STEVE FAN, ZHIYI LI, BECKY HANNA, JACKSON 1287-P TANG, JEAN WILLIAMS, Rahway, NJ, Hong Kong, China Effi cacy of Naltrexone/Bupropion, Administered as Recommended Sodium-glucose co-transporter 2 inhibitor (SGLT-2i) is a new class of in Clinical Practice, Compared with Usual Care oral antihyperglycemic agent (OAH) used to treat type 2 diabetes mellitus THOMAS A. WADDEN, BRANDON WALSH, AMY E. HALSETH, KEVIN SHAN, (T2DM). A retrospective study using MarketScan database was conducted KENNETH FUJIOKA, Philadelphia, PA, La Jolla, CA to understand characteristics of patients initiating SGLT-2i compared to Sustained-release naltrexone/bupropion (NB) is approved in the United those initiating other OAHs. States for chronic weight management as an adjunct to diet and physical Patients who initiated an OAH (index date) between 3/29/2013 and activity. Phase 3 studies demonstrated signifi cantly greater weight loss 6/30/2013, were ≥18 years old as of the index date, had continuous enroll- with NB vs. placebo in the setting of both standard and intensive lifestyle ment for ≥1 year before (baseline) and ≥90 days after the index date, were modifi cation counseling. The current study examined the effects of NB included. Those with T1DM, gestational or secondary diabetes, pregnancy, (32mg/360mg) combined with a commercially-available telephone/web- or metformin use for polycystic ovarian syndrome, were excluded. Patients based lifestyle intervention program, compared with usual care (UC; pe- were assigned to SGLT-2i and non-SGLT-2i cohorts based on their index drug. riodic diet and exercise advice), in overweight/obese subjects. Consistent Between-group differences were assessed using Wilcoxon rank-sum tests with prescribing information, this study prospectively required NB subjects for continuous variables and χ2 tests for categorical variables. to exhibit ≥5% weight loss at Week 16, with no sustained increase in blood 69,511 patients were included, of which 2.8% initiated an SGLT-2i and pressure, to continue treatment. Analyses were performed on subjects who 97.2% other OAHs. 14.2% of SGLT-2i patients received SGLT-2i monotherapy remained on treatment through Week 26 (per protocol [PP] population), and and 9.5% escalated their dose from 100 to 300 mg within 90 days. Com- on subjects with ≥1 post-baseline visit (modifi ed intent-to-treat [mITT] popu- pared to OAH cohort, SGLT-2i patients were younger (55.1 vs. 56.1 years, lation) using mixed-model repeated measures. The primary endpoint was p<0.01) and a greater proportion were male (56.1% vs. 51.0%, p<0.01). change in weight at Week 26 in PP subjects. The randomized population (NB SGLT-2i patients used more concomitant medications during baseline (anti- N=153, UC N=89) was 84% female, 78% white, with mean (SD) baseline hypertensive: 77.7% vs. 64.1%; lipid-lowering: 72.8% vs. 49.4%; NSAID: age of 47 y (9.8) and BMI of 36.3 (4.3) kg/m2. The mITT population consisted 26.8% vs. 22.8%; beta-blockers: 27.2% vs. 25.0%, all p<0.03) and had more of NB n=152 and UC n=88, and the PP population consisted of NB n=71 and advanced antihyperglycemic treatment regimens (i.e. oral-dual, oral-triple, UC n=82. The primary reasons for NB discontinuation were adverse events insulin-based, injectable-based). SGLT-2 patients were also more likely to (n=35) and not meeting the Week 16 criteria (n=32). At 26 weeks, PP NB sub- have micro-vascular complications (23.6% vs. 12.7%, p<0.01), hypertension jects exhibited 8.5% greater least squares mean [SE] weight change com- (62.0% vs. 56.5%, p<0.01) and hyperlipidemia (62.9% vs. 50.9%, p<0.01) at pared with UC subjects (-9.5[0.5]% vs. -0.9[0.5]%; p<0.001). Weight change baseline. in mITT subjects, which included subjects discontinued from treatment, was In conclusion, patients initiating SGLT-2i were more progressed at base- NB: -6.2% (0.5) vs. UC: -1.1% (0.6) (p<0.001). More patients with NB vs. UC line compared to patients initiating other OAHs, and 9.5% of SGLT-2i pa- achieved 5%, 10%, and 15% weight loss. AE profi le was similar to Phase 3 tients increased their initial dose. trials. NB, when combined with lifestyle modifi cation and used as recom- mended in clinical practice (i.e., ≥5% loss at week 16), resulted in nearly a 10% mean weight loss at 26 weeks.

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1288-P counted for the lower HYPO incidence, we conducted a post hoc analysis of Effects of Acetyl-CoA Carboxylase Inhibition on Lipid Metabolism the incidence of HYPO in subgroups based on quartiles (Q) of change in insulin in Rodents and Human Subjects dose from baseline for the entire study cohort (Table). PBO-adjusted ΔA1C in Q WILLIAM P. ESLER, SCOTT M. TURNER, PAUL A. AMOR, SANTOS CARVAJAL- 1-4 were -0.33%, -0.62%, -0.47% and -0.47%, respectively. For pts with the GONZALEZ, CARINE BEYSEN, R. KIRK MCPHERSON, CLARE BUCKERIDGE, LAU- lowest insulin dose increment (<=6 units), no difference in incidence of HYPO REL J. SWEET, JEFFREY PFEFFERKORN, MARC HELLERSTEIN, GABRIELE E. SON- was seen. For pts in the remaining 3 Qs, the incidence of HYPO was lower with NENBERG, Cambridge, MA, Emeryville, CA, Groton, CT SITA. Additionally, an analysis of the incidence of asymptomatic hypoglycemia Individuals with fatty liver disease have elevated hepatic de novo lipogen- showed similar between-group results in Q1 and Q2 but lower incidences in the esis (DNL). Agents that suppress DNL may lower liver fat and improve meta- SITA group in Q3 and Q4 (7.7% vs. 17.9% and 1.5% vs. 12.5% for SITA and PBO, bolic syndrome. Acetyl-CoA carboxylase (ACC) catalyzes the fi rst committed respectively). These analyses suggest that the reduced incidence of hypoglyce- step in DNL. We evaluated the effect of pharmacologic ACC inhibition (ACCi) mia seen when sitagliptin is used in conjunction with intensively titrated insulin on lipid metabolism in animal models and human subjects. ACCi treatment in may be due to factors other than the difference in insulin dose. rats dose-dependently suppressed hepatic and skeletal muscle malonyl-CoA Table. resulting in DNL inhibition and increased fatty acid oxidation (assessed via Within-quartile Mean Δ Mean Δ HYPO: HYPO: Difference in indirect calorimetry). Chronic ACCi treatment in high-fat fed rats reduced Change from Insulin Dose: Insulin Dose: Sitagliptin Group Placebo Group % HYPO liver fat and skeletal muscle fat by 45%, and ameliorated hyperinsulinemia baseline in Sitagliptin Placebo Incidence (n/N) Incidence (95% CI) resulting in improved insulin:glucose ratios. To assess ACCi in humans, he- Insulin Dose Group Group (n/N) 13 patic DNL was quantifi ed in healthy volunteers using C-labeled acetate. 1st quartile <=6 IU/Day 0.2 -0.8 37.0% (37/100) 30.8% (24/78) 6.2 (-7.9, 19.9) Single-oral doses of ACCi dose-dependently suppressed DNL relative to pla- nd cebo by up to 70%. Metabolomic changes were assessed in serum collected 2 quartile 6, 14.3 IU/Day 11.1 10.6 15.7% (13/83) 31.8% (21/66) -16.2 (-30.0, -2.5) from volunteers treated with ACCi or placebo for two weeks. ACCi-treated 3rd quartile 14.3, 32 IU/Day 22.7 22.6 25.6% (20/78) 45.3% (43/95) -19.6 (-33.0, -5.3) subjects showed 1.5-fold elevations in serum β-hydroxybutyrate indicative 4th quartile >32 IU/Day 49.1 53.7 20.0% (13/65) 37.5% (33/88) -17.5 (-31.0, -2.8) of increased hepatic fatty acid oxidation. Other organic acids (lactate, pyru- Supported By: Merck & Co., Inc. vate, malate, aspartate, α-ketogluterate, and citrate) and branched-chain amino acids showed little to no difference. Consistent with increased CPT1 fl ux, long-chain acylcarnitines (C16:0, C16:1, C18, C18:2) and acetylcarnitine 1291-P POSTERS were slightly elevated with ACCi treatment while mid-length acylcarnitines Improvement of Brain’s Microvasculature in Type 1 Diabetic Condi- Therapeutics (C10, C12 and C14) were unchanged. These observations demonstrate that tion after Curcumin Supplementation Clinical Diabetes/ ACCi suppresses DNL in rodents leading to reductions in ectopic lipid stores. VIPAVEE ANUPUNPISIT, HATTAYA PETPIBOONTHAI, WIPAPAN KHIMMAKTONG, Similarly in humans, ACCi suppressed DNL and altered lipid metabolism. Bangkok, Thailand, Songkla, Thailand Additional studies are required to determine if these metabolic alterations Hyperglycemia and cerebral arteriosclerosis of brain are pathological com- result in reduced liver fat and metabolic improvements in man. plications of diabetes. To investigate the amelioration of brain’s blood vessels Supported By: Pfi zer Inc. in type 1 diabetic rats, curcumin, a major element of Asian spice turmeric, is interested because of its anti-infl ammatory and antioxidant activities. 1289-P Three groups: control (C), diabetic (DM: streptozotocin, 60 mg/kg BW) and diabetic rats supplemented with curcumin (DMC: 200 mg/kg BW) were per- ALL HEART: A Prescription for a Heart-Healthy Community formed for 8 weeks. Two clusters of blood vessels at circle of Willis were in- JILL WEBBER, San Diego, CA spected under corrosion cast technique with scanning electron microscope Kaiser Permanente’s ALL (Aspirin, Lisinopril and Lipid-Lowering Medica- (SEM): 1) the large vessels; anterior cerebral artery (ACA), middle cerebral tion) Initiative was started in 2003 to reduce cardiovascular disease by en- artery (MCA), posterior cerebral artery (PCA) and 2) the small vessels; arte- rolling Kaiser Permanente patients with diabetes over age 50 in a therapeutic riole and capillary. program that prescribes the triad of medications using a team-based, panel Pathology and diameter of brain vessels in DM were recognized, ex- management approach. Based on the success of ALL, Kaiser Permanente ploring rough topography and shrinkage of ACA, MCA, and PCA, together Southern California Region Community Benefi t began to support the transla- with unhealthy tortuous branching. Diameters of DM vessels explored re- tion of the Initiative among safety net providers. As the Initiative grew and duced sizes; ACA (C=212.50±6.18, DM=206.00±7.55, DMC=209.50±4.03 evolved, ALL HEART was started in 2011. The HEART acronym (Heart Smart µm): MCA (C=207.75±4.92, DM=194.00±8.58, DMC=209.25±3.07µm): PCA Diet, Exercise, Alcohol Limits, Rx Medicine Compliance, and Tobacco Ces- (C=191.00±8.51, DM=189.25±9.26, DMC=189.25±7.72µm) at p=0.05. In sation) was to emphasize care coordination, self-management, and health contrast, the severity of damage in DM vessels obviously occurred at the education, increasing physical activity, and other such lifestyle changes like region of small blood vessels; arterioles and capillary, demonstrating criti- tobacco cessation. ALL HEART is administered by the Community Clinics cal distortions, shrinkage, and twisting characteristics. Moreover, oblitera- Health Network in San Diego, CA and currently has 14 participating clin- tion and narrowing diameters of these vessels were revealed as followings: ics with 77 sites with 37,339 patients enrolled. Most of these patients are arterioles (C=22.00±1.93, DM=11.78±0.81, DMC=20.96±1.00 µm): capillary low-income, uninsured, medically underserved and vulnerable patients with (C=9.14±0.30, DM=3.78±0.24, DMC=7.13±0.30µm) at p=0.05. After curcumin diabetes over age 50. ALL HEART collects monthly clinical measures from supplementation, the microvascular architectures of these small vessels these clinics such as blood pressure, HbA1c and medication prescription/ have attractively recovered, towards to normal characteristics. In conclu- adherence. As an example of some of the measures collected so far, since sion, the novel therapeutic potential of curcumin ambiguously restored the 2011, the percentage of patients on both statin and ACE/ARB has improved large vessels cluster (ACA, MCA, and PCA) but effi ciently recovered the from the baseline of 23% to 52%. The percent of patients on just a statin small vessels particularly at arterioles and capillary. increased to 66% from a baseline of 29%. 27% of ALL HEART Diabetic en- rollees’ HbA1c is >9, 7%, slightly over the program goal of 20%. 77% of ALL HEART patients are receiving tobacco counseling. 1292-P Supported By: Kaiser Permanente Impact of Canaglifl ozin Added on to Insulin and Metformin in Type 2 Diabetes: A Substudy of the CANVAS Trial 1290-P JULIO ROSENSTOCK, DAVID MATTHEWS, MEHUL DESAI, GEORGE CAPUANO, GARY MEININGER, WILLIAM CANOVATCHEL, Dallas, TX, Oxford, United Kingdom, Reduced Incidence of Hypoglycemia with Sitagliptin Used with Raritan, NJ Intensively Titrated Insulin May Be Due to Factors Other Than the Canaglifl ozin (CANA) is an SGLT2 inhibitor developed for the treatment of Difference in Insulin Dose type 2 diabetes mellitus (T2DM). The effi cacy and safety of CANA 100 and SAMUEL S. ENGEL, FAN WU, LEI XU, R. RAVI SHANKAR, Whitehouse Station, NJ, 300 mg vs. placebo (PBO) were evaluated in a subset of patients enrolled in Beijing, China CANVAS, a cardiovascular outcomes trial in patients with T2DM at high risk Addition of sitagliptin (SITA) relative to placebo (PBO) in patients (pts) of cardiovascular disease, who were on 30 IU/d of insulin and 2,000 mg/d (N=658) with type 2 diabetes who intensively titrate insulin glargine ± met- ≥ ≥ of metformin (N=432; mean age 61 yrs; A1C 8.2%; fasting plasma glucose formin has been shown to result in a lower incremental insulin dose require- [FPG] 166 mg/dL; BMI 34.9 kg/m2; insulin dose 93 IU/d). Relative to PBO, ment (mean Δ=-4.7 units), better glycemic control (mean ΔA1C=-0.45%), and a CANA 100 and 300 mg provided signifi cant least squares (LS) mean reduc- lower incidence of adverse events of symptomatic hypoglycemia (HYPO) (mean tions in A1C (−0.7% and −0.8%; P <0.001), FPG (−16 and −25 mg/dL; P ≤0.001), Δ=-11.6%). To determine if the reduced insulin dose requirement with SITA ac-

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and body weight (−1.7% and −2.7%; P <0.001) at Week 18 (Table). PBO-sub- 2014 #1041-P). In this study, pharmacological profi les of TMG in diabetic and tracted LS mean reductions in systolic blood pressure were −3.5 and −6.1 non-diabetic rats were investigated and compared with those of other three mmHg (P <0.001) with CANA 100 and 300 mg. Overall incidence of adverse GKAs (MK, AZD and PF), mainly focusing on the glucose lowering effects events (AEs) was 66%, 67%, and 61% with CANA 100 and 300 mg and PBO, and lipid homeostasis. respectively, with low rates of AE-related discontinuations across groups. In the oral glucose tolerance test in Goto-Kakizaki rats, dose-dependent Incidence of hypoglycemia (≤70 mg/dL) was similar with CANA 100 and 300 and comparable reduction of the plasma glucose level was obtained with mg and PBO (42%, 47%, and 46%), with low rates of severe episodes (1%, four GKAs. On the other hand, glucose lowering effects in non-diabetic rats 2%, and 3%). Genitourinary AEs were consistent with the reported frequen- differed between the GKAs. After 5 days of admixture treatment in Sprague- cy in the SGLT2 inhibitor class. In conclusion, short-term CANA treatment Dawley (SD) rats, plasma glucose level was reduced by MK and AZD dose- improved glycemic control, reduced body weight, and was generally well dependently and reached to the level under 50 mg/dL at high doses, which tolerated as add-on to insulin and metformin in patients with T2DM. was associated with elevation of plasma insulin levels. TMG moderately lowered plasma glucose level, not less than 50 mg/dL even at high doses. No effect was seen with PF. Next, effects on TGs were evaluated in SD rats. High dose of MK and AZD increased TG levels both in plasma and liver. PF dose-dependently increased plasma TG levels, but not in liver. On the other hand, TMG did not increase both plasma and liver TG. These results suggest that the hypoglycemic and TG-increasing effects of GKAs differ depending on the types of compounds and the risk of hypogly- cemia and hypertriglyceridemia may not be class effect of GKAs. Among the GKAs tested, TMG has a preferable pharmacological profi le. Supported By: Teijin Pharma Limited

CLINICAL THERAPEUTICS/NEW TECHNOLOGY— PHARMACOLOGIC TREATMENT OF COMPLICATIONS POSTERS Therapeutics

Clinical Diabetes/ Guided Audio Tour: Additional Benefi ts of Glucose Lowering Agents (Post- ers: 1295-P to 1302-P), see page 15.

& 1295-P Supported By: Janssen Research & Development, LLC Metformin Improves Arterial Stiffness and Possibly Mitochondrial Function in Type 1 Diabetes 1293-P LESLIE KNAUB, MELANIE CREE-GREEN, SHAWNA MCMILLIN, KRISTEN J. NA- Miglitol Inhibits Oxidative Stress-induced Apoptosis and Mito- DEAU, ELLEN LYON, NICHOLAS BIRDSEY, IRENE E. SCHAUER, Aurora, CO, Denver, chondrial ROS Overproduction in Endothelial Cells by Enhancement CO of AMP-activated Protein Kinase Cardiovascular disease (CVD) risk remains elevated in type 1 diabetes MASAAKI SAGARA, KUNIHIRO SUZUKI, CHIE AOKI, TERUO JOSHIMA, TOSHIE (T1D) despite advances in glycemic control. We hypothesized that metformin IIJIMA, YOSHIMASA ASO, Mibu, Japan (MF), a known modifi er of CVD risk in T2D, would improve insulin sensitivity Endothelial dysfunction caused by oxidative stress plays a key role in (IS), arterial stiffness, and mitochondrial function, correlates and possible atherogenesis. This study investigated whether anti-diabetic drug miglitol, mediators of CVD, in T1D. A placebo-controlled, double-blind, random order, an -glucosidase inhibitor (-GI), which is currently available in clinical prac- cross-over design six week intervention was done in adults with T1D. IS was tice, can prevent endothelial cell apoptosis, and whether it might restore assessed by euglycemic hyperinsulinemic clamp. Glucose control was as- impaired vascular relaxation under oxidative stress. The b.End3 cells, a mi- sessed with continuous glucose monitoring (CGM) on phase-identical fi xed crovascular endothelial cell line, were pre-treated with various concentra- macronutrient diets for 7 days. Augmentation index (AI) was measured by ra- tions of miglitol, and then were incubated with H2O2 for 1-2 h. Treatment of dial tonometry (Sphygmacor). Mitochondrial function was measured ex vivo b.End3 cells with miglitol resulted in the protection of cell viability, the sup- by high resolution respirometry in permeabilized muscle fi bers with carbo- pression of mitochondrial superoxide production and DNA strand breakage hydrate substrates (PMGS, Oroboros), and in vivo by 31P magnetic resonance under the oxidative stress. These effects of miglitol were associated with spectroscopy (MRS) in a subset. Results from an interim analysis (N=7, N=3 the activation of AMP-activated protein kinase (AMPK) and the phosphory- for MRS) are shown in Table 1. Glucose control and IS were similar with pla- lation of endothelial nitric oxide synthase (eNOS). In aortic rings with en- cebo and MF. AI decreased with MF, indicating improved arterial stiffness. dothelium, acetylcholine (Ach)-induced relaxation was attenuated by H2O2. Ex vivo mitochondrial function improved with MF, but did not reach statisti- We found that this impaired relaxation was restored by acute treatment cal signifi cance. Preliminary in vivo mitochondrial function results also sug- with miglitol. Compound C, an AMPK inhibitor, inhibited the amelioration of gest improvement with MF. MF does not improve glucose homeostasis, but vascular relaxations treated with miglitol. may provide CVD risk reduction through vascular and mitochondrial benefi ts These results suggest that miglitol might protect against endothelial cells in T1D. damage under oxidative stress via the inhibition of endothelial cell apoptosis Table 1. Metformin vs. Placebo Effects in T1D. and mitochondrial superoxide production, which are mediated by the activa- tion of AMPK and the phosphorylation of eNOS. Placebo Metformin P-value CGM: 7d avg glucose (mg/dl) 156 ± 27 160 ± 26 NS 1294-P SD 72 ± 16 69 ± 17 NS Differences in Pharmacological Profi les between Glucokinase Ac- % low (<70) 10 ± 7 9 ± 7 NS tivators: A Comparative Study in Diabetic and Nondiabetic Rats % target 44 ± 17 38 ± 12 NS YOSHINORI TSUMURA, YU TSUSHIMA, AZUSA TAMURA, MAKIKO HASEBE, % high (>170) 46 ± 18 52 ± 14 NS HIROYUKI SUGIYAMA, TSUNEFUMI KOBAYASHI, YOSHINORI KASAHARA, Hino, Japan Clamp:glucose (mg/dl) 92 ± 4 93 ± 7 NS Three different glucokinase activators (GKAs), MK-0941 (MK), AZD1656 GIR/fi nal insulin (mg/kg/µIU) 0.055 ± 0.037 0.047 ± 0.029 NS (AZD) and PF-04991532 (PF), have exerted HbA1c reductions in patients with Augmentation Index 26.1 ± 11.1 21.4 ± 10.6 0.01* type 2 diabetes. However, some problems emerged such as lack of durabil- ity, increased risk of hypoglycemia and elevation of triglyceride (TG) levels. It Ex vivo respirometry: has not been concluded yet whether these problems are common in all types PMGS state 3 O2 fl ux 31.7 ± 8.6 42.9 ± 9.7 0.067† of GKAs. We generated a novel GKA, TMG-123 (TMG), which showed du- PMGS state 4 leak (+oligomycin) 10.4 ± 2.2 14.0 ± 4.0 0.093† rable glucose lowering effect with no infl uence on TG in Goto-Kakizaki rats PMGS uncoupled max 58.9 ± 9.0 75.1 ± 24.1 0.19† while the effi cacy of MK was attenuated after long-term treatment (ADA

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In vivo 31P MRS (N=3): & 1297-P PCr TC (seconds) 34.9 ± 6.9 30.1 ± 5.1 0.49* Metabolic Predictors of Response to Pioglitazone Treatment in Patients with Prediabetes or Type 2 Diabetes Mellitus (T2DM) and ADP TC (seconds) 29.7 ± 5.6 21.6 ± 1.8 0.25* Nonalcoholic Steatohepatitis (NASH) OxPhos (mM/sec) 0.116 ± 0.030 0.153 ± 0.035 0.07* FERNANDO BRIL, PAOLA PORTILLO SANCHEZ, MARYANN MAXIMOS, ROMINA Qmax (mM/sec) 0.35 ± 0.06 0.52 ± 0.04 0.05* LOMONACO, BEVERLY ORSAK, JOAN HECHT, SRILAXMI KALAVALAPALLI, KEN- AnGly 0.26 ± 0.11 0.14 ± 0.10 0.59* NETH CUSI, Gainesville, FL, San Antonio, TX Pioglitazone treatment (PIO) improves insulin resistance and liver histolo- Mitochondrial effi ciency 0.12 ± 0.03 0.20 ± 0.05 0.25* gy in patients with prediabetes or T2DM and NASH. However, some patients GIR=glucose infusion rate; PMGS=pyruvate/malate/glutamate/succinate; do not achieve liver histological improvement. Thus, we aimed to determine PCr TC=phosphocreatine recovery time constant; ADP TC=ADP recovery metabolic factors that may predict response to PIO. time constant; AnGly=anaerobic glycolysis. Data are mean ± SD, except Forty patients with prediabetes or T2DM and NASH (age: 54±1 yrs; male: MRS data are mean ± SE. *paired t-test; † group t-test. 2 75%; BMI 33.7±0.7 kg/m ; A1c:6.4±0.2%) were treated with PIO 45mg daily Supported By: National Institutes of Health (5K23DK091553) for 18 months. At baseline and after treatment, we performed the following: 1) liver biopsy; 2) magnetic resonance spectroscopy (1H-MRS); 3) euglycemic & 1296-P hyperinsulinemic clamp to measure glucose turnover (n=36); and 4) an OGTT Effi cacy and Safety of Alirocumab in Individuals with Diabetes: to assess diabetes status. Analyses from the ODYSSEY LONG TERM Study After 18 months of PIO, 58% of patients had histological resolution of HELEN M. COLHOUN, HENRY N. GINSBERG, LAWRENCE A. LEITER, UMESH NASH. No differences were found in baseline characteristics between CHAUDHARI, CHRISTELLE LORENZATO, ROBERT PORDY, JENNIFER G. ROBIN- responders and non-responders. Changes in ALT and glycemic control did SON, Dundee, United Kingdom, New York, NY, Toronto, ON, Canada, Bridgewater, not predict PIO response, while changes in insulin resistance at the level NY, Chilly-Mazarin, France, Tarrytown, NY, Iowa City, IA of skeletal muscle and adipose tissue, but not liver, were associated with The effi cacy and safety of the PCSK9 inhibitor alirocumab (ALI) for lower- PIO response (Rd: r= -0.42, p=0.01; suppression of FFA: r= -0.36, p=0.049). ing LDL-C in individuals with diabetes (DM) vs. those without is unknown. Reduction in fi brosis correlated with a decrease in hyperinsulinemia (r=0.35, We compared the effects of ALI in individuals with and without DM from p=0.03). Changes in plasma adiponectin were signifi cantly higher in histolog-

the ODYSSEY LONG TERM study (NCT01507831). LONG TERM included 2341 ical responders compared to non-responders (18.5±2.3 vs. 11.4±2.2 µg/mL, POSTERS 1 Therapeutics individuals (832 with DM; 35.5%) at high CVD risk and LDL-C ≥70 mg/dL on p=0.04) and were strongly associated with changes in liver fat by H-MRS Clinical Diabetes/ maximally tolerated statin ± other lipid-lowering therapy, randomized (2:1) to (r= -0.42, p= 0.001). More importantly, changes in plasma adiponectin were ALI 150 mg or placebo Q2W (as 1 mL injection) for 78 weeks, with planned inversely correlated with the NAFLD activity score (NAS; r= -0.50, p=0.002). primary effi cacy analyses at 24 weeks and safety up to 78 weeks. ALI low- Conclusion: In patients with prediabetes or T2DM and NASH, histological ered LDL-C by 59% vs. placebo in those with DM and 63% in those without improvement with PIO is closely associated with an improvement in adipose tis- (p=0.0957 for interaction) at 24 weeks (Table). Decreases in TGs and increas- sue and skeletal muscle insulin sensitivity, as well as an increase in plasma adi- es in HDL-C were also similar between the groups. No increases were seen ponectin. Future models that combine clinical, metabolic and genetic parameters in adverse events in those with vs. without DM. Nasopharyngitis, URI and may help predict treatment response and assist clinical management. UTI occurred in ≥5% of individuals in all subgroups; injection-site reaction Supported By: American Diabetes Association (1-08-CR-08 to K.C.); Burroughs and myalgia were reported in ≥5% of ALI individuals without DM, but in <5% Wellcome Fund of those with DM. In post-hoc analyses of major CV events, hazard ratios (95% CI) vs. placebo were 0.41 (0.18-0.96) [with DM] and 0.51 (0.23-1.13) & 1298-P [without DM]. In summary, LDL-C reduction with ALI vs. placebo was inde- Inhibition of Cardiac Late Na+ Current Protects Against Diabetic pendent of DM status at baseline, with no specifi c safety signals observed Cardiomyopathy in Rat up to 78 weeks. Treatment with ALI for potential reduction of CV events is LIGUO CHI, HAIYUN LING, ALIYA ZENG, NESRINE EL-BIZRI, YUN NING, SRIDHA- under evaluation in the large ongoing ODYSSEY OUTCOMES study. RAN RAJAMANI, LUIZ BELARDINELLI, ARVINDER K. DHALLA, Fremont, CA + Cardiac late Na current (INaL) has been shown to be increased in myocytes in diabetic mice. However a correlation with cardiac function has not been established. We studied the effect of a selective INaL inhibitor GS-967 on cardiac function in streptozotocin (STZ)-induced diabetic rats and directly measured INaL in myocytes to more conclusively establish the role of INaL in diabetic cardiomyopathy. STZ (65 mg/kg, i.p.) was injected to rats to induce diabetes. Two weeks (wks) after STZ, rats were treated with GS-967 (1.0 mg/kg/day, n=10) or vehicle (Veh, n=11) for 6 wks. Two additional groups of rats that did not receive STZ were treated with either Veh (n=6) or GS-967 (n=6) as controls. Cardiac function was assessed using echocardiography at 0, 2, 4 and 8 wks post STZ. INaL in myocytes isolated from left ventricular (LV) was measured by using patch clamp. As diabetes progressed, STZ animals developed LV dilation, QTc prolon- gation, systolic and diastolic dysfunction. INaL (pA/pF) in isolated myocytes increased to 0.23±0.02 (p<0.05) and 0.39±0.06 (p<0.05) at 4 and 8 wks post STZ compared to control (0.13±0.02). GS-967 treatment signifi cantly reduced LV volume, improved cardiac function (Figure) and shortened the prolonged QTc, at doses that did not affected plasma glucose levels. In conclusion, the enhanced INaL in the diabetic hearts may contribute to the prolonged QTc and cardiac dysfunction in rats with STZ-induced diabetes.

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& 1299-P & 1301-P Modulating p75NTR as a Therapeutic Target in Preventing Diabe- Positive Translational Development of a Negative Allosteric Modu- tes-induced Retinal Vascular Permeability lator of the Insulin Receptor BARBARA A. MYSONA, SALLY L. ELSHAER, FRANK M. LONGO, AZZA B. EL- KIRK W. JOHNSON, RAJNEESH NATH, JULIE ROESSIG, ANN NEALE, KEN DER, REMESSY, Augusta, GA, San Francisco, CA PADMA BEZWADA, PAUL RUBIN, Berkeley, CA Purpose: Breakdown of the inner blood-retinal barrier (BRB), an event Hyperinsulinemic hypoglycemia (HH), caused by diseases such as insuli- which leads to macular edema, is a major cause of diabetic blindness. We nomas and Congenital Hyperinsulinism, remains a serious medical concern have previously shown that genetic deletion of the neurotrophin receptor with limited therapeutic options. p75NTR preserved BRB and prevented accumulation of the pro-form of nerve We recently described a fully human IgG2 monoclonal antibody (mAb; growth factor (proNGF) in diabetic retinas. LM11A-31 is an orally bioavail- XOMA 358) to the human insulin receptor (InsR) that allosterically inhibits able, small-molecule p75NTR ligand that inhibits its degenerative signaling insulin action in vitro and in HH mice (mAbs 6:262, 2014). Studies following In- including excess RhoA activation. This study aims to examine the therapeu- travenous (IV) dosing have now been completed in normal rats, monkeys and tic potential of modulating p75NTR by determining whether LM11A-31 is ca- adult male healthy volunteers (HVs). Clinical trial design details and some pable of preventing diabetes-induced BRB breakdown and affecting p75NTR results were recently described (Endocrine Society, May 2015). Herein, we downstream signaling. present new pharmacokinetic (PK) and pharmacodynamic comparisons of Methods: Male C57Bl6/J mice that were rendered diabetic using strep- XOMA 358 in normal animals and humans. Groups of 8-10 male S-D rats tozotocin injection were randomized to receive oral gavage of LM11A-31 or cynomolgus monkeys (n = 3-5 each gender) were randomized to single IV (50mg/kg/day) or saline for 4-weeks of diabetes. BRB breakdown was as- vehicle or XOMA 358 dosing at 1, 3, 10, 30, 100, 200 mg/kg in rats and 30, 60, sessed by extravasation of BSA-fl uorescein. Direct effects of proNGF were and 90 mg/kg in monkeys. In HVs, cohorts of 1-2 placebo and 3-5 XOMA 358 examined in human retinal endothelial cells (HRE) in the presence or absence recipients were enrolled in 0.1, 0.3, 1.0 and 3.0 mg/kg dose groups. of LM11A-31 (200 nM) or the Rho-kinase inhibitor Y-27632 (10 µM). Lysates XOMA 358 was safe and well-tolerated with linear PK in the preclinical and were analyzed by Western blot for RhoA activation and phosphorylation of clinical studies. In both animals and HVs, dose-dependent elevations in serum occludin, a tight junction protein. insulin levels and postprandial glucose levels were observed - indicative of Results: Diabetes caused 1.9-fold BRB breakdown that was mitigated XOMA 358 action. XOMA 358 was more potent and longer-acting in humans: by treatment with LM11A-31 (n=4-6, P<0.05). In HRE cells, treatment with whereas a three-fold increase in insulin was observed at 3 mg/kg in rats and POSTERS Therapeutics human mutant proNGF (10ng/ml) induced 1.5 fold increases in cell perme- 30 mg/kg in monkeys, 1 mg/kg in HVs yielded insulin levels that tripled at peak

Clinical Diabetes/ ability, 1.3 fold in RhoA activation, 1.6-fold in occludin phosphorylation and and with a more extended duration. Postprandial glucose levels, not followed F-actin redistribution. These effects were blocked by LM11A-31 as well as in monkeys, showed a 45% increase 1-2 days after a 10 mg/kg dose in rats with Y-27632 (n=6-8, P<0.05). whereas humans exhibited a 40% increase in post-meal blood glucose levels Conclusions: Targeting p75NTR and its downstream Rho kinase pathway at 1 and 3 mg/kg dose levels. The greater potency and duration of action of may be a potential therapeutic strategy for treating macular edema, a major XOMA 358 in humans coincided with better PK. Hence, XOMA 358 has transi- cause of diabetic blindness. LM11A-31 is an orally bioavailable inhibitor that tioned well into humans and is ready for investigation in HH patients. has successfully completed Phase-1 pharmacokinetic and safety study in normal subjects. & 1302-P Supported By: R01EY022408 Linagliptin Improves Retinal Endothelial Function and Blood Flow in Nondiabetic, Hypertensive Subjects & 1300-P THOMAS A. FORST, GEORG MICHELSON, STEPHAN DIESSEL, JOHANNES JAHNKE, A GLP-1R Agonist Improves NASH and Increases Survival after Par- CHRISTOPH KAPITZA, Mainz, Germany, Erlangen, Germany, Neuss, Germany tial Hepatectomy Several studies suggest vascular benefi ts of DPP-IV inhibition in patients PILAR VALDECANTOS, VIRGINIA PARDO, PETER RAVN, ANISH KONKAR, JOSEPH with diabetes mellitus. Little is known about effects of DPP-IV inhibitors in GRIMSBY, CRISTINA RONDINONE, ANGELA M. VALVERDE, Madrid, Spain, Gaith- non-diabetic patients at vascular risk. This was a double blinded, random- ersburg, MD ized, placebo controlled study addressing vascular effects of linagliptin in Epidemiologic and clinical studies have shown an association between hypertensive subjects. Twenty-one patients received 5 mg linagliptin p.d. non-alcoholic fatty liver disease (NAFLD), insulin resistance and impaired (5 female; age 67.6±6.0 years; mean±SD), while twenty-two patients were liver function. We have designed a pharmacological protocol with a GLP-1 randomized to placebo (5 female; age 64.8±7.1 years). All concomitant medi- receptor (GLP-1R) agonist aimed to investigate its effects in non-alcoholic cation was kept stable. Blood pressure, urine sampling, and retinal micro- steatohepatitis (NASH) in mice. 8 week-old C57BL/6 male mice were divided vascular assessments were performed at baseline, after 6 and 12 weeks of in 4 groups. Groups 1 and 2 were fed with chow diet (CHD) and groups 3 and treatment during an in house stay. Urinary albumin creatinine ratio (UACR) 4 with choline-methionine-defi cient diet (MCD), a model of NASH. After one was calculated, and retinal microvascular blood fl ow was assessed using week, groups 2 and 4 were injected (s.c.) with a GLP-1R agonist at 10 nmol/ Laser Doppler Flowmetry. Retinal capillary perfusion, arterial fl ow, retinal kg every two days for 2 weeks. Then, partial hepatectomy (PH) was per- endothelial function and the arterial wall to lumen ratio were evaluated. As formed and mice were maintained with the same diet and pharmacological shown in the table, a slight reduction in systolic and diastolic blood pressure treatment for another 2 weeks. In mice fed with MCD, the GLP-1R agonist was observed in both treatment groups. Retinal capillary perfusion, arterial decreased transaminases and improved liver histology compared to the CHD fl ow and the retinal hyperemic response improved during treatment with group. At this time-period, plasma TG decreased and liver TG increased in linagliptin. No signifi cant change in the UACR could be observed. Our study the MCD group, refl ecting the lower capacity of the liver to export VLDL in suggests retinal microvascular benefi ts of linagliptin treatment not exclu- the MCD model. However, in mice fed with MCD treated with the GLP-1R sively restricted to glucose mediated mechanisms. agonist, hepatic TG were restored to levels of CHD animals. Regarding gly- Table. cogen stores, in both treated and untreated mice fed with MCD intrahepatic glycogen was decreased as compared to the CHD group, but in the MCD plus baseline baseline 6 weeks 6 weeks 12 weeks 12 weeks placebo linagliptin placebo linagliptin placebo linagliptin GLP-1R agonist group an increase in free intrahepatic glucose was found. After PH, survival rate increased in mice treated with the GLP-1R agonist in UACR (mg/g creatinine) 19.5 +/- 6.6 8.1 +/- 0.8 12.7 +/- 2.3 9.4 +/- 0.9 11.9 +/- 2.0 12.5 +/- 2.0 both CHD and MCD groups compared with vehicle-treated animals. More- mean 24h syst. blood pressure 133.2 +/- 2.1 129.8 +/- 2.7 129.4 +/- 2.6 126.0 +/- 12.3 128.5 +/- 2.5 & 127.1 +/- 2.4 over, 2 weeks after PH the hepatic regeneration index remained similar in (mmHg) mice fed with MCD treated with vehicle or GLP-1R agonist and, surprisingly, mean 24h diast. blood pressure 76.9 +/- 1.8 75.8 +/- 1.7 74.7 +/- 2.1 73.9 +/- 1.8 73.9 +/- 1.8 & 73.9 +/- 1.9 the benefi cial effects of the GLP-1R agonist in the MCD group observed be- (mm Hg) fore PH in liver histology, intrahepatic TG and transaminases were partially retinal capillary perfusion (AU) 235.8 +/- 14.9 247.6 +/- 14.9 248.6 +/- 13.8 253.7 +/- 84.2 269.7 +/- 17.1 290.7 +/- 16.4 & reverted and those mice presented signs of NAFLD. These results suggest a benefi cial role of a GLP-1R agonist in alleviating NASH and improving sur- arterial fl ow (AU) 76.1 +/- 1.1 74.2 +/- 1.8 74.6 +/- 1.0 75.8 +/- 1.1 75.5 +/- 1.0 77.3 +/- 1.3 &,$ vival following PH but not in increasing hepatic regeneration during NAFLD. fl icker response (AU) 39.6 +/- 7.3 32.4 +/- 5.1 29.5 +/- 6.5 36.9 +/- 6.9 27.8 +/- 5.2 54.1 +/- 10.7 $ Supported By: MedImmune, Inc. arteriolar wall / lumen ratio 0.415 +/- 0.013 0.400 +/- 0.013 0.416 +/- 0.014 0.392 +/- 0.012 0.413 +/- 0.012 0.397 +/- 0.008 (mean+/-SE; AU arbitrary units; & p<0.05 vs. baseline; $ p<0.05 vs. placebo). Supported By: Boehringer Ingelheim

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1303-P ommend renin-angiotensin-aldosterone system inhibitors (RAASi) for the treat- Added Benefi t of Empaglifl ozin: Improvement of Erectile Dysfunc- ment of diabetic kidney disease (DKD), however pts with DKD are at high risk for tion in Diabetic Type 2 Rats hyperkalemia (HK), which may limit or prevent RAASi use. OPAL-HK evaluated RANA ASSALY, ERIC MAYOUX, DIANE GORNY, SANDRINE COMPAGNIE, JACQUES patiromer, the active moiety of which is a nonabsorbed potassium (K+)-binder, for BERNABÉ, FRANÇOIS A. GIULIANO, DELPHINE BEHR-ROUSSEL, Montigny-le-Bret- treatment of HK in CKD pts with HK on RAASi. This post hoc analysis examined onneux, France, Ingelheim, Germany patiromer use in T2DM pts with DKD and advanced CKD (eGFR <45 mL/min/1.73 Chronic hyperglycemia correlates with the occurrence and severity of erec- m2), stratifi ed by baseline serum K+ -- mild HK, s-K+ 5.1 -<5.5 mEq/L (Stratum 1) tile dysfunction (ED). It is hypothesized that empaglifl ozin, a SGLT-2 inhibitor, and mod-severe HK, s-K+ 5.5 -<6.5 mEq/L (Stratum 2). We studied 94 pts with could ameliorate type 2 diabetes-associated ED through effective glycemic T2DM (mean 14±10 yr since diagnosis), advanced CKD secondary to DKD, and control. Thus, the effect of chronic empaglifl ozin was assessed both in vivo HK on stable doses of ≥1 RAASi, many receiving other antihypertensive medica- on erectile function and ex vivo on endothelium-dependent, independent and tions, who then received patiromer at a starting dose of 4.2 or 8.4 g BID, respec- nitrergic relaxations of corpus cavernosum (CC) of diabetic Goto-Kakizaki tively, for mild or mod-severe HK for 4 wks. Signifi cant reductions from baseline (GK) rats, a validated model of type 2 diabetes-associated-ED. in s-K+ were observed in both groups at 4 wks (p<0.001). Male GK and age-matched Wistar rats (n=10-15 rats/experimental group) Table. Primary Effi cacy Endpoint Results in Patients with DM and received either control or empaglifl ozin diet (25.3±0.9 mg/kg/day) for 4 weeks. Advanced CKD Treated with Patiromer. Then, erectile function was assessed by electrical stimulation of the cavernous Patients with DM and Mean ± SE Baseline Mean ± SE Change in s-K+ P nerve at different frequencies in anesthetized rats and the effects of chronic CKD Stage 3b, 4-5 (n=94) s-K+, mEq/L at Wk 4 (95% CI), mEq/L value empaglifl ozin were compared to an ED standard of care treatment i.e. the pro- erectile facilitator compound sildenafi l, acute iv injection at 0.3mg/kg. Then, ex Stratum 1 - Mild HK (n=33) 5.2 ± 0.05 -0.57 ± 0.09 (-0.74, -0.39) < 0.001 vivo isometric tension studies were performed on CC from the same rats. Stratum 2 - Moderate-to-severe 5.8 ± 0.05 -1.18 ± 0.07(-1.32, -1.05) < 0.001 Erectile function in GK rats was markedly impaired compared to Wistar HK (n=60)* (p<0.001) and associated with altered endothelium-dependent (p<0.001) *One patient did not have an s-K+ result at Week 1 or later and was there- and nitrergic mediated relaxations (p<0.001) in CC. Either chronic empagli- fore excluded from the analysis. fl ozin or acute sildenafi l signifi cantly improved erectile responses in GK rats. Constipation was the most common adverse event (AE) (16% overall, none Ratios of area under the curve/mean arterial pressure during the electrical severe); 5 pts (5.3%) discontinued due to AEs. Patiromer demonstrated ef- stimulation were signifi cantly increased (p<0.001 for both) versus untreated +

fi cacy in reducing s-K to <5.0 mEq/L in pts with advanced DKD and HK on POSTERS GK. Improvement of erectile dysfunction with empaglifl ozin was associated RAASi and was well tolerated. Therapeutics to ameliorated nitrergic relaxations of isolated CC from GK rats (p<0.05). Supported By: Relypsa, Inc. Clinical Diabetes/ Empaglifl ozin improves erectile function of diabetic GK rats mediated by an amelioration of nitrergic relaxations of CC. These results suggest that besides 1306-P glucose control, SGLT-2 inhibition by empaglifl ozin might provide an additional Effect of Liraglutide on Cardiovascular Markers in Type 2 Diabetes potential advantage of improving erectile function in type 2 diabetic patients. Mellitus WEI REN, JIANJIN GUO, JIE LIU, GUANGXIA XI, Taiyuan, China 1304-P To investigate the levels of markers for cardiovascular disease in type 2 Exploring Central and Peripheral Effects of Transcutaneous Acu- diabetes mellitus and the effect of glimepiride and liraglutide which is a long- puncture Therapy in Patients with Diabetic Gastroparesis acting human glucagon-like peptide-1 (GLP-1) analog on these markers. This GENGQING SONG, RICHARD W. MCCALLUM, YAN SUN, HUGO SANDOVAL, STE- study included 48 T2DM patients have been treated with poorly controlled PHEN SANDS, IRENE SAROSIEK, JIANDE CHEN, El Paso, TX diabetes using metformin (1500mg) in the latest 3 months. The patients were Nausea, an unpleasant symptom of diabetic gastroparesis (DMGP), can be randomly divided into the treatment groups of glimepiride (4mg/d) or liraglutide alleviated by needleless transcutaneous electro-acupuncture (TEA). Inferior (0.6~1.2mg/d) for 12 weeks. The body weight, blood pressure, glucose, lipids frontal lobe is reported to regulate unpleasant and pleasant emotion. and the markers for cardiovascular disease including serum C-reactive protein Aims: To investigate the central and peripheral mechanisms of nausea (CRP), plasminogen activator inhibitor type-1(PAI-1), mannose binding lectin by performing simultaneous recordings of electroencephalography (EEG) and (MBL), serum matrix metalloproteinase-9 (MMP-9), homocysteine (Hcy) and electrogastrography (EGG). carotid intima media thickness (CIMT) were detected at the 12 weeks after Methods: Eleven nauseated DMGP patients underwent concurrent EEG the patients being treated. The level of blood sugar and HbA1c decreased in and EGG recordings while also grading that nausea severity during the fol- both groups (P<0.01 or P0.05). Signifi cant average weight loss compared with lowing sequence of experiments: 30-min baseline, 30-min visual stimula- baseline was seen in liraglutide group (P<0.01), while there was no signifi cant tion, 30-min visual stimulation plus TEA therapy at PC6 and ST36 acupoints, improvement in glimepiride group (P>0.05). The levels of CIMT, Hcy, CRP, PAI- 30-min with TEA alone, and 15-min post TEA. 1, MBL, MMP-9 were dramatically reduced after administration of liraglutide Results: 1) The nausea score was increased with visual stimuli, and then and glimepiride group, but the effect of liraglutide was signifi cantly superior decreased during TEA and Post TEA (All post baseline results were P<0.05, vs. to glimepiride (P<0.01). Liraglutide had similar blood glucose lowering effect as visual stimuli without TEA (Table 1). 2) The mean percentage of normal gastric glimepiride. Liraglutide decreases body weight effectively and have protective slow waves was decreased with visual stimuli, then improved during TEA and effect on macrovascular diseases through inhibition of theses markers. sustained post TEA (P<0.05, vs. visual stimuli without TEA). 3) During initial vi- Supported By: National Natural Science Foundation of China (81400836) sual stimulation, right inferior frontal activity was prominent but when the visual stimuli was presented simultaneously with TEA, left inferior frontal activity pre- 1307-P dominated. This effect of TEA on left inferior frontal activity was also maintained Long-Term Follow-up of Gastric Electrical Stimulation Therapy and after TEA stopped suggesting a carryover effect resulting from treatment. Pyloroplasty for Refractory Gastroparesis Conclusions: In DMGP: 1) TEA ameliorates nausea and improves gastric RICHARD MCCALLUM, BRIAN DAVIS, IRENE SAROSIEK, El Paso, TX slow wave abnormalities exacerbated by visual stimulation. 2) Combining Introduction: Gastric electrical stimulation (GES), does not accelerate TEA treatment with visual stimulation results in a change of dominance from gastric emptying (GET) which is only achieved when GES was accompanied right to left inferior frontal activity which is sustained even post TEA treat- by a pyloroplasty (PP). Our aim was to investigate long-term outcomes in ment and is correlated with reduced nausea and improved EGG signals. 3) gastroparesis (GP) patients undergoing GES & PP. This model for studying nausea in humans has the potentials to provide new Methods: 17 GP drug-refractory patients [12 diabetic; 5 idiopathic; 14 fe- insights into mechanisms and treatment targets. male; 9 Hispanic (H); mean age 43(21-64)] underwent GES and PP procedure Supported By: Texas Tech University Health Sciences Center at the same surgery from 2012 to 2014. Individual symptoms [nausea, vom- iting, bloating, fullness, early satiety, epigastric pain] and total symptoms 1305-P score (TSS) assessed by 4-points Likert scale, 4-h gastric emptying test (ab- Patiromer Lowered Serum K+ in Hyperkalemic Patients with Dia- normal >10% retention of isotope at 4h), and adverse events were captured betic Kidney Disease on RAAS Inhibitors at baseline and the last follow up visit. MATTHEW WEIR, GEORGE L. BAKRIS, MARTHA MAYO, DAHLIA GARZA, YURI Results: One patient died in post-op period from aspiration pneumonia. His STASIV, SUSAN ARTHUR, DANIEL WILSON, LANCE BERMAN, DAVID BUSHIN- data was not included in results. The mean follow up was 14 months (3-32). SKY, Baltimore, MD, Chicago, IL, Redwood City, CA, Rochester, NY The GET improved by 64% at 4 hr (P<0.001) and 60% of patients normolized Albuminuria and decreased GFR are associated with increased risk of ESRD their GET - <10% retention of isotope at 4 hrs. TSS signifi cantly improved and cardiovascular events in patients (pts) with diabetes (DM). Guidelines rec- from baseline (21) to follow up (9) (P<0.01).

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There was no increased number of infections related to placement of the GES system and/or PP. n=11 (60%) of GP patients had been diagnosed with chronic constipation before surgeries, and only 5 continued this complaint at follow-up. Two patients developed diarrhea soon after receiving GES, which resolved. Global assessment of changes in GP symptoms obtained in 14 patients by using the VAS tool improved by a mean value of 71%, particularly nausea, vomiting and early satiety. Conclusions: 1) In drug-refractory GP the addition of PP to GES markedly accelerates the rate of gastric emptying. 2) The overall signifi cant symptom reduction of 71% was similar in hispanic and caucasion groups. 3) No techni- cal or additional long term adverse events were recorded. 4) PP supplements the antiemetic effects of GES by improving/normalizing GET thus providing sustained control of symptoms in diabetic GP patients.

1308-P Differential Effects of Alpha-2 Adrenergic Agonist Anesthesia in Diabetic and Nondiabetic Rats: Implications for Diabetes Research ANNA R. CONNELL, MICHELLE B. HOOKHAM, DONGXU FU, TIMOTHY J. LYONS, JEREMY Y. YU, Belfast, United Kingdom Alpha-2 adrenergic agonists, coupled with ketamine, are increasingly used in animal research because of their favorable safety profi les. In dia- betic rodents however, we noted suboptimal anesthetic outcomes with these agents. We therefore compared the effects of xylazine (10 mg/kg, i.p.) or medetomidine (1 mg/kg, i.p.) in combination with ketamine (75 mg/kg,

POSTERS i.p.), vs. pentobarbital sodium alone (70 mg/kg, i.p.) in Sprague-Dawley rats Therapeutics with and without streptozotocin-induced diabetes. Anesthetic effi cacy was Clinical Diabetes/ determined by assessment of righting, pedal, tail and corneal refl exes. Blood glucose levels were measured before and over 24 hrs following anesthesia. In non-diabetic rats, both xylazine and medetomidine consistently elicited satisfactory surgical anesthesia, but in diabetic rats, adequate anesthesia was achieved in only 17% and 33% of animals by the two drugs, respectively (p<0.05 vs. non-diabetic controls, n=5-6). Furthermore, in non-diabetic rats, both drugs induced hyperglycemia with a mean peak blood glucose concen- tration exceeding 16.7 mM within 2 hrs, gradually recovering to normal over 1310-P the next 24 hrs. In contrast, pentobarbital induced a satisfactory level of Attenuation of Infl ammatory Response by a Novel Chalcone Pro- anaesthesia in both diabetic and non-diabetic rats, and had no effects on tects Kidney and Heart from Hyperglycemia-induced Injuries in blood glucose levels throughout the study. These data suggest that alpha-2 Type 1 Diabetic Mice adrenergic agonists have inadequate anesthetic effects in diabetic rats, and CHAO ZHENG, GUANG LIANG, Wenzhou, China that they cause acute hyperglycemia (to diabetic levels) in healthy non-dia- High glucose-induced infl ammation plays a pivotal role in diabetic com- betic animals. Pentobarbital does not exhibit this differential response with plications. In this study, we examined the effect of L2H17, a chalconoid, on regard to diabetes status, nor does it cause hyperglycemia, and therefore it infl ammation in mouse peritoneal macrophages and STZ-induced type 1 may represent a preferable anesthetic agent for diabetes research. diabetes mice. Our results showed that L2H17 exhibits a strong inhibitory effect on the expression of pro-infl ammatory cytokines via the MAPK/NF-κB 1309-P pathway (Fig. 1). Furthermore, in vivo oral administration of L2H17 resulted in No Decline of Brain Glucose Metabolism in Alzheimer’s Disease a signifi cant decrease in the expression of pro-infl ammatory cytokines and Patients Treated with Liraglutide improvement in fi brosis in both kidneys and hearts of diabetic mice (Fig.2). MICHAEL GEJL, ALBERT GJEDDE, LÆRKE EGEFJORD, ARNE MØLLER, SØREN B. Our fi ndings provide strong evidence that L2H17 is an anti-infl ammatory HANSEN, KIM VANG, ANDERS RODELL, HANS BRÆNDGAARD, HANNE GOT- agent and may have a therapeutic potential in the prevention and/or treat- TRUP, ANNA SCHACHT, NIELS MØLLER, BIRGITTE BROCK, JØRGEN RUNGBY, ment of diabetic renal and cardiac complications. Aarhus, Denmark, Copenhagen, Denmark In rodent models of Alzheimer’s Disease (AD), the GLP-1 receptor ago- nist liraglutide limits amyloid (Aβ) deposition and infl ammation and blocks memory deterioration. As a marker of synaptic dysfunction and neuronal ac- tivity, [18F] fl uorodeoxyglucose (FDG) uptake in brain is sensitive to disease progression, and decline of the cerebral metabolic rate of glucose (CMRglc) is closely related to cognitive impairment. We predicted that treatment with liraglutide would reduce the accumulation of Aβ and improve CMRglc mapped with positron emission tomography (PET) in AD patients. In this dou- ble-blinded RCT, we randomized 38 patients with moderately advanced AD to treatment with liraglutide or placebo for six months as add-on medication. We measured the Aβ load in brain, as mapped with labeled Pittsburgh com- pound B (PIB) by PET, and the changes of CMRglc, as measured with FDG. Re- gional and global increases of PIB retention (P<0.0001-0.0003) did not differ between the liraglutide and placebo groups, but the CMRglc declined signifi - cantly in the placebo group (P<0.0001, see fi gure for regional comparisons). In contrast, patients treated with liraglutide had an insignifi cant increase of CMRglc after the 6 months of treatment. In conclusion, in AD patients, lira- glutide treatment is not associated with the decline of CMRglc that refl ects cognitive impairment, synaptic dysfunction, and disease evolution. Supported By: Novo Nordisk A/S; Aarhus University

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A340 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—PHARMACOLOGIC TREATMENT OF COMPLICATIONS

1313-P Metformin Administration into the Ileum Is Not Associated with In- creased Systemic Lactate KIM CHEN, COLLEEN BURNS, MARK S. FINEMAN, San Diego, CA Metformin delayed-release (Met DR) is formulated to deliver Met to the ileum where Met bioavailability is poor. Clinical studies have shown that gut- restricted Met DR is comparably effi cacious to conventional Met but at 40% 1311-P lower doses and markedly reduced exposure indicating that Met acts at the Pioglitazone Therapy Improves Insulin Suppression of Branched- gut epithelial level to lower glucose. While the gut is a major source of lactate chain Amino Acids in Patients with Prediabetes or T2DM and NAFLD production, it is unknown if Met gut exposure contributes to blood lactate NISHANTH SUNNY, FERNANDO BRIL, SRILAXMI KALAVALAPALLI, PAOLA POR- increases observed with conventional Met use. In this study, Wistar rats were TILLO SANCHEZ, MARYANN MAXIMOS, DIANE BIERNACKI, ROMINA LOMO- administered vehicle or Met by chronic indwelling catheters in the stomach NACO, KENNETH CUSI, Gainesville, FL (IG), the ileum, or a peripheral vein (IV). Plasma Met concentrations follow-

ing intra-ileum administration were ~10% that after IV administration and IG POSTERS Elevated plasma branched-chain amino acids levels (BCAAs) have been as- Therapeutics results were intermediate. Vehicle resulted in no changes in blood lactate by sociated with insulin-resistant states, such as T2DM and nonalcoholic fatty Clinical Diabetes/ liver disease (NAFLD). Pioglitazone improves liver histology in NAFLD, but its any route. IV and IG Met delivery at 500 and 750 mg/kg signifi cantly increased long-term effect on plasma BCAAs has not been explored in prior studies. blood lactate AUC (p<0.05 vs. vehicle) and blood lactate strongly correlated To this end, we measured in 50 patients (age: 54±1 yr; BMI: 34.0±0.7 kg/m2; with plasma Met (p<0.001). Intra ileum delivery did not increase blood lactate A1c: 6.5±0.1%) with biopsy-proven steatohepatitis (NASH) and prediabetes or and no lactate/met correlation was observed (p=0.65). Thus, blood lactate T2DM, plasma amino acids by targeted metabolomics, both fasting and during increases associated with Met are a result of plasma and not gut exposure. a 80 mU/m2/min euglycemic insulin clamp. Patients were then randomized to Given that lower bowel Met delivery lowers glucose without blood lactate pioglitazone (n=27) or placebo (n=23), and all measurements were repeated increases, Met DR may be a better alternative for patients with renal impair- after 18 months. No signifi cant differences were observed between groups at ment where Met plasma accumulation can be associated with lactic acidosis. baseline. Skeletal muscle insulin sensitivity (Rd) was modestly correlated with fasting plasma BCAAs, but strongly with insulin suppression of plasma BCAAs (Val: r=0.64, p<0.001; Leu: r=0.72, p<0.001; Isoleu: r=0.70, p<0.001). Pioglita- zone lowered fasting plasma BCAAs (i.e., Val: 298±11 vs. 333±9 µM, p<0.001), and this was associated with a signifi cant increase in insulin suppression of plasma BCAAs when compared to placebo (i.e., Val: 29±9% vs. 2±8%, p=0.03). Pioglitazone therapy did not signifi cantly affect suppression of any other amino acid, except tyrosine (29±9% vs. 0±9%, p=0.02), with a reduction of its levels 1314-P after therapy (85±4 vs. 96±4 µM, p=0.04). Most importantly, improved insulin Human Placenta-derived Adherent Cells (PDA-002) Enhance Angio- suppression of plasma BCAAs inversely correlated with positive changes in genesis and Muscle Repair, and Modify Adipose Tissue Homeosta- liver histology (NAFLD activity score; r=-0.44, p=0.003), Rd (r=0.41, p=0.006), sis in a Diabetic Mouse Model of Hindlimb Ischemia and in insulin suppression of plasma FFA (r=0.36, p=0.02). SHUYANG HE, EWA FIK, JOSEPH GLEASON, ANDREA FERULLO, ELLEN Z. BAUM, Conclusions: Pioglitazone treatment lowers fasting plasma BCAAs and im- WOLFGANG HOFGARTNER, ROBERT HARIRI, URI HERZBERG, Warren, NJ proves insulin suppression of BCAAs in patients with prediabetes or T2DM and Peripheral Artery Disease (PAD) is associated with reduced blood fl ow to NASH. Both liver histology and plasma BCAAs are modulated by pioglitazone, the lower extremities and is a common co-morbidity in type 2 diabetes melli- suggesting that future studies should examine shared metabolic pathways. tus. Animal models manifesting diabetic complications are an important tool Supported By: American Diabetes Association (1-08-CR-08 to K.C.); Burroughs to identify new, innovative therapeutic approaches for treating PAD, and the Wellcome Fund hindlimb ischemia (HLI) model in db/db mice replicates several aspects of the complex and multifactorial nature of PAD and type 2 diabetes. PDA-002 is a mesenchymal- like population of human placenta-derived adherent cells 1312-P for intramuscular administration and is currently in Phase 2 clinical trials for PAD and diabetic foot ulcer (DFU). Previously we demonstrated that PDA-002 treatment is anti-infl ammatory and promotes angiogenesis and tissue repair WITHDRAWN in Balb/c (non-diabetic) mice with HLI. In the current study, we examined PDA-002 activity in db/db mice with HLI. Treatment with PDA-002 resulted in increased blood perfusion and vascularity in the ischemic limb and in en- hanced repair of damaged tissue. PDA-002 also had benefi cial effects on aspects of the underlying diabetic disease, as demonstrated by a reduction in adipocyte infi ltration in both the ischemic and non-ischemic control limb, a reduction in plasma leptin by ~50%, and an enhanced anti-infl ammatory response as evidenced by (i) stimulation of M2 macrophage differentiation and (ii) upregulation of anti-infl ammatory and (iii) downregulation of infl am- matory adipokines in adipose tissue. Our results suggest that PDA-002 may offer a promising therapeutic approach to address the high unmet medical needs of the PAD/DFU patient population.

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A341 CLINICAL THERAPEUTICS/NEW TECHNOLOGY—PHARMACOLOGIC TREATMENT OF COMPLICATIONS

1315-P 1317-P Pharmacological Treatment Changes in 4,143 Patients with Dysreg- Effect of Spironolactone on Glycemic Control in Patients with Type ulated Diabetes Referred to a Tertiary Diabetes Center 2 Diabetes Mellitus NARGES SAFAI, MARTIN RIDDERSTRÅLE, Gentofte, Denmark RAJESH GARG, AJAY D. RAO, GAIL ADLER, Boston, MA Pharmacological changes are common when addressing dysregulated Mineralocorticoid receptor antagonists (MRA) are being increasingly used for type 2 diabetes (T2D). Our aim was to describe these changes in subjects treatment of resistant hypertension in patients with type 2 diabetes mellitus referred to a diabetes center with T2D. (T2DM). However, based on a few studies in heart failure, there are concerns Treatment data for patients with T2D referred between Jan 1st 2001 and about worsening of glycemic control after adding an MRA. We conducted a post- Jan 1st 2013 were extracted. Metabolic outcomes have been described pre- hoc analysis to evaluate glycemic control and frequency of diabetes treatment viously. Only between class comparisons were performed. intensifi cation in 65 patients with T2DM completing a 6 month, double blind, Metformin (Met) alone (18%) or combined with SU (28%), or insulin (Ins; randomized controlled trial. During a 3 month run in period, medications were 14%) was the most common medication at referral. Triple combinations were adjusted with a goal to achieve HbA1c ≤7%. Patients were then randomized to rare (1%). SU or Ins alone was seen in 10% and 7% of patients, respectively. spironolactone 25 mg daily or hydrochlorothiazide (HCTZ) 12.5 mg plus potassium 67% were on Met at discharge (Figure): Met alone 19%; Met/SU 20%; 10 meq daily or placebo daily. The subjects continued to monitor their blood glu- Met/Ins 18%; and 11% on other combinations: Met/GLP-1 4.2%; Met/GLP-1/ cose with weekly reporting to study staff. Changes in medications were allowed Ins 2.1%; Met/DPP4-i 1.3%; Met/SU/Ins 1.1%; Met/SU/GLP-1 1.0%; Met/ if required for optimal glycemic control. Treatment intensifi cation was defi ned as SU/DPP4-i 0.9%; Met/DPP4-i/Ins 0.4%. 91% of subjects on Met at referral addition of a new medication or increase in dose of current medications. There remained on Met. SUs were more commonly withdrawn (39%), whereas Ins were no differences in baseline characteristics among the 3 groups. HbA1c, fruc- was rarely discontinued (6%). tosamine and fasting blood glucose did not change signifi cantly in any of the 3 The HbA1c lowering effect differed signifi cantly between patients receiv- groups (Table 1). We found that 8% (2/25) patients in spironolactone, 12% (3/24) ing different treatment alternatives and was particularly benefi cial when in- in HCTZ and 6% (1/16) in placebo group required treatment intensifi cation (P = cluding a GLP-1 analogue in triple therapy (-18 vs. -12 mmol/mol, p=0.0001). NS). We conclude that in well controlled T2DM patients, spironolactone does not Ins and Met are the most likely drugs to be continued or newly prescribed, impair glycemic control. whereas SUs are more likely to be discontinued. The role for newer agents Table 1. Baseline Glycemic Control Parameters and Changes with Treatment. and triple combinations merits further investigation. Baseline At 2 months At 6 months POSTERS Therapeutics Spironolactone Group (N=25) Clinical Diabetes/ HbA1c, % 6.6 ± 0.5 6.8 ± 0.6 6.7 ± 0.5 Fructosamine, µmol/L 242 ± 25 238 ± 23 247 ± 28 Fasting Blood Glucose, mg/dL 106 ± 22 110 ± 22 115 ± 22 HCTZ Group (N=24) HbA1c, % 7.0 ± 0.9 6.9 ± 0.8 7.0 ± 0.9 Fructosamine, µmol/L 237 ± 37 238 ± 30 247 ± 35 Fasting Blood Glucose, mg/dL 106 ± 25 111 ± 22 114 ± 24 Placebo Group (N=16) HbA1c, % 7.0 ± 0.7 6.8 ± 1.0 7.0 ± 0.8 Fructosamine, µmol/L 245 ± 46 252 ± 52 248 ± 42 Fasting Blood Glucose, mg/dL 105 ± 24 106 ± 34 108 ± 29 1316-P Effect of Rebamipide on Gastrointestinal Symptoms in Patients with Supported By: National Institutes of Health (1RO1HL087060-01A2) Type 2 Diabetes Mellitus SANG YOUL RHEE, SEJEONG PARK, YU JIN KIM, SOO MIN HONG, SO YOUNG 1318-P PARK, SUK CHON, SEUNGJOON OH, JEONG-TAEK WOO, SUNG WOON KIM, YOUNG SEOL KIM, Seoul, Republic of Korea WITHDRAWN Atypical gastrointestinal symptoms are common in patients with type 2 diabetes mellitus (T2DM). The current study was designed to evaluate the symptom improvement after the administration of rebamipide, a mucopro- tective agent that stimulates prostaglandin biosynthesis in patients with T2DM. T2DM subjects whose age was 18 to 80 years with atypical gastrointes- tinal symptom were enrolled. Participants were obliged to answer DBSQ (Diabetes Bowel Symptom Questionnaire) before and after the 12 weeks administration of rebamipide and the change in gastrointestinal symptoms were assessed. DBSQ is comprised of 10 questions assessing the severity of gastrointestinal symptom by 1 to 6 scoring system. Follow-up assessments were done to identify drug related side effects at 6 weeks and 12 weeks. Total 107 patients were enrolled and 84 patients completed the study. Mean age was 65.0±7.8, 24.8% of the subjects were male, mean DM dura- tion was 14.71±9.12 years and mean HbA1c level was 6.97±0.82%. Rebamip- ide 100mg was administered three times daily for each participant. DBSQ to- tal score was reduced from 24.9±8.0 to 20.4±7.3 before and after the admin- istration of rebamipide demonstrating a signifi cant change (p<0.001). Each score of the variables assessing heartburn, refl ux symptoms, postprandial dyspepsia, nausea or vomiting, abdominal bloating or distension, heartburn associated with gastric ulcer, abdominal pain, and constipation were im- proved after the administration of rebamipide (p<0.05). However, there were no signifi cant changes in irritable bowel symptoms and bowel incontinence. Severe adverse event was not reported throughout the study. Treatment with rebamipide for 12 weeks could be an effective treatment option for atypical gastrointestinal symptoms in subjects with T2DM. Supported By: Otsuka Pharmaceutical Group; Ministry of Health and Welfare of the Republic of Korea (HI10C2020)

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A342 HEALTH CARE DELIVERY—ECONOMICS

HEALTH CARE DELIVERY—ECONOMICS 1320-P WITHDRAWN Guided Audio Tour: Barriers to Patient-Centered Diabetes Care in the Cur- rent Era (Posters: 1319-P to 1326-P), see page 13.

& 1319-P Geographic Variations in Endocrinologist Access for U.S. Adults with Diagnosed Diabetes HUA LU, YILING J. CHENG, JAMES B. HOLT, XINGYOU ZHANG, JANET B. CROFT, Atlanta, GA Endocrinologists are specialists who treat hard-to-control diabetes (DM). To explore county-level variations in endocrinologist access for U.S. adults with DM, we used service locations of endocrinologists from the 2012 National Pro- vider Identifi er Registry and the CDC 2011 estimates of adults aged ≥20 years with diagnosed DM. The number of endocrinologists in a county was estimated using the container approach with a 20-mile buffer distance. Fig 1 shows num- ber of endocrinologists per location overlaid with county-level numbers of adults with DM. Fig 2 shows the ratio of number of adults with DM to number of endo- crinologists by county. Our fi ndings show that the U.S. has a shortage of endo- crinologists in the Midwest, and there are substantial county-level geographic variations in endocrinologist access for U.S. adults with DM. POSTERS Therapeutics Clinical Diabetes/

& 1321-P Real-World Medication Utilization and Glycemic Control in Type 2 Diabetes Patients: A Longitudinal Database Analysis ARTHI CHANDRAN, MONIKA PARISI, RITA SALTIEL-BERZIN, DRILON SALIU, MACHAON BONAFEDE, Franklin Lakes, NJ, Boston, MA Type 2 diabetes (T2D) affects 95% of 29.1 million patients with diabetes in the U.S. Guidelines from the ADA recommend stepwise treatment intensifi ca- tion. This study describes medication utilization patterns in T2D patients start- ing treatment with oral anti-diabetics (OADs), basal insulin, or prandial/mixed insulin, and associated changes in HbA1c. A retrospective analysis using Truven Health MarketScan® Research Databases identifi ed adults (≥18 years) with T2D diagnosis from 2006-2012 based on ICD-9 codes 250.x0 or 250.x2. Patients were placed into four cohorts based on their initial T2D therapy: cohort 1 (n=597,664) - newly diagnosed, not on therapy; cohort 2 (n=342,511) - OAD initiators; cohort 3 (n=99,578) - basal insulin initiators; and cohort 4 (n=62,876) - prandial/mixed insulin initiators. Patients transitioned cohorts once they met the criteria for the next one. Mean age ranged from 56.2 (cohort 2) to 59.1 years (cohort 1). In cohort 1, patients increasingly initiated OADs by years 2 (9%), 3 (15%) and 4 (19%). In co- hort 2, metformin use decreased from year 1 through 4 (77% to 54%), while use of DPP-4s and GLP-1s increased from 10% to 14% (years 1 and 2). Approximately 1% of patients added basal insulin to their OAD regimen annually. In cohort 3, basal insulin usage decreased from 71% to 47% (years 1 to 4), and 33%-38% of patients switched to prandial/mixed insulin each year. In cohort 4, 69% of pa- tients were using basal insulin at year 1, which decreased to 54% by year 4. Use of prandial/mixed insulin decreased to 61% by year 4. Patients in cohort 1 who were not on OADs had a mean HbA1c of 6.3% during follow-up. Mean HbA1c val- ues decreased from pre-index to year 1 but then remained stable during follow- up for cohorts 2 (7.2%), 3 (8.1%), and 4 (8.0%), respectively. While HbA1c levels were elevated during the follow-up period, treatment intensifi cation was low. Findings suggest the need for more timely treatment intensifi cation to better control diabetes in the T2D population.

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A343 HEALTH CARE DELIVERY—ECONOMICS

& 1322-P HbA1c (mean 9.1± 1.3%) and 4 meetings with 46 primary care physicians Hypoglycemia and Medical Expenses in Patients with Type 2 Dia- (PCPs) to investigate barriers and facilitators to effective communication betes Mellitus: An Analysis Based on the Korea National Diabetes during primary care visits. Study participants were all from a single inte- Program Cohort grated healthcare system. We iteratively reviewed transcripts and fi eld SANG YOUL RHEE, SOO MIN HONG, SUK CHON, KYU JEUNG AHN, SUNG HOON notes to develop a thematic coding scheme. Patients reported a range of KIM, SEI HYUN BAIK, YONGSOO PARK, MOONSUK NAM, KWAN WOO LEE, facilitators and barriers to communication including: 1) whether (or not) JEONG-TAEK WOO, YOUNG SEOL KIM, Seoul, Republic of Korea, Incheon, Republic their doctors asked about stressful life events affecting their diabetes; 2) of Korea, Suwon, Republic of Korea the extent to which the provider focused on lifestyle counseling vs. medica- Hypoglycemia is one of the important adverse events in people with type 2 tions; and 3) amount of time reserved to discuss patient concerns. Some diabetes mellitus (T2DM). However, hypoglycemia related events had usual- patients reported “shutting down” after perceiving that the provider was ly overlooked and less documented in the clinical practice. We evaluated the not listening to them, or not setting realistic lifestyle change expectations. incidence, clinical characteristics, and medical expenses of hypoglycemia- PCPs reported a willingness to discuss non-medical issues that was sharply related events in T2DM patients based on the Korea National Diabetes Pro- balanced by a consistent theme of insuffi cient time during visits. Similarly, gram (KNDP), which is the largest multi-center, prospective cohort in Korea while PCPs reported that discussing non-medical issues such as stress at (n=4,350). To determine precise outcomes, we simultaneously used national work or home were important for diabetes care, they tended to express a representative databases: claims data from the Health Insurance Review & preference for discussing actionable data (e.g. blood glucose levels, medica- Assessment Service of Korea and death certifi cation from Statistics Korea. tion discrepancies). Addressing multiple medical and non-medical concerns During a median follow-up period of 3.3±0.8 years, 149 subjects (3.3%) were during time-limited primary care visits is a challenge. Both patients and newly identifi ed to experience hypoglycemia by diagnostic codes, and the in- physicians identifi ed the importance of creating and sustaining relationships cidence of hypoglycemia was 10.1 cases per 1,000 person-years. Those with with good communication, but this goal was hampered by numerous barri- hypoglycemia were signifi cantly older (61.7±11.1 years vs. 52.2±10.4 years, ers. Structured pre-visit patient preparation and/or longer visits planned to p<0.001), had much numbers of hospital visit (35.4±1.3/year vs. 24.3±0.7/ enable greater discussion of patient concerns may be needed to improve year, p<0.001), longer length of hospital stay (25.0±9.5 day/year vs. 14.7±1.0 diabetes primary care. day/year, p<0.001), spent more cost ($2,424±410/year vs. $1,183±170/year, Supported By: National Institute of Diabetes and Digestive and Kidney Diseases p<0.001), and demonstrated higher tendency of mortality (0.67% vs. 0.18%)

POSTERS compared to the subjects who have not experienced hypoglycemia. In con- & 1325-P Therapeutics clusion, hypoglycemia-related events infrequently identifi ed in the medical Patients’ Perspectives on Improving Health Care for Diabetes and Clinical Diabetes/ record among T2DM subjects. However, it was signifi cantly associated with Chronic Kidney Disease their poor clinical outcomes and thus could raise a substantial burden on CLEMENT LO, DRAGAN ILIC, HELENA J. TEEDE, GREG FULCHER, MARTIN GAL- national healthcare system in Korea. LAGHER, GREG JOHNSON, PETER KERR, TIM MATHEW, KERRY MURPHY, KEVAN Supported By: Republic of Korea Ministry of Health and Welfare (HI10C2020) POLKINGHORNE, ROWAN WALKER, SOPHIA ZOUNGAS, Clayton, Australia, Mel- bourne, Australia, Sydney, Australia, Camperdown, Australia, Canberra, Australia, & 1323-P Prahran, Australia Patient and System Factors Associated with Persistence vs. Reso- This qualitative study explored barriers, enablers and possible health- lution of Poor Glycemic Control care improvements for the treatment of diabetes and chronic kidney disease YOU M. WU, HONG XIAO, RICHARD W. GRANT, Oakland, CA (CKD), by examining the perspectives of patients and their carers. Prolonged hyperglycemia leads to diabetic complications and increased Patients with diabetes and CKD (eGFR < 60 ml/min/m2) were purposively health care costs. Many care systems have adopted team-based strate- sampled for focus groups conducted at 4 major health services in Australia’s gies to improve diabetic care, but optimal team response to elevated HbA1c 2 largest cities. Separate focus groups were conducted for patients with results is not known. We conducted a case control study to examine pa- CKD stage 3, 4, and 5 respectively. Findings were triangulated with 8 semi- tient- and team-level factors associated with persistence vs. resolution of structured interviews of carers of patients with CKD stage 5. All discus- elevated A1c levels. Among patients with type 2 diabetes receiving care in sions were audiotaped, transcribed verbatim and thematically analysed by an integrated care system from 2011 to 2014, we identifi ed a cohort with 2 researchers. newly elevated A1c (i.e. 2 A1c levels of ≤8% followed by an “index” elevated A total of 58 participants, aged 66.9 +/- 9.3 years with type 2 diabetes A1c ≥10%). From this cohort, we selected cases with persistent HbA1c el- of duration 19.2 +/- 10.6 years, partook in 12 focus groups. Thirty-eight % evation (subsequent 2 A1c values after the index A1c also ≥10%, n=100) and had stage 3B, 26% stage 4 and 36% stage 5 CKD (most on dialysis). Partici- controls who regained glycemic control (subsequent 2 A1c’s after index ≤8%, pants emphasised the importance of implementing a patient-centred care n=100). Cases were more likely to be on insulin prior to index A1c (4.5 [2.0- approach, with specifi c emphasis on two key domains: patient, and health- 10.2], p <0.001) and have longer DM duration (OR >10 years 2.71, [1.38-5.33], care factors. Barriers and enablers for patient facilitated care included: 1) p=0.004), but had similar psychiatric diagnosis prevalence (p=0.52). Initial social situation 2) patient empowerment 3) psychological disposition and ef- team response to the index elevated A1c was similar: both groups were con- fects from illness 4) fi nances 5) patient self-management 6) adverse effects tacted within 3-5 days (p=0.13), initial outreach (e.g. by phone, mail, secure and demands related to disease and its treatment. Although participants message or in-person) was similar (p=0.41) with similar contact success rate expressed a level of satisfaction regarding their experience with the health- (p=0.10). However, cases had longer delay to next A1c result (146 days vs. care system, barriers requiring improvement included: 1) long waiting room 103 days; OR=1.01, CI [1.006, 1.02]), p < 0.001) and next PCP visit (61 days vs. times 2) poor continuity and coordination of care 3) problems with access, 22 days, p < 0.001), were less likely to have their regimen intensifi ed (0.26 and 4) poor recognition of psychological comorbidity. They also suggested [0.11, 0.64] p=0.004), and had fewer follow-up visits within 3 months that greater patient empowerment and implementation of public health interven- were DM-specifi c (58% vs. 68%, p=0.02). Cases were more likely to have tions preventing the onset and progression of diabetes and CKD. life stressors (e.g. family death, caregiving, fi nancial issues) compared to the Patients and their carers emphasized the importance of patient empower- control group (2.5 [1.3-4.7], p <0.01). Adjusting team responses to increase ment and self-management in the health-care of diabetes and chronic kidney PCP involvement at an earlier stage and scheduling diabetes-specifi c visits disease via a patient-centred, holistic, coordinated and preventative health- may represent one team-based strategy for more challenging patients. care system. Supported By: National Institute of Diabetes and Digestive and Kidney Diseases Supported By: Australia National Health and Medical Research Council (10555175) & 1324-P Patient-Provider Communication in Primary Care: A Qualitative & 1326-P Study of Patients with Poorly Controlled Diabetes and Their Primary Overcoming Language and Cultural Barriers among Spanish-Speak- Care Physicians ing Latino Health Plan Members with Poorly Controlled Diabetes RICHARD W. GRANT, CONNIE S. URATSU, GABRIELA X. SANCHEZ, KAREN R. GABRIELA SANCHEZ, CINDY D. BONILLA, RICHARD W. GRANT, Oakland, CA HANSEN, ANDREA ALTSCHULER, Oakland, CA Diabetes is rising to epidemic levels among U.S. Latinos. Latinos also Most patients with type 2 diabetes are managed in the primary care set- have poorer glycemic control, even among those with health insurance. We ting. Many patients have multiple concerns that cannot be addressed in a conducted a qualitative study of Latino health plan members with poorly single visit. We conducted 4 focus groups with 29 patients with elevated controlled diabetes to gain insight into how these patients prepare for and interact during visits with their primary care physicians (PCPs). We conduct-

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A344 HEALTH CARE DELIVERY—ECONOMICS ed 4 focus groups with 36 Spanish-speaking adults (19 men, 17 women) with global healthcare expenditures related to diabetes. The 2014 IDF Diabetes Atlas elevated HbA1c. Two groups had Spanish-speaking PCPs and 2 groups had estimates for the North America and Caribbean Region are reported here. English-speaking PCPs. Study participants were all from a single integrated Health care expenditures due to diabetes for the region were calculated healthcare system. We iteratively reviewed transcripts and fi eld notes to as a sum of the expenditures from 28 countries and territories, which was develop a thematic coding scheme. Patients were 57.9 (11.2) years old, all estimated using an attributional fraction model. Data needed for the model were foreign born, mean HbA1c was 8.6% (1.5%), and mean health plan were obtained from: 2014 estimates of population by age and sex from the membership was 24.81 (11.63) years. Key themes related to communication United Nations World Population Prospects (2012), diabetes prevalence es- included: 1) Deference (patients viewed MDs as respected experts and tend- timates from the IDF Diabetes Atlas (2014), health expenditure estimates ed to defer their own questions until the end of the visit if there was time), (2012) from the World Health Organization, and expenditure ratios between 2) Pragmatism (patients tended to expect tangible solutions to symptomatic persons with and without diabetes from U.S. Kaiser health insurance claims problems), 3) Lack of proactivity (patients tended not to prepare for visits data. Expenditures were expressed in 2012 U.S. dollars (USD). and allowed PCPs to set the visit agenda). When we compared subjects with The estimated total healthcare expenditure due to diabetes in the region Spanish-speaking vs. English-speaking PCPs, we found that patients with was 310 billion USD or 1 dollar in 8 of the regional total health spending Spanish-speaking PCPs felt much more comfortable but still had a tendency in 2014. The age-group with the highest spending was the 5.2 million fe- to defer, while patients with English-speaking PCPs were reluctant to switch males aged 60-69 (47 billion USD). The age-group with the lowest level of to Spanish-speaking PCPs because they had an established relationship and spending was the 0.7 million males aged 20-29 (5.7 billion USD). There were as long as they felt personally respected. As Latino patients with diabetes great disparities in health spending between countries. Haiti had the lowest grow in number, supporting effective patient-provider communication dur- per capita spending of 145 USD, compared to the U.S. with the highest per ing time-limited visits becomes increasingly important. Our results suggest capita spending at 10,902 USD. that interventions to help Latino patients prepare for visits by eliciting their Diabetes imposes a large economic burden on the region’s healthcare priorities and concerns may support more productive visit encounters. systems. Our data reveals the urgency of preventing new cases of diabetes Supported By: National Institute of Diabetes and Digestive and Kidney Diseases and of effi cient management of the existing diabetes population to reduce this economic burden. Guided Audio Tour: From Greater Costs to Greater Value—Evaluations of Diabetes Care Delivery (Posters: 1327-P to 1334-P), see page 17. & 1329-P

Provider Type and the Quality of Diabetes Care: Implication for the POSTERS Affordable Care Act (ACA) Therapeutics & 1327-P Clinical Diabetes/ SALIM S. VIRANI, JULIA M. AKEROYD, DAVID J. RAMSEY, SUJA S. RAJAN, Medical Expenditures Associated with Diabetes in U.S. Adults (Age CHRISTIE M. BALLANTYNE, LAURA A. PETERSEN, Houston, TX 20 to 64 Years) in 2012: Private vs. Medicaid Insurance With the ACA implementation, the current number of physicians will SUNDAR SHRESTHA, PING ZHANG, GIUSEPPINA IMPERATORE, Atlanta, GA not be suffi cient to accommodate 30-40 million Americans who will obtain Whether or not the fi nancial burden associated with diabetes (DM) var- health care access. A proposed solution is to utilize non-physicians (nurse ies between privately and Medicaid insured adults is unclear. We provide practitioners, physician assistants) for chronic disease care. Whether dia- such estimates using data from U.S. adults (age 20 to 64 years) enrolled in betes care quality delivery by non-physicians and physicians is comparable fee-for-service payment plans in the 2012 MarketScan database. Our analy- is not known. We utilized a national cohort of outpatients with diabetes sis included 739,694 and 4,733 persons with DM and 3,698,470 and 23,655 (n=849,849) receiving care in 130 Veterans Affairs facilities between Oc- age- sex-matched persons without DM using private and Medicaid insurance, tober 2012 and September 2013. Using hierarchical regression adjusting for respectively. We stratifi ed the study population into two age groups and used illness-severity and other covariates (Table), we compared quality of gly- two-part regression models to estimate the medical expenditure in total and cemic (HbA1c<7%), blood pressure [BP] (<140/90 mmHg), and cholesterol by service (outpatient, inpatient, and prescription drug) for persons with and (LDL-C<100 mg/dL, statin use) care between patients receiving care from without DM. The expenditures associated with DM were calculated as the dif- physicians (n=649,121) and non-physicians (n=200,728). The quality (Table) of ference in predicted expenditures between persons with and without DM. glycemic and BP control was marginally higher for diabetic patients receiv- Total medical expenditures associated with diabetes paid under Medic- ing care from non-physicians, whereas, cholesterol care quality was mar- aid were higher than those under private insurance, especially in younger ginally higher for those receiving care from physicians. Outpatient diabetes adults. The higher expenditure was mainly due to the higher expenditures care quality delivered by physicians and non physicians was mostly com- on outpatient care and drugs (Table). Further study is needed to investigate parable. Therefore, a collaborative diabetes care delivery model employing the reasons for and implications of the higher expenditures due to DM in physicians and non-physicians may deliver at least a comparable quality Medicaid than private insurance. compared with a physician-only model. This has implications as more Ameri- Table. Annual Mean Excess Predicted Medical Expenditures ($) Associated cans access care. with Diabetes among Adults. Table. Expenditures Age: 20-44 years Age: 45-64 years Private Medicaid Difference Private Medicaid Difference Outpatient 2089 3657 1568† 3357 3739 382† (2051, 2127) (3573, 3742) (3336, 3379 (3567, 3912) Inpatient 2040 1255 -785† 1623 1562 -61 (2023, 2057) (1203, 1307) (1618, 1627) (1436, 1687) Prescription Drugs 1585 3105 1520† 3313 3664 351† drugs (1578, 1529) (3069, 3141) (3307, 3319) (3510, 3819) Total 5715 8017 2302† 8293 8966 673† (5659, 5770) (7861, 8174) (8265, 8321) (8597, 9334 †difference in mean between private and Medicaid is statistically signifi cant (p<0.05); Figures in brackets are 95% lower and upper confi dence limits.

& 1328-P Estimated Health Care Expenditures due to Diabetes in the North America and Caribbean Region JOAO DIOGO DA ROCHA FERNANDES, LYDIA E. MAKAROFF, LEONOR GUAR- IGUATA, UTE LINNENKAMP, PING ZHANG, TILL SEURING, KATHERINE OGURT- SOVA, Brussels, Belgium, Atlanta, GA Diabetes imposes a large economic burden on healthcare systems due to costs of preventing and treating the disease and its related complications and comorbidities. The International Diabetes Federation (IDF) Diabetes Atlas tracks Supported By: American Diabetes Association (1-14-CE-44 to S.S.V.)

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& 1330-P & 1332-P Benchmarking T2DM Treatment Effectiveness in Clinical Practice The Effect of HbA1c Admission Testing Strategies on Diabetes Med- MARCIA A. TESTA, ALEXANDER TURCHIN, OLUKAYODE A. SOSINA, DONALD C. ication Management at Discharge SIMONSON, Boston, MA MOLAIN SAINTILUS, JONAH FELDMAN, TONY MATHEWS, KHALILAH DALEY, We previously developed a clinical treatment algorithm to personalize VIRGINIA PERAGALLO-DITTKO, Mineola, NY HbA1c goals and establish high benchmark probabilities (HBPs) for achiev- One of The Joint Commission inpatient diabetes care certifi cation stan- ing glycemic control using clinical, demographic and social markers from dards requires that patients with known diabetes have a HbA1c drawn on ad- a pooled clinical trials database. To test the model in clinical practice, we mission. To meet this standard, our 591-bed teaching hospital implemented used a 10-year electronic health record (EHR) database of 2,477 patients programmatic interventions intended to improve ordering habits through with T2DM (58% female, 57.3% White, 16.8% Black, 16.6% Hispanic) who standardized admission order sets. This resulted in a 90-98% adherence rate were recently diagnosed, medication naïve, with mean ± SD age=59±13 with the performance measure. The benefi t of testing admission HbA1c levels yrs, HbA1c=8.7±1.8%, BMI=33±7 kg/m², and median income =$51,296. Ini- can be maximized if the results are coupled with adjusting diabetes medica- tial monotherapy was metformin (MET; 77.8%) or sulfonylurea (SU; 22.2%). tions at discharge. The goal of this study is to investigate whether standard- The prototype logistic regression model applied to the EHR yielded clinical ized interventions to ensure HbA1c testing lead to an increase in medication performance probabilities (CPPs) for achieving HbA1c < 7.0% and < 8.0% adjustment at discharge for patients with uncontrolled diabetes. using inputs of initial HbA1c, sex, age, BMI, DM duration, race/ethnicity and We performed chart reviews on patients with uncontrolled diabetes income. Both HBP and CPP models revealed covariate-dependent treatment [HbA1c ≥ 10% (86 mmol/mol)] admitted to the hospital during two different effectiveness heterogeneity, p < 0.001. The predictive validity of the HBP time periods: one prior to the interventions (April-June 2009) and one after model (ROC area=0.91) was higher than the CPP model (ROC area=0.73). (October-December 2012). Data were adjusted for mean HbA1c, age, gender, HBPs for a reference White male, age=50 yrs, BMI=30, FPG=150 mg/dl, cardiovascular co-morbidities, medication type, and reason for admission HbA1c=9.0%, and DM duration=1 yr were 0.06 and 0.48 for achieving HbA1c (diabetes-related vs. other). < 7% and < 8% without treatment, compared to 0.51 and 0.94 on SU. The We found that patients in the 2012 cohort (N=123) whose HbA1c tests corresponding CPPs were 0.46 and 0.62 for HbA1c < 7% and < 8% on SU, but were ordered through a standardized order set were signifi cantly less likely were higher on MET {CPPs =0.66 and 0.79 [OR (95% CLs): 1.8 (1.5, 2.3) and to have a change in medication type or dosage on discharge when compared 2.2 (1.7, 2.8) for HbA1c < 7% and < 8%; p < 0.001]}. HBPs for a reference Black to the 2009 cohort (N=124) whose HbA1c tests were purposefully ordered POSTERS Therapeutics female, age=50 yrs, BMI=36, FPG=150 mg/dl, HbA1c=9.5%, DM duration=1 (64.2% vs. 83.1%, Adjusted Odds Ratio 4.30, p-value < 0.001).

Clinical Diabetes/ yr were 0.04 and 0.18 without treatment, and 0.41 and 0.78 with SU. Cor- These results reveal an unintended consequence of programmatic mea- responding CPPs were 0.42 and 0.55 with SU, and 0.57 and 0.73 with MET. sures designed to improve ordering habits for HbA1c. Medications were less Standard glycemic control targets are typically static, population-based, likely to be adjusted when HbA1c was not purposefully ordered. Our fi ndings and seldom benchmarked against a high quality reference. In contrast, a suggest that admission HbA1c ordering strategies alone do not lead to an personalized benchmark using clinical and sociodemographic data refl ecting increase in the likelihood of using the results to adjust diabetes medications treatment heterogeneity might yield more realistic patient-centered glyce- at discharge. The diminished mindfulness associated with health informa- mic goals for T2DM. tion technology highlights the importance of formal evaluation of intended Supported By: Patient-Centered Outcomes Research Institute (CE1304-6756) effects.

& 1331-P & 1333-P Acute Admission Rates among Patients with Diabetes Mellitus to Effectiveness of Telehealth Management of Diabetes among Veterans Assess Performance of Accountable Care Organizations WINNIE Y. LIU, DAVID SAXON, REBECCA SANAGORSKI, NEDA RASOULI, Aurora, KASIA J. LIPSKA, ERICA S. SPATZ, HAIKUN BAO, YING DAI, CRAIG S. PARZYN- CO, Denver, CO SKI, ZHENQIU LIN, FASEEHA K. ALTAF, ERIN K. JOYCE, JULIA A. MONTAGUE, JO- Telehealth (TH) is a signifi cant and rapidly growing component of health- SEPH S. ROSS, SUSANNAH M. BERNHEIM, HARLAN M. KRUMHOLZ, ELIZABETH care in the United States. The Department of Veterans Affairs (VA) has DRYE, New Haven, CT spearheaded the use of several TH modalities including live interactive Population-based admission rates are important indicators of ambulatory video visits between providers and patients. However, there is limited data care quality among people with chronic conditions, such as diabetes. Un- on the effectiveness of TH in improving glycemic control in patients with der contract with the Centers for Medicare & Medicaid Services (CMS), we diabetes. Thus, we aimed to examine the effectiveness of clinical video developed a claims-based quality measure for Accountable Care Organiza- TH versus face-to-face (FTF) visits in delivering diabetes care to Veterans. tions (ACOs) based on risk-standardized acute, unplanned admission rates Our primary outcome was improvement in glycemic control measured by a (RSAARs) among patients with diabetes. CMS recently added this measure change in A1c levels before and after consultation. We hypothesized that to the ACO pay-for-reporting and pay-for-performance measure set. glycemic control through TH would be non-inferior to traditional FTF care. Using 2010-2012 Medicare claims data, we fi t a hierarchical negative bi- The study employed a retrospective, cohort design and included Veterans nomial model that adjusted for age and comorbidities based on all Medicare received fi rst-time consultations for diabetes care from Denver VA Medical Fee-For-Service (FFS) patients with diabetes. We estimated risk-standard- Center between 10/1/2013 and 9/30/2014. Patients who received a mix of ized ratios of predicted to expected numbers of admissions for 114 ACOs TH and FTF visits as well as patients who did not have any follow-up A1c in the Medicare Shared Savings Program (MSSP) in 2012. We calculated values were excluded. To eliminate variability in providers, only consultation the RSAARs by multiplying these ratios by the national rate of admissions performed by licensed nurse practitioners in the division of endocrinology among Medicare FFS benefi ciaries with diabetes. We used bootstrapping to were included. A total of 154 Veterans (144 male, age of 63 ± 9 years) with estimate 95% confi dence intervals and assigned ACOs to 3 performance cat- diabetes were included in this study (94 in the TH and 60 in the FTF group). egories: “no different,” “worse than,” and “better than” the national rate. The initial A1c levels were similar between two groups (9.81 ± 1.74% in the Among 6.5 million Medicare FFS benefi ciaries with diabetes (mean age TH and 9.57 ± 2.36% in the FTF, p=0.49). Both groups had improvements in 76.4, 45.3% male, 5.2% in MSSP ACOs), the national rate of acute, unplanned glycemic control at the follow up visits; A1c decreased to 8.45±1.41% (p=1.98 admissions was 41.4 per 100-person years. Among 341,193 Medicare FFS pa- x10-8 vs. baseline) and 8.50 ± 1.79% (p=0.006 vs. baseline) for the TH and tients in MSSP ACOs (mean age 75.9, 50.7% male), the median RSAAR was FTF groups. The changes in A1c were not signifi cantly different between the 39.1 per 100 person-years (interquartile range 34.8 to 43.9; range 23.9-68.1). two groups (1.40% in the TH and 1.08% in FTF groups, p=0.39). The days to 51 ACOs (44.7%) had RSAARs that were “no different” from the national fi rst follow up A1c after initial consultation was similar between the two rate, 45 ACOs (39.5%) had RSAAR scores “better than” and 18 ACOs (15.8%) groups (110.3±62.1 in the TH vs. 94.2 ± 56.4 in the FTF, p=0.10). These data had RSAAR scores “worse than” the national rate. suggest that TH is non-inferior to FTF care with regards to the improvement A substantial proportion of MSSP ACOs achieved lower RSAARs compared in glycemic control in Veterans with poorly controlled diabetes. with the national rate, suggesting that many ACOs may manage patients with diabetes better than non-ACO providers. However, ACO performance varied pointing to further opportunities to improve care. Supported By: Centers for Medicare and Medicaid Services

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1336-P & 1334-P Primary Care Is Central for Health Care Improvement for Diabetes Development and Validation of HealthImpact: An Incident Diabetes and Chronic Kidney Disease Prediction Model Based on Administrative Data CLEMENT LO, HELENA TEEDE, DRAGAN ILIC, KERRY MURPHY, GRANT RUSSELL, ROZALINA G. MCCOY, VIJAY NORI, STEVEN A. SMITH, CHRISTOPHER A. HANE, TIM USHERWOOD, SOPHIA ZOUNGAS, Clayton, Australia, Melbourne, Australia, Rochester, MN, Cambridge, MA Notting Hill, Australia, Westmead, Australia Type 2 diabetes can be prevented or delayed if high risk individuals are Provision of effective health-care for people with diabetes and chronic identifi ed early. Current individual and population screening methods rely kidney disease (CKD) in the primary care setting can be challenging. In this on laboratory detection of hyperglycemia, which can be burdensome and qualitative study we explore barriers, enablers and possible strategies for costly, and fail to capture all those at risk. We therefore developed the improving health-care in this patient cohort. ™ HealthImpact model to prospectively identify patients at risk for diabetes We sought to recruit a representative sample of primary care physicians using only administrative data. HealthImpact was developed and internally (PCPs) working in the health regions of 4 major hospitals in Australia’s 2 validated in a population of commercially insured adults, age ≥18 years, us- largest cities. Respondents to a widely distributed letter of invitation at- ing administrative data from Optum Labs Data Warehouse (OLDW); n=473049 tended a single focus group in each region. Focus groups were led by the in training dataset and n=776074 in the internal validation dataset. We then same facilitator, audio recorded and transcribed verbatim. Data analysis externally validated HealthImpact in 2000000 non-diabetic adults in OLDW was completed independently by 2 researchers using a thematic approach, followed prospectively for 3 years. HealthImpact, scored on a linear scale before consensus was reached about the emerging themes. 0-100, includes 47 demographic, medical, and medication variables obtained Twenty-two PCPs participated (20 male and 2 female) in 4 focus groups. from administrative data; bias-corrected c-statistic 0.80815. In the training The following prevalent themes emerged as barriers to optimal diabetes and population, we identifi ed HealthImpact scores of 50, 75, and 90 as indicative CKD management in primary care: 1) Patient factors impacting involvement in of low, intermediate, and high risk of incident diabetes. HealthImpact had very health-care (including understanding of disease, psychosocial and economic good discrimination in the internal (c-statistic 0.8270) and external (c-statistic factors) 2) Lack of a preventive approach to health-care, 3) Poor access to 0.8171) validation cohorts. In the external validation dataset, the sensitivity, specialist care, 4) Suboptimal communication between specialists and PCPs, specifi city, positive predictive value, and negative predictive value of Health- and 5) Inadequate coordination of care, with poor role defi nition between Impact >50 for incident diabetes at 3 years were 66.60%, 67.18%, 4.92%, and health professionals. Overall, PCPs were of the view that the PCP-patient 98.7%; for HealthImpact >75, 32.84%, 90.98%, 8.49%, and 98.15%; and for relationship was central with input from specialist health-professionals. The POSTERS HealthImpact >90, 14.43%, 97.23%, 11.73%, and 97.81%. In sensitivity analy- majority of PCPs expressed a desire to be included in the health-care of Therapeutics sis, HealthImpact performed comparable to invasive glycosylated hemoglobin, patients with advanced CKD. From their perspective, health-care improve- Clinical Diabetes/ glucose, and glucose tolerance testing in predicting incident diabetes. Heal- ment for diabetes and CKD could include greater access to specialist care, thImpact is an effi cient and effective method of risk stratifi cation for incident better coordination, collaboration, communication and role clarity between diabetes that does not rely on patient-provided information or lab tests, and specialists and PCPs, and a greater preventive approach. can be used by health systems and payers that administrative data. In this study, PCPs express a desire for a central role in the care of patients with diabetes and CKD. Their perspectives suggest that PCP engagement in 1335-P the care of diabetes and CKD is important for health-care improvement. Impact of High Deductible Health Plans on Medication Use in Dia- Supported By: Australia National Health and Medical Research Council betes: A NEXT-D Study (1055175) DENNIS ROSS-DEGNAN, CHRISTINE LU, FANG ZHANG, EMMA B. MORTON- EGGLESTON, ROBERT LECATES, STEPHEN SOUMERAI, JAMES F. WHARAM, 1337-P Boston, MA Real-World Outcomes of Patients with Type 2 Diabetes Mellitus High deductible health plans (HDHP) will soon be the predominant insur- (T2DM) Treated with Canaglifl ozin in a U.S. Managed Care Setting ance benefi t in the U.S., and the Affordable Care Act (ACA) will dramatically WING CHOW, ERIN K. BUYSMAN, MARCIA F.T. RUPNOW, HENRY J. HENK, Rari- increase enrollment. HDHPs include potential annual out-of-pocket costs of tan, NJ, Eden Prairie, MN $1000-$6000 for most services and might reduce medication adherence. Canaglifl ozin (CANA), an agent that inhibits sodium glucose co-transporter Scant data exists regarding the impact of HDHPs on medication use in DM. 2, improves glycemic control through an insulin-independent mechanism. We studied claims data of 2090 patients with DM who were continu- This study evaluates the impact of CANA on glycemic control in a real-world ously insured for ≥3 years between 2004-12. We assessed insulin fi lls per setting. month and 30-day oral hypoglycemic, statin, and non-statin lipid lowering This retrospective cohort study used data from a large U.S. health plan medication fi lls for 1 year before and 2 years after mandated switch from for adult commercial and Medicare Advantage enrollees with T2DM fi lling traditional to HDHPs, compared with 1:1 propensity score matched controls. CANA between April-October 2013. Change in A1C was calculated as the We analyzed differenced measures from the interrupted time series with difference in the pre-period result closest to the fi rst CANA prescription and comparison series plots using aggregate segmented regression. the last result in the 6-month post-period. We found no level or trend changes in any of the medication use measures (Fig 1). Of the 826 patients in the fi nal sample, 41% were female and mean age HDHP members with DM experienced no changes in use of insulin, oral was 56 years. In the pre-period, mean A1C was 8.59% and patients, on aver- hypoglycemics, statins, and non-statin lipid lowering medication. Results age, used 2.3 antihyperglycemic agents (AHAs) including injectables. Among might reassure policymakers overseeing the ACA, but future studies should patients with an estimated glomerular fi ltration rate reading, 44% had val- examine low income and high morbidity members. ues <90 ml/min/1.73m2. In the post-period, patients had a mean of 3.7 CANA fi lls and a median days covered of 87%. Patients had a mean A1C reduction of 0.81%; greater reductions were observed in those with higher pre-period A1C levels (Figure). CANA was prescribed to patients across a range of A1C who were often uncontrolled despite treatment with multiple AHAs. Signifi cant improve- ments in A1C were observed in the 6 months following the fi rst CANA pre- scription, with results consistent to those observed in the CANA randomized clinical studies.

Supported By: National Institute of Diabetes and Digestive and Kidney Diseases-Centers for Disease Control and Prevention (1R01DK100304)

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1339-P Cost-Effectiveness of Insulin Detemir and Insulin Aspart in People with Type 1 Diabetes Prone to Recurrent Severe Hypoglycaemia ULRIK PEDERSEN-BJERGAARD, PETER LOMMER KRISTENSEN, KIRSTEN NØR- GAARD, HANS PERRILD, TONNY JENSEN, BIRGER THORSTEINSSON, ANNIE NIKOLAJSEN, LISE TARNOW, Hillerød, Denmark, Gentofte, Denmark, Hvidovre, Denmark, Copenhagen, Denmark, Søborg, Denmark Treating a severe hypoglycaemic event (SHE) requires external help. The HypoAna trial documented that SHE’s and nocturnal hypoglycaemic events (NHE) in people with type 1 diabetes (T1DM) prone to recurrent SHE’s were signifi cantly reduced when treated with insulin analogues (detemir (IDet)+aspart (IAsp)) compared to human insulin (NPH+regular human (RHI)). The objective was to assess the cost-effectiveness (CE) of treating this group of people with IDet+IAsp in a Danish health care setting. A 1-year CE analysis was conducted using pharmacy costs (insulin, nee- dles, blood glucose test strips) and costs of treating SHE’s. The clinical input was obtained from the HypoAna trial and included the rate of SHE’s, non- SHE’s and NHE’s, daily insulin doses and number of injections. Use of test strips after SHE’s and NHE’s was obtained from literature and unit costs from Danish tariffs and drug prices. Quality-adjusted life years (QALY) were 1338-P calculated by applying published disutilities to SHE’s, non-SHE’s, and NHE’s. “Act on Threes” Paradigm for Treatment Escalation of T2DM: Pre- In the HypoAna study, IDet+IAsp had lower rates of SHE’s (1.25 vs. dictors of Insulin Initiation in a Managed Care Setting 1.76 per patient year (p<0.0120)) and NHE’s (8.0 vs. 10.9 per patient year SHANNON L. REYNOLDS, NELLA BIESZK, WENHUI WEI, CRALEN DAVIS, PRAVIN (p<0.0001)) compared to NPH+RHI. Treating SHE’s in IDet+IAsp compared KAMBLE, CLAUDIA URIBE, Louisville, KY, Bridgewater, NJ to NPH+RHI required following actions: 13% vs. 20% needed ambulance, Poor glycemic control increases the risk of diabetes-related morbidity, 2% vs. 1% resulted in hospitalization, 3% vs. 1% was treated by a health- POSTERS Therapeutics complications, and mortality. Identifying factors associated with the delay care professional (HCP) and 8% vs. 10% had HCP follow-up visits. Although Clinical Diabetes/ of insulin initiation can help target interventions to better align physicians pharmacy costs were higher with IDet+IAsp (2 598 USD/patient vs. 2 187 and patients with American Diabetes Association treatment guidelines. USD/patient) costs of treating SHE’s and NHE’s was lower (155 USD vs. 216 This is a post hoc analysis of data from a randomized interventional study USD) yielding total annual costs of 2 753 USD with IDet+IAsp vs. 2 403 USD evaluating the impact of an educational program among adults with type 2 for NPH+RHI. A QALY difference of 0.035 was in favour of IDet+IAsp. The diabetes mellitus who had received no A1C testing, or had A1C ≥ 8.0% dur- CE result was 9 985 USD/QALY gained, which is well below the commonly ing a 12 month baseline period, as identifi ed using the Humana, Inc. claims accepted CE threshold of approximately 41 265 USD/QALY in Denmark. The database between May 1, 2011 and February 28, 2013. Insulin initiation dur- analysis shows that treating people with T1DM prone to recurrent SHE’s ing 12-month follow-up was examined using pharmacy claims, and its de- with IDet+IAsp is cost-effective compared to NPH+RHI. terminants were identifi ed from patients’ baseline demographic and clinical Supported By: Novo Nordisk A/S characteristics using multiple logistic regressions. Data from 2,042 patients were included of which 10.8% initiated insulin during follow-up (Table). 1340-P Clinical inertia in insulin initiation in a managed care setting remained, Sustained Use of a Diabetes Clinical Decision Support Tool in Pri- despite a targeted educational intervention. A1C level strongly predicted mary Care Practices insulin initiation. Other signifi cant predictors included comorbidity index and PATRICK J. O’CONNOR, HEIDI L. EKSTROM, JOANN M. SPERL-HILLEN, KAREN use of GLP-1 RA at baseline. Further profi ling of determinants of treatment L. MARGOLIS, A.L. CRAIN, GERALD H. AMUNDSON, DEEPIKA APPANA, Minne- intensifi cation with insulin can help design and target appropriate interven- apolis, MN tions to patients who are likely to benefi t most. For effi cacious clinical decision support (CDS) tools to improve diabetes care, they must be consistently used in primary care and other practice set- tings. However, achieving and maintaining high rates of CDS use in primary care settings has been challenging. We conducted a clinic randomized trial of an EHR-based point-of-care CDS tool that provides prioritized treatment recommendations to optimize management of glucose, lipids, blood pres- sure, tobacco use, aspirin use, and weight in adults with diabetes and other high CV risk adults. We assessed use (the number of times the tool was opened and printed) at targeted offi ce visits for two groups of primary care providers (PCPs) at 11 intervention clinics; (a) PCPs who provided written informed consent to use and evaluate the tool, with up to $500 in compensa- tion for survey completion (n=54), and (b) PCPs who did not provided consent, but still had routine access to the CDS (n=69). The goal was to use the CDS at 80% of targeted outpatient visits. We reported monthly use-rates by PCP and by clinic to clinic and medical group leaders, and provided up to $2000 in compensation to clinics that achieved and maintained the use goal. Gen- eralized linear models tested whether PCP consent predicted use. Among consented PCPs, mean use rates at 4, 8, and 12 months after the intervention “go live” date were 57.0, 73.9, and 75%. Among PCPs at the same inter- vention clinics who did not provide consent, use rates were 57.3, 70.7, and 58.9% (signifi cant 12 month difference, p<.05). There was good persistence of use of the CDS tool at targeted visits among PCPs, but use was better sus- tained in those PCPs who consented to participate in the study. Limiting CDS deployment to targeted visits by high risk patients, medical group and clinic leadership support, PCP design input, implementation process measurement Supported By: Sanofi U.S. and feedback, and small fi nancial incentives may have contributed to robust use rates. Additional evaluation to explain why use rates declined in the non-consented providers is of interest.

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A348 HEALTH CARE DELIVERY—ECONOMICS

1341-P 1343-P The Willingness to Pay for Improvements in Insulin Injectable Ther- Impact of Patient-perceived Glucose Control on Diabetes-related apies for People with Type 2 Diabetes in North America Health Care Expenditure METTE BOEGELUND, MICHAEL FEHER, ANNIE NIKOLAJSEN, GABRIELA VEGA- MELANIE SIAW, PORLIN NG, JOYCE LEE, Singapore, Singapore HERNANDEZ, JOHN E. BRAZIER, Holte, Denmark, London, United Kingdom, Søborg, Poor diabetes control due to hyperglycemia or hypoglycemia has been Denmark, Sheffi eld, United Kingdom linked to increased healthcare cost. However, evidence on the association The study aims were to investigate patient’s preferences in clinical out- between patient-perceived glucose control and healthcare expenditure re- comes and administrative burden in insulin injections, as measured by pa- mains limited. In this prospective, multicenter study, we aimed to examine tients’ willingness to pay (WTP). the effect of patient- perceived glucose control in relation to outpatient Existing national email panels in the U.S. and Canada were used to collect medical cost of diabetes. In this study, all patients aged ≥ 21 years with survey-based data from adults >18 years with type 2 diabetes (T2DM) treat- uncontrolled type 2 diabetes defi ned as HbA1c >7% were included while ed with injectable insulin. Results were analysed using a standard choice patients with limited language profi ciency were excluded. Cost data were model designed for discrete choice experiment (DCE). Clinical outcomes re- retrieved from the electronic database of three primary health institutions, lated to effi cacy and safety (reduction in HbA1c, severe (SH) and non-severe and followed prospectively for six months. The perceived frequency of hy- hypoglycaemic (NSH) events, change in weight) and the patient burden of perglycemia and hypoglycemia measured on a scale of 0 (none of the time) insulin administration (preparation of insulin prior injecting and number of to 6 (most of the time) were obtained using the Diabetes Treatment Satisfac- daily injections) were found to be relevant factors in qualitative research in tion Questionnaire. A total of 270 patients were eligible for this study. The patients and were examined in the DCE. mean age was 59.9 ± 8.1 years with 57.4% men and 42.6% women. Overall, A total of 646 people with T2DM (58% males) completed the survey. Par- the average diabetes duration was 13.0 ± 8.9 years, and the baseline HbA1c ticipants placed high monetary value on effi cacy and safety outcomes; they was 8.4 ± 1.2%. The mean ratings on the perceived frequency of hypergly- would pay 116 USD/month to reduce HbA1c with 1% and 99 USD/month to cemia and hypoglycemia were 2.9 ± 1.8 and 1.4 ± 1.5, respectively. The aver- reduce one SH event per year. To reduce one NSH per week participants age diabetes-related total outpatient cost which consisted of consultation were willing to pay 147 USD/month. Participants wanting to lose weight re- fees, laboratory tests and prescriptions was USD 573.44 ± 257.62 per pa- ported a WTP of 63 USD/month to lose 3 kg. Participants also placed a high tient over the six- month period. Using the linear mixed model with pertinent monetary value on administrative burden of insulin: to avoid preparation of socio-demographic variables as adjustment, every 1 unit increase in patient- insulin prior injection, participants reported a WTP of 47 USD/month. The perceived frequency of hyperglycemia was associated with an increase of POSTERS monthly WTP for one fewer daily injection was 25 USD. Potential limitations USD 20.38 in the outpatient medical cost of managing diabetes (p = 0.025). Therapeutics of this study are that the preferences expressed may not match preferences Interestingly, patient-perceived frequency of hypoglycemia was not associ- Clinical Diabetes/ in real-life situations, and bias through recruiting via an internet panels since ated with the outpatient medical cost (p = 0.827). In conclusion, patient- these may not be representative of typical patients. perceived poor control of diabetes, especially in a form of hyperglycemia, In conclusion, clinical outcomes and administrative burden were signifi - may infl uence health-seeking behavior of patients, leading to increased use cant predictors of choice in people with T2DM. Reducing HbA1c as well as of healthcare resources. number of SH and NSH (weekly) were the highest valued outcomes. In ad- Supported By: Singapore Health Services Research Competitive Research Grant dition, the administrative burden of insulin injections was also considered important. 1344-P The Willingness to Pay for Improvements in Insulin Injectable Ther- 1342-P apies for People with Type 2 Diabetes in the UK, France, and the Electronic Documentation of Lifestyle Counseling and Glycemic Netherlands Control in Patients with Diabetes MICHAEL FEHER, ANNIE NIKOLAJSEN, GABRIELA VEGA-HERNANDEZ, METTE NAOSHI HOSOMURA, SAVELI GOLDBERG, MARIA SHUBINA, MARY ZHANG, AL- BOEGELUND, JOHN E. BRAZIER, London, United Kingdom, Søborg, Denmark, Holte, EXANDER TURCHIN, Boston, MA Denmark, Sheffi eld, United Kingdom As lifestyle counseling is usually documented in narrative notes rather The study aims were to investigate patient’s preferences in clinical out- than structured data, there are currently no methods that can assess the comes and administrative burden in insulin injections, as measured by pa- quality of lifestyle counseling delivered to the patient. We therefore con- tients’ willingness to pay (WTP). Existing national email panels in the UK, ducted this study to establish quantitative characteristics of electronic life- France and Netherlands were used to collect survey-based data from adults style counseling documentation associated with improved glycemic control >18 years with type 2 diabetes (T2DM) treated with injectable insulin. Re- in patients with diabetes. sults were analysed using a standard choice model designed for discrete We retrospectively studied 10,870 hyperglycemic (HbA1c ≥ 7.0%) adults choice experiment (DCE). Clinical outcomes related to effi cacy and safety with diabetes followed at primary care practices affi liated with two aca- (reduction in HbA1c, severe (SH) and non-severe hypoglycaemic (NSH) events, demic hospitals between 2000 and 2010. Documentation intensity was rep- change in weight) and the patient burden of insulin administration (prepara- resented by the mean number of characters per note documenting lifestyle tion of insulin prior injecting and number of daily injections) were found to be counseling. Heterogeneity was calculated as the normalized Levenshtein relevant factors in qualitative research in patients and were examined in the distance between lifestyle counseling sentences between consecutive DCE. A total of 971 people with T2DM (58% males) completed the survey. notes. Cox proportional hazards model was constructed to assess associa- Participants placed high monetary value on effi cacy and safety outcomes; tion of heterogeneity and intensity of lifestyle counseling documentation to they would pay 66 EUR/month to reduce HbA1c with 1% and 93 EUR/month time to HbA1c < 7.0% while adjusting for demographics, initial HbA1c level, to reduce one SH event per year. To reduce one NSH per week participants insulin therapy, medication intensifi cation, and frequency of lifestyle coun- were willing to pay 72 EUR/month. Participants wanting to lose weight re- seling. ported a WTP of 51 EUR/month to lose 3 kg. Participants also placed a high Comparing patients in the highest versus lowest tertile by documentation monetary value on administrative burden of insulin: to avoid preparation of heterogeneity and documentation intensity, median time to HbA1c < 7.0% insulin prior injection, participants reported a WTP of 35 EUR/month. The was 26 versus 39 months, and 24 versus 39 months, respectively (P < 0.001 monthly WTP for one fewer daily injection was 20 EUR. Potential limitations for all). In multivariable analysis, an increase of documentation heterogene- of this study are that the preferences expressed may not match preferences ity by 0.15 units (1 SD) and an increase of documentation intensity by 51 in real-life situations, and bias through recruiting via an internet panels since characters/note (1 SD) was associated with hazard ratios of 1.08 (95% CI these may not be representative of typical patients. In conclusion, clinical 1.04 to 1.12 ; P < .001) and 1.27 (95% CI 1.23 to 1.31; P < 0.001) for time to outcomes and administrative burden were signifi cant predictors of choice HbA1c target, respectively. in people with T2DM. Reducing HbA1c and number of SH and NSH (weekly) Higher heterogeneity and intensity of lifestyle counseling documentation were the highest valued outcomes. In addition, the administrative burden of in provider notes were associated with better glycemic control. These quan- insulin injections was also considered important. titative characteristics of electronic documentation of lifestyle counseling may be used as indicators of quality of diabetes care. Supported By: Agency for Healthcare Research and Quality

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1345-P 1347-P Inpatient Glucose Management (IGM) Program in Asian Health Care Risk and Cost of Diabetes in the United States, 2009-2012 Setting MAN YEE (MALLORY) LEUNG, NILS CARLSSON, GRAHAM COLDITZ, SU-HSIN DU SOON SWEE, WEE MAY HENG, XUE-YUAN LEE, YONG MONG BEE, SU-YEN CHANG, St. Louis, MO GOH, MING MING TEH, Singapore, Singapore Diabetes is one of the most prevalent and costly chronic diseases in the Suboptimal glycemic control in inpatients is an established marker of United States. This study analyzed lifetime risk and annual cost of diabetes adverse outcomes. However, it often receives inadequate attention and for a general U.S. population. variable treatment, especially in non-critically ill patients. The IGM program Our study cohort was assembled from the National Health Interview Sur- improves glycemic control and shortens length of stay (LOS) in European vey (NHIS), 2009-2012, and linked to the Medical Expenditure Panel Survey and North American countries but there is paucity of data on IGM program (MEPS) to analyze (1) the probabilities of developing diabetes and (2) annual from Asia. total healthcare expenditures for diabetics. An IGM program was piloted at a medical ward in Singapore General Hos- The probabilities of developing diabetes were estimated by fi tting an ex- pital, the largest hospital in Singapore, from July to November 2014.The IGM ponential survival function to age at fi rst diabetes diagnosis. Annual total team comprised of endocrinologists, pharmacists and diabetes nurse edu- healthcare expenditures were estimated using a two-part model with a lo- cators. The IGM team reviewed patients with suboptimal glycemic control gistic model in the fi rst part and a generalized linear model in the second part. [defi ned by ≥3 point-of-care blood glucose readings of >10 mmol/l (180 mg/ All analyses were stratifi ed by gender and adjusted for age, race, body mass dl) and/or <4mmol/l (72 mg/dl) within a 24 hour period]. Glycemic and LOS index (BMI) category, insurance status, duration of diabetes, and duration of data for patients from the study period (intervention group) were compared diabetes squared. Complex sampling designs in the NHIS and the MEPS were with similar data from patients who were admitted to the same ward prior also adjusted for. All dollar values were presented at 2010 price levels. to the piloting of the IGM program (control group), over a similar period of We observed a 6-fold increase in probabilities of developing diabetes 4.5 months. for class III obese individuals, compared to normal weight individuals. The There were 124 patients in the intervention group and 108 patients in probability increased from 0.07% for normal weight females to 0.45% for the control group with mean age of 70.0+13.5 and 68.6+14.0 years old re- class III obese females; and from 0.08% for normal weight males to 0.58% spectively. It took 2 days less for the overall mean BG to reach target range class III obese males. We found that races other than blacks and whites had in the intervention group. The intervention group has signifi cantly lower the highest probabilities of developing diabetes. In our cost analysis, we mean glucose [10.5+3.0 vs. 11.1+3.2 mmol/l (189.0+54.0 vs. 199.8 +57.6 found that annual healthcare expenditures increased with age. Moreover, POSTERS Therapeutics mg/dl), p<0.05] and stay-weighted mean glucose [10.9+1.9 vs. 11.7+2.4 the expenditures demonstrated an inverted U-shape across BMI categories Clinical Diabetes/ mmol/l (196.2+34.2 vs. 210.6+43.2 mg/dl), p<0.05] than the control group. with the peak at the class II obese group. Blacks incurred higher costs than Crucially, this was achieved with a signifi cant reduction in patients’ days whites. Insured individuals had higher annual healthcare expenditures com- with hypoglycemia (3.7% vs. 5.9%, p<0.05). Higher discharge rate was seen pared with uninsured individuals. from Day 5 onwards, such that at Day 14, the intervention group has less Our results suggested that the probabilities of developing diabetes in- than half of patients who remained hospitalized than in the control group. creased with BMI category. We found that total healthcare expenditures IGM program improved inpatient diabetes, resulting in improved glycemic demonstrated an inverted U-shape over BMI categories with the peak at the control and shorter LOS. With rising disease burden in Asia, this could be class II obese group. one effective strategy for inpatient diabetes. Supported By: Foundation for Barnes-Jewish Hospital; Breast Cancer Research Foundation (U54CA155496 to G.C.) 1346-P Simple CSII Is Highly Cost-Effective 1348-P OLE HENRIKSEN, MADS DALL, JAY WARNER, CHRISTOPHER PARKIN, Copenha- Cost Implications of a Multifactorial Diabetes Care Improvement gen, Denmark, Hellerup, Denmark, Marlborough, MA, Boulder City, NV Strategy: The CARRS Trial Continuous subcutaneous insulin infusion (CSII) in people with type 2 dia- KAVITA SINGH, MOHAMMED K. ALI, RAJI DEVARAJAN, DIMPLE KONDAL, ROO- betes (T2DM) has proven to improve glycemic control (HbA1c) and reduce PA SHIVASHANKAR, VAMADEVAN S. AJAY, MUHAMMAD MASOOD KADIR, insulin dosage compared to multiple daily injections (MDI). However, CSII KOLLI SRINATH REDDY, VISWANATHAN MOHAN, K.M. VENKAT NARAYAN, has not been widely adopted in T2DM due to costs, complexity and train- DORAIRAJ PRABHAKARAN, NIKHIL TANDON, New Delhi, India, Atlanta, GA, Gur- ing requirements. New devices that provide simple CSII reduce complexity gaon, India, Karachi, Pakistan, Chennai, India and training requirements. This analysis assessed the cost effectiveness in Adoption of strategies to improve diabetes care cannot occur without un- the United States of simple insulin infusion (SII) compared to MDI in people derstanding what resources are required to implement the intervention. To with T2DM not in glycemic control. The UKPDS Outcomes Model was used address this gap, we estimated the resource use and costs of a multifactorial to project long-term cost-effectiveness over 40 years, based on results of intervention (non-physician care coordinator [CC] and clinical decision-support recently published studies and costs for the U.S. Costs and outcomes were software [DSS]) versus usual care within the CARRS Trial, a multicenter ran- discounted at 3%. Cost-effectiveness was pre-defi ned in relation to per domized controlled study. We assigned 1146 people with A1c ≥8% and either capita gross domestic product (GDP) with Incremental Cost Effectiveness systolic blood pressure (BP) ≥140mmHg or LDL ≥130mg/dl, to intervention Ratios (ICERs) below 1X, respectively 3X GDP per capita per life year gained, (n=575) or usual care (n=571) and we found that signifi cantly higher proportions defi ned as highly “cost-effective,” respectively “cost-effective.” Our analy- of intervention group achieved multiple risk factor control (HbA1c <7% and ≥1: sis showed 0.11 life year gained on average and annual discounted savings BP <130/80mmHg or LDL <100mg/dl) than usual care: 14.6% vs. 5.4%. on complication costs and insulin reductions of $3,005. Based on projected We collected data from 1146 patients (mean age 54 years) on self-report- costs and life expectancy, a simple CSII device will be highly cost-effective ed resource use (clinic visits, lab tests, ECG, eye and foot exam) and direct in the United States at a price of $13.40 per day and cost-effective at a medical costs of out- and in-patient care. We excluded indirect and research price of $23.70. This implied an ICER at 0.56, 0.98 times per capita GDP per costs. We report costs in 2014 U.S. dollar ($) and the uncertainty around life year gained for the two cases, respectively. These estimates were very costs through bootstrap 95% CI. robust to sensitivity analyses on both reductions in HbA1c and dose effects. At trial end (mean 30 months), care utilization was signifi cantly higher in For people with T2DM not in glycemic control on MDI, simple CSII is highly the intervention group compared to usual care: mean (95% CI) number of cost-effective at a daily cost in the U.S. of $13.40 or less and cost-effective clinic visits: 7.3 (5.0, 9.3) vs. 4.0 (3.6, 4.4), A1c test: 5.2 (2.5, 5.9) vs. 1.3 (1.1, at a daily cost of $23.70 or less in the United States. 1.5), preventive exams: 1.3 (1.1, 3.6) vs. 0.3 (0.2, 0.4). The total undiscounted Supported By: CeQur SA cost per patient in the intervention arm was $860.9 ($681.3, $1040.6) com- pared to $550.3 ($434.2, $666.5) for usual care arm; the incremental cost was $310.6 ($96.6, $524.6). Medicines, lab test and clinic visits were the main cost drivers and inpatient care was a cost mitigator. Use of DSS and CC, while effective in improving diabetes care, incurs greater costs than usual care. The cost difference may neutralize with long term follow-up as events and hospitalizations accrue; long term cost-effec- tiveness analyses will provide a clearer understanding of the value of this intervention and guide adoption by policy makers and providers. Supported By: National Heart, Lung, and Blood Institute; National Institutes of Health; United Health Group

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1349-P Outcomesc Mental Well-Being and Outcomes in Patients with Type 2 Diabetes Any hospitalization, %d 35.3 23.3 < 0.001 SUSAN C. BOLGE, NATALIA M. FLORES, ENNIFER PHAN, Raritan, NJ, Foster City, d CA Any ED visit, % 51.3 32.3 < 0.001 The U.S. healthcare system is becoming increasingly patient-centric; how- Annual total all-cause health care costs, per patient, $e 28,253 19,459 < 0.001 ever, need to contain costs remains. The study purpose is to evaluate the as- Annual total diabetes-related health care costs, per 13,458 7,668 < 0.001 sociation of mental well-being with outcomes that impact costs. A sample patient, $e of 7852 adults (aged ≥18 years) self-reporting type 2 diabetes diagnosis was Average quarterly incremental total cost, per patient, $e 7,787 5,181 < 0.001 identifi ed from the 2013 U.S. National Health and Wellness Survey, a cross- Average quarterly incremental diabetes-related costs, 3,835 2,076 < 0.001 sectional, Internet-based study. Mental well-being was defi ned using the per patient, $e SF-36v2 mental component summary (MCS) and categorized as good (MCS ≥ 50), poor (40 ≤ MCS < 50), and very poor (MCS < 40). Outcomes included Insulin discontinuation based on a gap of ≥ 45 days in 5,495 (74.5%) 93,529 (73.3%) 0.020 insulin prescription coverage, n (%)b healthcare resource use in the past 6 months, which impacts direct costs and lost productivity (measured by the Work Productivity and Activity Im- aT-tests were used for continuous variables; bChi-squared tests were used for dichotomous variables; cAll outcomes are adjusted for differences at pairment questionnaire), which impacts indirect costs. Poorer mental well- d being was associated with greater healthcare resource use. Among labor baseline. Logistic regression was used to model any inpatient admission and any ED visit; eGeneralized linear model was used to model health care force participants, poorer mental well-being was associated with greater costs. ED, emergency department. work impairment. These associations remained signifi cant when adjusting for patient demographics and disease characteristics through regression Supported By: Sanofi U.S. analyses. Interventions designed to improve mental well-being may also have a cost benefi t by affecting outcomes which impact costs. 1351-P Table. The Societal Burden of Diabetes ANIKET A. KAWATKAR, Pasadena, CA The most current economic burden of diabetes has been estimated using prevalence based cost-of-illness model. The objective of this study was to

validate the effect of diabetes on the total direct medical expenditure, out- POSTERS of-pocket costs and health related quality of life (HRQOL) in U.S. population Therapeutics using nationally representative samples. Clinical Diabetes/ Data from the MEPS’s Longitudinal Household Component (2011-2012), a nationally representative survey of the U.S. civilian non-institutionalized population, was used. Analysis accounted for the survey’s clusters, strata and sampling weights. Direct medical expenditure attributable to diabetes was estimated by generalized linear models (GLM) with log-link and Gamma family adjusting for the following covariates: age, sex, race, ethnicity, in- come, geographic-location, and comorbidities. Incremental expenditure summed over population with diabetes gave the total expenditure. Impact of diabetes on SF12 mental and physical health component was assessed by ordinary least square regressions. The annual incremental expenditure of diabetes in 2012 USD, was $3,379 (95% CI = $1,955 to $4,802). Total direct 1350-P expenditure of diabetes was $265 billion (95% CI = $239 to $291 billion). The Impact of Hypoglycemia on Health Care Use and Costs in T2DM The incremental out-of pocket expenditure in diabetes patients was $287 Patients Newly Initiated on Basal Insulin (95% CI = $178 to $397) resulting in a total of 28.3 billion spent by patients MEHUL R. DALAL, MAHMOOD KAZEMI, FEN YE, LIN XIE, Bridgewater, NJ, Ann out-of-pocket. SF12 physical component score was lower by 3.9 (p<0.001) Arbor, MI while the mental component score was not signifi cantly different from those Insulin use is associated with an increase in hypoglycemia, which may without diabetes. have a negative impact on insulin therapy persistence, target A1C achieve- Diabetes exerts an enormous economic and humanistic burden on the U.S. ment, and health care costs. This retrospective cohort study assessed civilian non-institutionalized population. This study validates the recent eco- health care use and costs in T2DM patients who experience hypoglycemia nomic costs of diabetes using nationally representative samples from MEPS. soon after initiating insulin. The MarketScan™ claims databases were used to identify adult patients with T2DM who initiated basal insulin therapy (defi ned as having no insulin 1352-P prescription ≥ 12 months [mo] before starting insulin glargine, insulin de- Nurse Practitioner-mediated Intervention Is Highly Effective in Pre- temir, or NPH insulin) between January 2007 and March 2013. Hypoglycemic operative Control of Diabetes in Elective Surgery Patients events were identifi ed by health care encounters with ICD-9-CM diagnosis RAJESH GARG, CHEYENNE METZGER, RAQUEL REIN, MEGHAN LORTIE, PATRI- code 250.8x during the fi rst 6 mo of basal insulin use. Data were assessed CIA UNDERWOOD, SHELLEY HURWITZ, JANE ASHLEY, ANGELA BADER, KYLE for 12 mo prior (baseline) and 12 mo after insulin initiation. Differences in CARBONE, BROOKE SCHUMAN, Boston, MA, Chestnut Hill, MA demographics, clinical characteristics, and baseline health care use were Nurse practitioners (NP) have been playing an important role in the manage- adjusted using regression analyses. ment of diabetes in inpatient as well as in outpatient settings. We studied the Of the 134,934 patients identifi ed, 7,371 (5.5%) had hypoglycemia in the fi rst effectiveness of an NP-led program versus a physician-led program for preop- 6 mo and had signifi cantly different baseline characteristics (Table). At 12 mo, erative glycemic control in patients with HbA1c ≥8% before elective surgery. more patients with hypoglycemia, versus those without, had hospitalizations The program was implemented in Feb 2013 and was initially led by an endocri- and ED visits, and greater total and diabetes-related health care costs (Table). nologist. However, in Mar 2014, the protocol was changed to make it an NP-led Hypoglycemia was seen in 5.5% of T2DM patients within 6 mo after basal program under supervision of the endocrinologist. The goal of intervention dur- insulin initiation and was associated with greater costs and health care re- ing both time periods was preoperative blood glucose (BG) <200 mg/dl on the source use. day of surgery. Data were collected prospectively from Feb 2013 to Feb 2014 (phase 1) and Mar 2014 to Sep 2014 (phase 2). Data were also collected from Table. Parameters of Patients Who Initiated Basal Insulin. a historical control group (Jan 2011-Dec 2012) that included 222 patients with Hypoglycemia No hypoglycemia P value HbA1c ≥8% who underwent elective surgery. Proportions of patients achiev- in the fi rst 6 mo in the fi rst 6 mo ing target BG on the day of surgery were compared among the 3 groups. Out of (n = 7,371) (n = 127,563) a total 315 patients, 218 were managed during phase 1 and 97 during phase 2. Age, mean (SD), yearsa 59.9 (13.7) 57.4 (13.0) < 0.001 Mean BG levels (mg/dl) on the day of surgery were 171.4 ± 66.5 in the control Female, n (%)b 3,184 (43.2) 58,630 (46.0) < 0.001 group, 163.5 ± 58.3 during phase 1 and 148.5 ± 45.5 during phase 2 (p <0.01). Baseline hypoglycemia, n (%)b 2,377 (32.2) 5,046 (4.0) < 0.001 More patients achieved target BG in phase 2 (92%), as compared to phase 1 a (78%) (p <0.01) and the control group (71%) (p <0.001). Signifi cantly more pa- Charlson Comorbidity Index, mean (SD) 1.36 (1.88) 0.94 (1.61) < 0.001 tients received an intervention during phase 2 (95%) than during phase 1 (75%)

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A351 HEALTH CARE DELIVERY—ECONOMICS

(p <0.001). Among those receiving an intervention, 92% patients achieved the history, HRU, out-of-pocket (OOP) costs, insurance and PNR status were sur- target BG during phase 2 as compared to 82% during phase 1 (p=0.03). In a veyed. Patients underwent physical exam for LH and HbA1c testing. Costs multivariate logistic regression analysis, shorter duration of diabetes, lower were assigned to HRU using publicly available sources and compared using HbA1c, and active intervention by NP (versus physician alone) were indepen- descriptive statistics and logistic regression (high vs. low costs). P-values < dent predictors of target BG levels. We conclude that NP-led intervention is 0.05 were considered signifi cant. effective for preoperative glycemic control. This observation is important for LH prevalence = 52.9%. PNs were reimbursed for 35.6% of patients. institutions attempting to set-up diabetes management programs for elective Logistic regression controlling for demographic and clinical characteristics surgery patients. showed lack of PNR was associated with increased odds of high costs (OR Supported By: UD7HP25059 4.09, 95% CI = [1.93, 8.68], p<0.001). Table. 1353-P Clinical/Economic Factors -PN +PN p value (Determined using Factors Affecting Satisfaction with Providers among Adults with Reimbursement Reimbursement χ2 tests for categorical Type 1 Diabetes: A Web-based Survey variables and Wilcoxon JOHN D. RUCK, VIRAL N. SHAH, ASHER M. RUNION, JANET K. SNELL-BERGEON, rank sum tests for Aurora, CO, Boston, MA continuous variables.) Patient satisfaction is one of the major components of health care quality Prevalence of LH (%) 59.1% 41.3% 0.001 and is associated with better patient outcomes. However, factors affect- HbA1c (%), mean 8.0% 8.0% 0.748 ing satisfaction with providers have not been studied in adults with type 1 diabetes (T1D). This study was conducted through the T1D Exchange online Daily insulin dose (units), mean 3=4.9 29.2 0.027 patient community, Glu (myglu.org). A questionnaire assessing demograph- Daily insulin costs, (RMB), mean 7.5 6.3 0.027 ics, A1c, components of comprehensive care (11 question scale), provider 6 month hospital costs (RMB), mean 1583 770 0.023 empathy (5 question scale), updates on diabetes-related technologies (3 6 month hospitalization (%), mean 17.4% 9.2% 0.024 question scale), and time spent with the provider was made available to all Glu T1D members aged 18-75 years. 6 month total direct cost (RMB), mean 6115.63 4058.57 <0.001 Of 7,276 adult Glu members with T1D, 356 respondents (70% females) 6-month patient OOP cost (RMB), mean 1207.31 2212.21 <0.001

POSTERS were included in the study. The mean ± SD for age was 43±15 yrs, and mean Frequency of PN reuse, median 13 7.5 <0.001 Therapeutics satisfaction (scale from 1-10) was 8.1±1.9. In age and sex-adjusted linear re- Clinical Diabetes/ Results show excess costs to China’s healthcare system and to those gression models, satisfaction was positively correlated to provider empathy, lacking PNR. Despite higher insulin doses (and LH prevalence) if no PNR, comprehensive care, technology updates, and time spent with the provider HbA1c remained uncontrolled. China may decrease future HRU and cost by (Figure 1). In multivariable analysis, patient satisfaction was associated with reimbursing PNs for all who use insulin pens. provider empathy, technology updates and comprehensive care. Satisfaction was minimally associated with A1c and time spent with the provider (regard- less of specialty). 1355-P Provider empathy is strongly associated with higher satisfaction among Admission Hyperglycemia Led to Increased Short-Term Mortality and adults with T1D. Providers should consider prioritizing empathy as an impor- Length of Stay Irrespective of Diagnoses or Caregiving Specialty tant part of diabetes care. MARIA THUNANDER, THOMAS FRISK, MAGNUS B.E. BJÖRK, Växjö, Sweden, Lund, Sweden Admission hyperglycemia negatively infl uences the prognosis of myocardial infarction, stroke, pneumonia, trauma and ICU patients. It is unclear whether it implies increased mortality in heterogeneous patient populations. No Swedish studies have investigated glucose and mortality or length-of-stay in acutely ill general patients, and over-all few studies irrespective of diagnosis, none irrespective of discipline. We aimed to explore the relationship between ad- mission glucose and mortality, and length-of-stay, irrespective of diagnosis, in patients seeking emergency care at a secondary hospital in Sweden. Retrospective electronic records data for 01/01/2014 - 06/29/2014 of 8146 patients aged ≥18 years, seeking via departments of internal medicine, sur- gery or infectious diseases, with p-glucose available. Information on age, gender, dates of contact, admission, and discharge, and diagnoses plus p- glucose, s-sodium, s-potassium, b-Hb, b-LPK and s-CRP was collected, in groups of admission plasma glucose levels: hypoglycemia (≤ 4.0 mmol/l), normoglycemia (>4.0 - ≤7.0 mmol/l), modest hyperglycemia (>7.0 - ≤11.1 mmol/l) and severe hyperglycemia (>11.1 mmol/l). 30-day-mortality was 1.5% in the normoglycemic and increased to 4.0%, and 4.5%, in the patients with modest or severe hyperglycemia, both p<0.001, with COR 2.84 (2.08-3.86) and 3.20 (2.05-3.86). Adjusted for glu- cose, age and laboratory variables AOR was 1.63 (1.16-2.39) for modest and 1.66 (1.00-2.76) for severe hyperglycemia. The average length-of-stay in- 1354-P creased with mean 1.21 and 1.66 days in the groups with modest and severe hyperglycemia, p<0.001. Relationship of Pen Needle Reimbursement (PNR) to Health The 30-day-mortality was increased 2-3 times and length-of-stay with Resource Utilization (HRU) and Costs in Chinese Diabetes (DM) 1-2 days, in all groups with admission hyperglycemia, all irrespective of dis- Patients charge diagnoses or whether medical, surgical or infectious patients. QIFU LI, LINONG JI, ZILIN SUN, GUIJUN QIN, LAURENCE HIRSCH, ZHENG WEI, JUNHAO LIU, LUAN LUAN, ARTHI CHANDRAN, STEFAN DIMARIO, RICHARD CHAPMAN, TIMOTHY INOCENCIO, Chongqing, China, Beijing, China, Nanjing, 1356-P China, Zhengzhou, China, Franklin Lakes, NJ, Washington, DC The Virtual Inpatient Glucose Management Service (vGMS): Contin- China spends >RMB 173 bn (U.S. $28 bn) yearly on DM. Cost is expected ued Improvement in Glucose Control and User Survey Results to grow as patients are diagnosed, treated, and/or develop complications. ROBERT J. RUSHAKOFF, HEIDEMARIE WINDHAM MACMASTER, MARY M. SUL- Lipohypertrophy (LH) is associated with improper injection technique, PN LIVAN, ARTI SHAH, San Francisco, CA reuse, and increased insulin consumption. Currently, payers in China widely In 2013, we developed our vGMS, remotely identifying inpatients who in reimburse insulin pens but do so infrequently for PNs. We evaluated the the past 24 hours had 2 or more glucoses over 225 mg/dl and/or a glucose relationship of PNR with HRU and costs in China. 60 under mg/dl. Utilizing a series of prewritten notes that discuss rationale An observational study was conducted among 401 insulin-injecting adult for changing orders, insulin recommendations are typed in the note in a style patients from 4 cities, 2 with and 2 without PNR. Demographics, medical similar to the actual insulin order sets. We previously reported signifi cant

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A352 HEALTH CARE DELIVERY—ECONOMICS benefi cial impact of this service after 1 year in place. Below we present the 1358-P continued improvements and the results of a survey of inpatient providers Financial Burden of Hepatitis B in Patients with Diabetes Mellitus about the vGMS. GAURAV DESHPANDE, ANDREW KLINK, RAHUL SHENOLIKAR, DEBRA EISEN- We compared 10 days of report data from October 2013 (before service BERG, JOSEPH SINGER, GIRISHANTHY KRISHNARAJAH, Wilmington, DE, Re- started) and October 2013 (5 months after service started) and again in Oc- search Triangle Park, NC, Philadelphia, PA tober 2014 (17 months after service started). The daily average number of In 2011, Advisory Committee on Immunization Practices issued recommen- patients with 2 or more glucoses over 225 mg/dl decreased from 27.4±1.3 dations for hepatitis B vaccine in people with diabetes mellitus. Vaccination (SEM) to 16.9±1.3 (p < 0.001) and then 12.4±1.3 (p < 0.001). Full review of rate of Hepatitis B remains low in diabetic population. Data on economic the patients on the report, with notes to the chart, now takes less than 25 burden of Hepatitis B virus (HBV) infection in diabetes mellitus is limited. minutes/day. To address this gap this study compared healthcare utilization and cost in Inpatient Providers (MDs and NPs) were sent a link to a survey about the patients with diabetes and HBV to patients with diabetes alone. vGMS. 102 inpatient providers responded with the following results: 81% This retrospective database analysis used the HealthCore Integrated found the vGMS to be helpful, 76% implement the recommendations, 83% Research Database (HIRDSM). Subjects were adults having diabetes with see improvement in glucoses when the recommendations are implemented, HBV (cases) and without HBV (controls) identifi ed using ICD 9 diagnosis 68% felt this changed the way they managed inpatient diabetes, and 93% codes (Diabetes: 250.xx, Hepatitis B: 070.2x or 070.3x). The study period felt that continuing the vGMS would be helpful. Many respondents com- was January 2006-March 2014. Propensity score matching was employed to mented that this service helped them to learn about diabetes management match each case with four controls using baseline characteristics. Annual- and improved housestaff engagement in diabetes management. One com- ized healthcare utilization and costs were compared and incremental effect mented: “it works as a perfect ‘just-in-time’ teaching mechanism to inform was assessed using multivariable analysis to adjust for baseline diabetes appropriate responses to high blood sugars for inpatients.” treatment. We conclude that a remote, virtual inpatient diabetes service effi ciently A total of 6,180 patients (1,236 cases, 4,994 controls; mean age 54 years) leads to fewer patients with glucoses out of control and promotes just in were included. Among cases, 282 patients (22.8%) had late-stage liver dis- time provider education and changes in provider behavior with continual ease. In the adjusted analyses, the mean number of hospitalizations, outpa- improvement in insulin orders. tient services, and offi ce visits were 41%, 68%, and 11% higher respectively in cases vs. controls (all p<0.05). Among those hospitalized length of stay was signifi cantly higher by 67% higher for cases vs. controls. Gastroenterol- 1357-P POSTERS Differences in Medical Costs among Patients with Type 2 Diabetes ogist visits and Infectious disease visits were 80% and 18% higher (p<0.05) Therapeutics Treated with Dapaglifl ozin vs. Other Antidiabetic Drugs for case vs. controls in patients with these events. Unadjusted mean (SD), Clinical Diabetes/ JAY LIN, PRAVEEN DHANKHAR, KELLY BELL, JAGPREET CHHATWAL, MELISSA median total cost was $34,356 ($80,378), $10,160 for cases and $19,867 LINGOHR-SMITH, Green Brook, NJ, Fort Washington, PA, Houston, TX ($44,010), $7,373 for controls. Adjusted total, medical and pharmacy cost This study evaluated the differences in medical costs of patients with was signifi cantly higher by 71%, 74%, and 57 % respectively for cases vs. type 2 diabetes (T2DM) treated with dapaglifl ozin (dapa) vs. other antidi- controls (p<0.05). abetic drugs, including daily dosage glucagon-like peptide-1 (GLP-1) ago- HBV infection was associated with an increased fi nancial burden in dia- nists, dipeptidyl peptidase-4 (DPP-4) inhibitors, thiazolidinediones (TZDs), betes patients. Providers should consider Hepatitis B vaccination in patients and sulfonylureas (SUs). Incremental annual medical costs for changes in with diabetes. HbA1c, weight, systolic blood pressure (SBP), and risk of hypoglycemia were Supported By: GlaxoSmithKline obtained from published literature. Changes in clinical endpoints associated with treatment of T2DM patients for 52 weeks with the different antidi- 1359-P abetic drugs were based on results of a network meta-analysis. Differences Managing Your Medication for Education and Daily Support: Clini- in total annual medical costs for clinical endpoints among T2DM patients cal Pharmacists in Primary Care for Patients with Diabetes treated with dapa vs. other antidiabetic drugs were then estimated. Differ- CAROL M. MANGIONE, GERARDO MORENO, JEFFREY FU, JANET CHON, NATA- ences in changes of clinical endpoints and the estimated total annual medi- LIE WHITMIRE, CHI-HONG TSENG, ROBIN CLARKE, DOUGLAS BELL, Los Angeles, cal cost differences for clinical endpoints are shown in Table 1. Results from CA univariate (one-way) sensitivity analyses and multivariable Monte Carlo Pharmacists are an under-utilized resource for co-management with the analyses showed that the estimates of the medical cost differences were primary care doctor of complex patients with diabetes and polypharmacy. robust when model parameters were varied. In conclusion, use of dapa for Our objective was to test the value of a new model of care that integrates a the treatment of patients with T2DM was associated with reductions in to- clinical pharmacist into primary care teams. tal annual medical costs for the evaluated clinical endpoints vs. daily dosage We conducted a quasi experiment with control group among 214 patients GLP-1 agonists, DPP-4 inhibitors, TZDs, and SUs. with type 2 diabetes from 14 primary care practices and one of the follow- ing: hemoglobin A1c (A1c) >9%, blood pressure (BP) > 140/90 mmHg, LDL- cholesterol (LDL-c) >130mg/dL or fi ve or more prescribed medications. Outcome was change in A1c, SBP, and secondary outcomes were change in LDL-c, satisfaction with care, and medication-related problems at 3 months. Paired t-test or Wilcoxon signed rank test was used to compare the change in continuous outcomes and chi-squared tests were used to compare categorical outcomes. Linear regression analysis was also carried out to compare the change in outcomes between intervention and control patients (n=549), adjusted for baseline demographic and clinical variables. Controls were from 14 primary care practices without a clinical pharmacist. We found that patients who saw the pharmacist (n=217) were 59% female and had a mean age of 66±14 years. Patients who saw a clinical pharmacist and had a baseline A1c>9% had a decrease of -1.7% (n=88, P<0.001) com- pared to a decline of -1.2% (n=110, P140mmHg, the decrease in SBP was -9.6 mmHg (n=129) compared to -9.0 mmHg for those (n=305) in control practices (P<0.05). LDL-c change was similar in both intervention and control groups. 776 medication related problems were detected and patients were highly satisfi ed with the pharmacist. Clinical pharmacists are an important addition to clinical care teams in primary care practices and may help improve intermediate cardiovascular risk factors and glycemia among patients with uncontrolled diabetes. Supported By: Resource Centers for Minority Aging Research; National Insti- tutes of Health-National Institute on Aging (P30-AG021684); University of Califor- nia, Los Angeles Clinical and Translational Science Institute (UL1TR000124)

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A353 HEALTH CARE DELIVERY—ECONOMICS

1360-P 1362-P Clinical Action Measures Describing Progress toward Achieving Are Medicare and Medicare-Medicaid Insulin Users Different? Personalized A1c Treatment Goal in Medicare Elderly Comparisons in a Nationally Representative Claims Database RITUPARNA BHATTACHARYA, STEVE ZHOU, SANDIPAN BHATTACHARJEE, JONATHAN H. WATANABE, RENU SINGH, CANDIS MORELLO, JAN HIRSCH, USHA SAMBAMOORTHI, Morgantown, WV, Bridgewater, NJ, Tucson, AZ MARK BOUNTHAVONG, La Jolla, CA, Seattle, WA American Diabetes Association standard of care for type 2 diabetes mel- The advancing age of the U.S. population coupled with escalating diabe- litus (T2DM) includes personalizing glycosylated hemoglobin (A1C) goals tes prevalence motivates a focus on diabetes management in seniors. Prior based on patient characteristics and using the personalized A1C goals (PA1C) research has shown worse outcomes for the poor, but little research exists for clinical action measures. This study evaluated clinical action measures to contrasting the elderly from the elderly poor. achieve PA1C among elderly with T2DM. We compared characteristics of pharmacy services use of Medicare en- This study included elderly with T2DM between July 2007 and August rollees (‘traditional’) versus dual-eligible Medicare-Medicaid enrollees (“du- 2012 and continuously enrolled in Humana Medicare Advantage with Part D als”) using insulin. plans for 12 months and whose fi rst observed A1C did not meet PA1C goals The nationally representative 2012 MarketScan Databases were used (N=11,315). In the absence of clinical information, PA1C goals were defi ned to compare characteristics of traditional insulin users to dual insulin users. with a modifi ed approach using the following characteristics from claims Variables related to cost, claims, and medication types for their complete data: severe hypoglycemia, age, macro- and/or micro-vascular complica- medication list were analyzed. We then performed analyses specifi cally on tions, cognitive impairment, and number of co-existing chronic conditions. their insulin regimen. We also compared the frequency of basal insulin be- First observed A1C during the study period was “index date”; baseline and tween the groups. Differences in means compared via T-Test. Differences follow-up periods were defi ned as 6-months prior and 6-months subsequent in proportion compared via Chi-squared test with α < .05. All analyses used to index date. The following hierarchy was used to defi ne clinical action SAS 9.4 (Cary, NC). measures: insulin initiation, PA1C met without insulin initiation; added oral 139,406 traditional Medicare and 11,965 duals were analyzed. Comparing antidiabetes drugs (OAD), and having only T2DM related visits. Elderly with duals to traditionals, duals were more likely to be women (68% to 47% re- A1C>9% were categorized as “FAIL.” spectively) and were associated with increased basal insulin use (64.0% of Only 9.1% had insulin initiated, 39.3% had OAD added, 16.7% had only dual to 59.1% respectively). All comparisons were statistically signifi cant. T2DM-related visits, 16.7% met PA1C goals and 18.2% had A1C>9%. Insulin Poor and disabled senior insulin users had increased medication use and initiation was compared to other clinical actions with multivariable regres- were prescribed more medications than traditional Medicare patients. Co- POSTERS Therapeutics sions. African-Americans (AOR: 0.82; 95% CI: 0.68, 0.98) and those in HMO payments for duals were much lower. However, the relative cost given re- Clinical Diabetes/ (AOR: 0.81; 95% CI: 0.68, 0.96) were less likely to be initiated on insulin duced income is a concern. compared to whites and those in fee-for-service. Elderly with inpatient use, polypharmacy, and greater number of OADs were more likely to have insu- 1363-P lin initiation compared to those without inpatient use, polypharmacy, and An Interdisciplinary Team-based Group Visit Improves Access and 1OAD. HbA1c Levels to Specialty Endocrine Care for a High Risk Diabetic Personalized clinical action measures can be used by clinicians to promote Population timely insulin initiation in Medicare managed care. STEVEN KAUFMAN, RACHEL ADAMS, VALERIE S. GANETSKY, JEFFREY BRENNER, Supported By: Sanofi U.S. Camden, NJ, Philadelphia, PA Group medical visits (GMVs) in an urban, resource-poor community (Cam- 1361-P den, NJ) were initiated to provide an interdisciplinary team approach to on- Effect of Intensive Follow-up by a Diabetes Care Team on HbA1c going patient-centered care and improved access for high-risk DM patients. Three Months after Hospital Discharge Clinical protocols and task shifting to LPNs were used to promote effi cient RAJESH GARG, RAQUEL REIN, PATRICIA UNDERWOOD, CHEYENNE METZGER, access to high-cost, specialty care to a population with a historic high no- KYLE CARBONE, BROOKE SCHUMAN, Boston, MA show rate. Patients with poorly controlled diabetes admitted to the hospital are of- Patients referred for DM consultation were offered a GMV or individual ten discharged back to their established diabetes care providers without a endocrinologist visit. Up to 12 patients were scheduled for one-hour long proper follow-up plan. We present preliminary results of an ongoing random- initial or follow-up visits in English or Spanish. The GMV was composed ized controlled trial to evaluate the effect of continued follow-up by a hospi- of a pre-visit review of history, labs, and medications, and 4 visit compo- tal diabetes team on A1C after discharge. Patients with A1C ≥8% admitted nents: DM questionnaire completion by a “Navigator” (LPN, APN or clinical to the hospital for an elective surgery were enrolled and are being followed PharmD), medical review, DM education, and interactive group discussion. for 1 year. This report presents data at 3 months after discharge. All patients Clinical protocols for BP, lipid, and insulin titration were used and the plan were seen by the diabetes team during their hospital stay as part of stan- was reviewed and approved by the endocrinologist. Patient demographics dard care. At the time of discharge, patients were randomized to one of the and clinical measures (HbA1c, BP, and lipids) were collected. Patient satis- two groups: 1. Continued follow-up (CF), 2. Referral to established providers faction was surveyed. (EP). Patients in the CF arm received weekly to monthly phone calls from A total of 188 patients accounted for 419 visits from Oct 2013-14. The a diabetes specialist nurse practitioner (NP). The NP reviewed home blood majority of patients were Hispanic (58.7%) or African-American (33.9%). glucose data, counseled patients on diet, exercise and medications, and The prevalence of insulin use, antihypertensive therapy, and lipid therapy discussed with an endocrinologist once a week. The NP coordinated with was 73%, 83.8%, and 89.2%, respectively. 20% of patients were insured by patients’ established providers for medication changes, follow up visits and Medicaid. Median HbA1c in the total cohort was 8.4%. Time to next follow- laboratory tests. Out of 88 patients enrolled to date, 45 were randomized to up appointment was 24.4 days for GMV, 40.3 days for individual urban, and the CF arm and 43 to the EP arm. Mean age in the CF arm was 63±10 years 42.2 days for the suburban offi ce. Median HbA1c in the Medicaid population and in the EP arm 62±12 years (p=NS). Duration of diabetes was 10.9±10 and in this cohort was 9.7% with a 0.3% HbA1c reduction (p>0.05). Average pa- 14.2±10.5 years in the CF and EP arms respectively (P=NS). Similar propor- tient satisfaction since Oct 2014 was 4.55 (Likert scale 1= worst, 5= best). tions of patients had microvascular complications in the CF (40%) and EP Our novel interdisciplinary specialty GMV model improved access to care arms (37%) and similar proportions were receiving insulin (73% and 83% with a non-signifi cant decline in HbA1c for an urban, resource-poor commu- respectively). Baseline A1C (%) was 9.2±1.3 in the CF arm and 9.3±1.3 in the nity. GMVs are a viable alternative to the shortage of endocrinologists. EP arm (p=NS). A1C decreased to 7.9±1.3 at 3 months (p <0.0001 compared Supported By: Nicholson Foundation to baseline) in the CF and to 7.7±1.3 (p <0.0001 compared to baseline) in the EP arm. There was no signifi cant difference in the change in A1C at 3 months 1364-P between the CF (1.3±1.3) and the EP arms (1.6±1.5) (p=NS). These data show Evaluation of Insulin Pump Therapy in the Hospital Setting that post-discharge follow-up by a hospital diabetes team has no effect on JENNIFER TRUJILLO, KEVIN SPANGLER, Aurora, CO the A1C at 3 months after discharge. Previous studies indicate that continuous subcutaneous insulin infusion Supported By: UD7HP25059 (CSII; insulin pump) therapy can be used safely in the hospital setting when a standardized inpatient policy and set of procedures are in place. Studies have not shown a signifi cant difference in glycemic control between pa- tients who have continued CSII therapy during hospitalization and those that have not. This study was performed to evaluate adherence to our institu-

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A354 HEALTH CARE DELIVERY—ECONOMICS tional policies and glycemic control related to inpatient CSII use. Formalized by 2.4 mg/dL (CI [2.0, 2.8], p<0.001) for the mean fi rst 12-hour postopera- inpatient CSII policy and procedures were approved in 2009 and require pa- tive glucose and 2.2 mg/dL (CI [1.8, 2.5], p<0.001) for the mean fi rst 24-hour tient consent, completed orders, and glucose management team consulta- postoperative glucose levels. Diabetes status of the patient (regression tion. We examined 48 hospitalizations between 2009 and 2014 involving 20 coeffi cient = 12.2, p<0.001) and intraoperative use of steroids (regression patients on outpatient CSII therapy. Average age and duration of diabetes coeffi cient = 10.1, p<0.001) had positive effect in elevating postoperative was 49 (14) and 35 (13) years. Average baseline A1C 8.2 (1.5)%, length of stay glucose levels. Compared with starting insulin to prevent hyperglycemia (> 5.3 (3.6) days, 100% had type 1 diabetes, 60% were women, and 92% were 180 mg/dL) when intraoperative glucose exceeded 140 mg/dL, an insulin white. CSII therapy was continued in 19 admissions (39%) or used intermit- therapy to treat intraoperative hyperglycemia, was associated with an in- tently in 21 admissions (44%). Among these, glucose management team crease in postoperative glucose levels (7 mg/dL, p< 0.001) and postoperative was consulted in 92.5%, patient consent documented 20%, and order set hyperglycemia incidences (OR = 1.53, p=0.01). Higher intraoperative glucose documented 20%. Mean POC glucose was lower in patients who remained level is associated with higher postoperative glucose level. Initiating insulin on CSII [181.5 (82.1) mg/dL] or intermittently used CSII [182.4 (88.3) mg/dL] infusion when intraoperative glucose level exceeds 140 mg/dL is associated compared to those who did not use CSII during hospitalization [218.1 (117.0) with better postoperative glucose levels and lower incidences of postopera- mg/dL; p<0.001 for both]. Rates of severe hyperglycemia (POC glucose>350 tive hyperglycemia. mg/dL) were lower in patients who remained on CSII or intermittently on CSII Supported By: University of Washington compared to patients who did not use CSII during hospitalization [3.2 vs. 4.6 vs. 15.8% respectively; p<0.0001 for both comparisons]. Rates of severe hy- 1367-P poglycemia (POC glucose & lt50 mg/dL) were not different between patients Telenursing Is a Useful Tool to Optimize Metabolic Control in Pa- on CSII, intermittently on CSII, or off CSII (1.3 vs. 1.9 vs. 1.3% respectively; tients with Type 1 Diabetes Mellitus p>0.05). Despite low adherence with some policies and procedures; glyce- KALLIOPI KOTSA, KONSTANTIA KOTSANI, PANAGIOTIS TSAKLIS, KIRIAKOS KA- mic control was better in patients on or intermittently on CSII compared to ZAKOS, Thessaloniki, Greece those that were not with no differences in hypoglycemia. The results on the clinical outcomes of telemedicine in the group of pa- tients with type 1 Diabetes Mellitus (DM) have been confl icting. The aim of 1365-P this study was to evaluate the impact of a telephone-based interaction sys- Early Glycemic Response Predicts Achievement of Subsequent tem with a specialized nurse on the intensifi cation of blood glucose control

Treatment Targets in the Treatment of Type 2 Diabetes and the improvement of blood glucose values of patients with type 1 DM. POSTERS HAODA FU, DACHUANG CAO, KRISTINA S. BOYE, BRADLEY H. CURTIS, DARA Patients and Methods: 96 diabetic patients with type 1 DM were included Therapeutics Clinical Diabetes/ SCHUSTER, DAVID M. KENDALL, HAYA ASCHER-SVANUM, Indianapolis, IN in the study. Two groups matched for age, sex, HbA1c and diabetes duration ADA consensus guidelines emphasize individualized treatment in the were formed, telenursing group (48 patients) and control group (46 patients). management of type 2 diabetes mellitus (T2DM). Early glycemic response is Participants of both groups were informed on the benefi ts of frequent glu- a clinical marker that may predict longer-term effi cacy for individual patients cose monitoring and were asked to record their blood glucose values three and provide a clinical tool to enhance personalized treatment. This analysis times a day for 3 months. The intervention consisted of a weekly contact evaluated whether glycemic response measured at week 12 (“early”) could with a specialized nurse. The parameters studied were blood glucose values serve as a reliable predictor of glycemic control at weeks 24 and 52 of ther- in different time points during the day (morning, preprandial, postprandial) apy in patients with T2DM. and the frequency of blood glucose measurements. We used data from 3 randomized, controlled clinical trials that evaluated Results: The telenursing group had higher morning values (BG 120,01±25,69 patients with T2DM treated with 3 common anti-diabetic drugs: metformin mg/dl) than the control group (BG 107,18±12,61 mg/dl) in the beginning of (n=597), sulfonylurea (n=626), and insulin glargine (n=1046). Gradient boost- the study, while at the end of the study there was a statistically signifi - ing methods were used to identify predictors of subsequent response and cant difference favoring the intervention group (BG 93,18±13,30 mg/dl) vs. their predictive accuracy represented by sensitivity, specifi city, positive pre- control (BG 105,17±13,74 mg/dl), p=0,000. Both groups improved preprandial dictive value (PPV), and negative predictive value (NPV). Treatment success and postprandial values with the telenursing group achieving lower values at weeks 24 and 52 was assessed for each patient and defi ned as achieving at both time points (preprandial BG 108,92±9,66 vs. 120,84±4,05 mg/dl, HbA1c <7.0% or HbA1c reduction from baseline ≥1.0%. For metformin, sul- p=0.000 and postprandial BG 179,46±23,07 vs. 207,84±18,8 mg/dl, p=0.004). fonylurea, and insulin glargine, the ranges of predictive values for improve- There was a statistically signifi cant decrease in the missed measurements in ments in HbA1c at week 24 were 0.67-0.83 (sensitivity), 0.81-0.94 (specifi c- the telenursing group in the whole study period (54,1±17,02 vs. 69,72±13,67 ity), 0.44-0.71 (PPV), and 0.90-0.96 (NPV). For metformin and sulfonylurea, missed measurements, p=0.000). predictive values for improvements in HbA1c at week 52 were 0.73 and 0.45 Conclusions: Our results indicate that the use of interactive telenursing (sensitivity), 0.84 and 0.94 (specifi city), 0.56 and 0.74 (PPV), and 0.92 and appointments in patients with type 1 DM is an effi cient strategy resulting in 0.82 (NPV). High predictive values identifi ed in this analysis support “early” improvement in glycemic fl uctuations and self-care treatment adherence. response as an appropriate tool for predicting treatment success at weeks 24 and 52. The high NPV (lack of early glycemic response) appears to be 1368-P an accurate indicator of the likely need for a change in (or intensifi cation Impact of a National Gestational Diabetes Register: Does It Make of) therapy. These data support the current guideline recommendations on a Difference? evaluating therapeutic response to pharmacologic intervention as early as SHARLEEN L. O’REILLY, TIMOTHY C. SKINNER, JAMES A. DUNBAR, Burwood, week 12. Australia, Darwin, Australia Supported By: Eli Lilly and Company Women who have had gestational diabetes (GDM) are at increased risk of developing type 2 diabetes (T2DM). Australia is the only country to have 1366-P a National Gestational Diabetes Register (NGDR). The register commenced Effect of Blood Glucose Management during Noncardiac Surgery on July 2011 and aims to: Improve risk awareness; promote diabetes prevention Postoperative Blood Glucose Levels through lifestyle modifi cation; and encourage regular diabetes screening. BALA G. NAIR, MAYUMI HORIBE, MONI B. NERADILEK, Seattle, WA This study aimed to identify postnatal diabetes screening patterns and the Postoperative hyperglycemia has been associated with poor surgical out- impact of NGDR awareness in a nationally representative sample of Austra- come in both diabetic and non-diabetic patients. The effect of intraopera- lian women after a GDM pregnancy. tive glucose management on postoperative glucose levels and the optimal A cross-sectional anonymous online survey of women previously diag- intraoperative glycemic threshold for initiating insulin remain unclear. A ret- nosed with GDM occurred from June-November 2014. Of 11,860 invited rospective cohort study of adult, non-cardiac surgery patients that required from a stratifi ed NGDR sample, 966 consented to participate (response rate intraoperative glucose management was undertaken to compare intraopera- 8.2%). Those currently pregnant or with subsequently diagnosed T2DM were tive glucose levels and insulin therapy against postoperative glucose levels excluded (n=21). Reported postnatal diabetes screening rates remain stable within the fi rst 12 and 24 hours of postoperative admission. Logistic regres- since the fi rst Australian GDM survey in 2006 (74% survey respondents). sion models, adjusting for patients and surgical covariates, were used to de- 44% women reported receiving information from the NGDR postnatally. Lo- termine the association between intraoperative glucose management and gistic regression showed factors associated with women reporting receiving postoperative glucose levels. In 2440 patients that required intraoperative NGDR information were younger age [odds ratio (OR) 0.96, 95% Confi dence glucose management, an increase in mean intraoperative glucose level by Interval (CI) (0.92, 1.00)), recall of a NGDR screening reminder [(OR) 3.84, 10 mg/dL was associated with an increase in postoperative glucose levels 95% CI (1.89, 7.79)] and a higher level of personal control in perceived risk

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A355 HEALTH CARE DELIVERY—ECONOMICS

((OR) 1.37, 95% CI (1.02, 1.85). No signifi cant difference for postnatal screen- Table. ing occurring, total T2DM risk perception or lifestyle risk factors was seen. Although women registered on the NDGR receive postnatal information, only about half of those will engage with the material. While their engage- ment is not associated with healthier lifestyles or higher levels of postnatal T2DM screening, some effect on risk perception and understanding screen- ing reminders was seen. Registries need system-level integration to function optimally and these results suggest improvements to the NGDR could yield better diabetes prevention outcomes with stronger ties to GP follow-up. Supported By: Australia National Health and Medical Research Council (1069254)

1369-P Factors Predictive of Weight Gain and Implications for Diabetes Modelling: A Study in Type 2 Diabetes Patients Initiating Metformin and Sulphonylurea Combination Therapy JASON GORDON, PHILIP C. MCEWAN, DANIEL SUGRUE, JORGE PUELLES, Mon- mouth, United Kingdom, London, United Kingdom The relationship between resource utilisation and patient phenotype in people with type 2 diabetes mellitus (T2DM) is not well researched. More- over, the accurate prediction of the consequences associated with the man- agement of T2DM is crucial to reliably inform healthcare decisions. The objectives of this study were to (a) assess the factors associated with weight gain in a population of T2DM patients escalating from metformin (M) to M + sulphonylurea (M+S) and (b) evaluate whether healthcare resource 1371-P

POSTERS utilisation associated with being overweight or obese is underestimated in Development and Pilot Testing of a Nurse-Facilitated Intervention Therapeutics typical health economic evaluations. for Screening and Management of Diabetes in Primary Care Set- Clinical Diabetes/ The study was a retrospective cohort study using UK CPRD linked to HES tings in India: The mPower Heart Project data. The association between baseline phenotypic factors and weight gain DEVRAJ JINDAL, AJAY VAMADEVAN SARALA, RAKSHIT SHARMA, ABHA was assessed using logistic regression. Hospitalisation incidence rates PAWAR, AMBUJ ROY, SANJAY KINRA, NIKHIL TANDON, DORAIRAJ PRABHA- per 1000 person-years for major diabetes-related complications according KARAN, Gurgaon, India, New Delhi, India, London, United Kingdom to body mass index (BMI) at baseline were estimated from the data (ob- Diabetes is a major public health challenge in India. Although diabetes can served) and compared to those obtained from a validated diabetes model be effectively managed at primary care, poor quality of care results in high (predicted). burden of undiagnosed and under-treated diabetes cases in India. In order 11,071 patients were included in the analysis; approximately 40% gained to address the gaps in diabetes care, a nurse facilitated, smartphone-based weight in the fi rst year following escalation to M+S. Baseline age, HbA1c, decision-support enabled intervention was developed and tested in the So- and gender were found to be predictors of weight gain (odds ratios 0.99 [1- lan district of Himachal Pradesh. year increment], 1.11 [1% increment] and 0.81 [female vs. male] respectively, Following the Medical Research Council framework for developing com- p<0.001). Observed vs. predicted incidence rates were 64 vs. 13 (Normal), plex interventions, the sequential process in the development of the mPower 297 vs. 31 (Overweight), 223 vs. 50 (Obese) and 378 vs. 41 (Severe Obese). Heart intervention was: 1) literature review and contextualization of clinical This analysis suggests there are identifi able patient characteristics pre- management guidelines for Community Health Centres (CHCs); 2) needs as- dictive of weight gain that may be informative to clinical and economic sessment of doctors and nurses at CHCs; 3) development of smartphone- decision-making in the context of patients escalating to a M+S regimen. based clinical decision support system software (DSS); 4) deriving feedbacks Hospital admissions in people with T2DM were generally under-predicted. A from the healthcare team to refi ne the intervention; and 5) implementing and particular focus of future research should be the need for diabetes models to integrating the intervention into routine care at the CHCs and evaluating the make the likelihood of experiencing an event conditional on BMI. impact on process of care outcomes. Supported By: Takeda Pharmaceutical Company Limited During 25 months of implementing the intervention, trained nurses carried out opportunistic screening of 23,542 patients, using DSS, at the out-patient 1370-P department of fi ve CHCs. A total of 1,727 subjects were identifi ed with dia- Extremely Short (1 day) Length of Stay (LOS) in Patients with Diabe- betes, of which 525 (30%) subjects were newly detected during screening. tes (DM) Is Associated with High Readmission Rates (RR) Using DSS generated management plan, nurses facilitated diabetes care VARINDER KAMBO, LARRY LUTSKY, LEONID PORETSKY, New York, NY with the concurrence of doctors. In this group, 635 subjects attained one DM is associated with increased RR within 30 days. We examined the year follow-up and the mean reduction in fasting blood sugar level observed relationship between RR and LOS in 2013 for patients with DM (N=889) and was 2.38 mmol/l. without DM (N=3360) for the hospitalist group at an urban teaching hospital. The mPower Heart project demonstrated that a nurse-facilitated, DSS en- DM was a secondary diagnosis in 88% of patients in the DM group. RR was abled intervention is feasible and acceptable at primary care setting in India. higher for patients with DM than for patients without DM (p=0.016). This Supported By: Medtronic Foundation difference was driven by the group of patients with LOS of 1 day (N=676 discharges for patients without DM and N=116 for patients with DM, 1372-P p=0.023). There was no statistically signifi cant difference for RR in all other LOS categories that we examined (days 2-30). Case Mix Index (CMI) was WITHDRAWN similar for the two groups. We conclude that LOS of 1 day is associated with high risk of readmissions at 30 days for patients with DM. We hypothesize that intensive and early outpatient management of patients with diabetes may prevent readmissions. A prospective randomized trial to explore this hypothesis is in progress.

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1373-P 1375-P Preoperative Glucose Management and Length of Hospital Stay in Insulin-related Costs Associated with Injection-related Lipohyper- Diabetic Patients Undergoing Elective Surgery trophy (LH) in Chinese Diabetes (DM) Patients RAJESH GARG, BROOKE SCHUMAN, KYLE CARBONE, ANGELA BADER, ALEX- ZILIN SUN, LINONG JI, QIFU LI, GUIJUN QIN, LAURENCE HIRSCH, ZHENG WEI, ANDER TURCHIN, CHEYENNE METZGER, RAQUEL REIN, Boston, MA JUNHAO LIU, LUAN LUAN, ARTHI CHANDRAN, Nanjing, China, Beijing, China, Patients with diabetes mellitus have a high risk of complications after Chongqing, China, Zhengzhou, China, Franklin Lakes, NJ surgery. We recently showed that preoperative HbA1c was associated with DM affects an estimated 114 million people in China with another 497 increased length of hospital stay (LOS) in patients undergoing any major sur- million classifi ed as pre-DM(1). LH is an addressable complication among gery. Based on these data, we initiated a preoperative glucose management insulin-injecting DM patients that may affect insulin absorption and thereby program that systematically identifi ed and treated diabetic patients sched- related costs. This study evaluates the prevalence of LH and its relationship uled for major elective surgeries. The goal of this program was to intervene to insulin consumption in China. before admission to hospital in order to improve glycemic control on the day An observational study was conducted among 401 DM patients from 4 of surgery. The program focused on patients with HbA1c ≥8% for treatment cities (Beijing, Nanjing, Chongqing, Zhengzhou). Participants were continu- but provided guidance and support for all patients with diabetes who were ously injecting insulin for ≥1 year, 18-80 yrs old with a BMI ≥18.5 kg/m2. otherwise managed by the preoperative anesthesia and surgery teams. Demographics, medical history, direct and indirect costs and disease man- The interventions were individualized based on clinical situation and time agement data were collected via patient survey, followed by a physical exam available before surgery. Data were collected from an electronic patient and HbA1c tests. database for 2 years before (Jan 2011-Dec 2012) and 16 months after (Feb Patients were mean(SD) 59.6(11.5) yrs old, and took insulin 5.6(4.6) yrs, 2013-May 2014) implementation of the program. All patients with diabetes averaging 33.0(18.4) U/day. Prevalence of LH was 52.9%. HbA1c = 8.2(1.8)% undergoing elective surgery and admitted to the hospital for >24hours after in those with, and 7.7(1.5)% in those without LH (p=0.003). Patients with LH surgery were included in analysis. There were 2,266 surgeries on patients used an average of 11 U/day more in comparison with non-LH injectors (38.1 with diabetes before the program and 1,566 surgeries during the program. U vs. 27.1 U, p<0.001) and were more likely to have HbA1c ≥7% (58 % vs. Among these patients, LOS decreased from 4.8±5.5 days before the program 42%, p=0.002). Daily insulin cost (RMB 8.2 vs. 5.8, p<0.001) and BMI-normal- to 4.5±4.3 days after the program (p=0.03). Among patients with HbA1c ≥8% ized daily insulin cost (RMB 0.31 vs. 0.24, p<0.001) were higher in those with (N=273), LOS was 4.9±4.3 days after implementation of the program but no LH. There are approximately 8.4 million insulin injectors in China(2), where control data were available for comparison. Among non-diabetic patients the average insulin price is RMB 0.215 per U. The cost of excess insulin use POSTERS undergoing elective surgery during the same respective periods, there was associated with LH is estimated to be approximately RMB 3,892,593,600 Therapeutics no difference in LOS (3.9 ± 4.6 days before and 3.9±4.3 days after the pro- ($630 million) per year. Clinical Diabetes/ gram, p=NS). Overall, average LOS decreased by 0.3 day per diabetic patient LH in insulin-taking patients presents a signifi cant, avoidable economic for a total savings of about 325 hospitalization days per year. We conclude burden in China due to excess insulin consumption in the setting of worse that preoperative glucose management reduces LOS and thus, may save glycemic control among those affected. Implementing techniques to avoid hospitalization costs for diabetic patients undergoing elective surgery. or limit LH development could result in decreased insulin expenditure, lower Supported By: UD7HP25059 insulin consumption, and may improve glycemic control. (1) Yu Xu, Limin Wang, Jiang He, et al. Prevalence and Control of Diabe- 1374-P tes in Chinese Adults. JAMA 2013; 310(9): 948-59. (2) IMS Health Report, The Impact of Postprandial Hyperglycaemic Episodes (PPH) on Diabetes-China December 2013. Health Care Resources among People with Type 1 or Type 2 Diabe- tes in the U.S., UK, and Germany 1376-P MERYL BROD, ANNIE NIKOLAJSEN, JAMES WEATHERALL, KATHRYN M. PFE- Outcomes after Institution of a Hospital-Wide Perioperative Glyce- IFFER, Mill Valley, CA, Søborg, Denmark mic Control Protocol Respondent-reported post-prandial hyperglycaemic episodes (PPH) LINDSAY M. ARNOLD, MUFADDAL MAHESRI, MARIE E. MCDONNELL, SARA M. among people with diabetes are a well-known clinical challenge to dia- ALEXANIAN, Boston, MA betes management. While the impact of post-prandial hypoglycaemia on In 2010 Boston Medical Center implemented a protocol for the periopera- healthcare resource use has been well studied, little is known about the tive management of patients with diabetes presenting for elective surgery. impacts of PPH episodes on healthcare resource use. The purpose of this The protocol includes preoperative blood glucose (BG) monitoring and use study was to assess the impact of respondent-reported PPH on healthcare of IV insulin infusion or bolus for patients with a BG >180 mg/dL. Patients resource use among people with diabetes taking meal-time bolus insulin. admitted after surgery received a consult by the Diabetes Consult service in Data were collected in a web-survey of 906 adults with T1DM (39%) and the postoperative area for further management. In order to assess the effect T2DM (61%) taking bolus insulin in the U.S. (40%), UK (26%), and Germany of this protocol we conducted a retrospective chart review before and after (34%). Inadequate post-prandial glucose control was prevalent; 66% of re- the intervention to review BG results and clinical outcomes. We analyzed spondents reported diffi culty getting blood glucose (BG) stable after eat- patients who underwent surgery and were admitted to the hospital during ing during the past week, with 17% experiencing hypoglycaemia 3 or more the 2 years prior to and after protocol implementation. Patients >18 years old times and 30% experiencing PPH episodes 3 or more times. Respondents with a preoperative BG >180 mg/dL were analyzed. Pregnant patients and who experienced PPH episodes reported measuring their BG 1.9 additional patients undergoing cardiothoracic surgery were excluded. The control and times on days they experienced symptoms of PPH compared to an average intervention groups had similar demographics. BG results are shown in Table day. Further, respondents who experienced PPH episodes in the past week 1. Rates of mortality and wound infection as coded by ICD-9 were low and called/emailed their physicians about their diabetes an average of 2.7 times similar between groups. After implementation of a perioperative glycemic in the past year compared to 1.4 times for those who did not experience protocol we saw a signifi cant improvement in glycemia in the immediate PPH episodes (p<.001) and made an average of 5.5 diabetes related visits postoperative period. Mean hospital glucose was not different between the to their physician or healthcare professional in the past year, compared to groups though assessment was impacted by a lower sampling in the control 4.4 visits for those who did not experience PPH episodes (p<.001). Of those group. There was a very low rate of wound infection and mortality in both who experienced PPH episodes during the past week, 72% had at least one groups. medical complication related to diabetes, compared to 55% of those who Table. Glucose Results. did not experience PPH episodes (p<.001). These results indicate that PPH episodes among adults with diabetes are common and signifi cantly associ- control (N) Intervention (N) P value ated with greater use of healthcare resources, which may increase costs of Mean preoperative glucose 227.6 +/- 93.3 212.6 +/- 68.0 0.01 diabetes management. (260) (558) Supported By: Novo Nordisk A/S Mean glucose on arrival in the 194.3 +/- 68.0 182.2 +/- 57.3 0.009 postoperative care unit (255) (551) Mean of all glucoses in OR 195.2 +/- 69.9 173.2 +/- 55.3 <0.0001 Mean hospital glucose 173.0 +/- 39.3 174.2 +/- 36.3 0.6723 (257) (552) Rate of hypoglycemia 2.43% 1.94% 0.0008

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1377-P 1379-P Disseminating Web-based EHR-linked Diabetes Clinical Decision Seven Success Factors of Diabetes Primary Care in Sweden Support System from One Medical Group to Another: Case Study CLAES-GORAN OSTENSON, SARA EKEBLAD, SOFFIA GUDBJORNSDOTTIR, TONY PATRICK J. O’CONNOR, JOANN M. SPERL-HILLEN, HEIDI L. EKSTROM, DEEPIKA HOLM, Stockholm, Sweden, Gothenburg, Sweden APPANA, GERALD H. AMUNDSON, SHAUN D. FROST, JANE E. DUNCAN, RASH- In Sweden, a well-developed National Diabetes Register (NDR), that cov- MI SHARMA, Minneapolis, MN ers about 90% of all people with known diabetes, has shown large geo- Broad dissemination of effective EHR-linked clinical decision support (CDS) graphical differences between and within the 21 Swedish counties in type 2 systems to many care delivery systems is an essential step to improve health diabetes (T2D) treatment outcomes. This study of the design and control of care for America’s 25 million diabetes patients. However, there are numerous diabetes care in primary care was conducted to identify factors associated potential barriers to such dissemination of CDS systems across delivery sys- with good outcomes of T2D care based on glycosylated hemoglobin (HbA1c), tems, including concerns about resources, data privacy, variation in EHR func- blood pressure and use of lipid-lowering drugs. Four counties with good tionality, impact on clinic workfl ows, agreement on clinical content of CDS, outcomes, and four with less favorable outcomes, were selected based updating CDS algorithms as evidence evolves, programming challenges, and on NDR outcome data from 2012. Differences in the provision of T2D care network maintenance issues. Here we report on a successful dissemination were explored using a combination of quantitative and qualitative analysis. effort and the strategies used to overcome potential barriers to success. Semi-structured in-depth interviews were made with a total of 80 selected A health plan has sponsored dissemination of a proven EHR-linked web- individuals with key roles in the control of diabetes, either as clinical leaders, based CDS system from one delivery system to another for purposes of improv- or as members of the management organization or the political leadership, ing diabetes care at the recipient system. This fi rst attempt at dissemination including 22 in-depth interviews with clinical staff from nine primary health took 8 months and costs required $80,000 at the donor system and $25,000 for care centers. The study showed large differences in the design and manage- recipient system to pay for programmer and clinician time to work through tech- ment of diabetes care between counties and health centers. Systematic dif- nical, clinical, implementation, and training issues described above. Problems ferences, where counties and primary care units with good outcomes stand related to agreement on the clinical content of algorithms and data security out, can be described in terms of seven success factors. These relate to were identifi ed but readily solved. The costs and time required for the trans- the primary care unit´s design and delivery of healthcare (1. Focus on pa- fer will vary substantially depending on complexity of the CDS, programming tients´ target values e.g. HbA1c, BP, lipids; 2. Early targeted efforts to help expertise at the recipient system, and dissemination experience at the donor patients with suboptimal outcomes; 3 Own results always on the agenda), system. We estimate that this process could be replicated in additional delivery the leadership and management of care (4. Easily accessible knowledge POSTERS Therapeutics systems in about 6 months and for about 30% less money using programming and evidence-based guidelines; 5. Follow-up and feed-back on results; 6. Clinical Diabetes/ tools and the benefi t of other experience gained in this initial dissemination Continuous efforts for improvements of care), and the culture that perme- project. We conclude that broad dissemination of effective EMR-linked web- ates the organization (7. Ownership of results and focus on prevention). Our based CDS to improve diabetes care is feasible, but that the resources needed hope is that the description of these seven success factors, mainly related are substantial. Further efforts to streamline broad dissemination of effective to the organization of care, will stimulate discussions and inspire to changes CDS systems to multiple recipient care systems are needed. towards a more evidence-based and equal care. Supported By: Swedish Association of Local Authorities and Regions 1378-P An Opportunity to Save $1 Billion Yearly on Diabetic Foot Ulcer Care 1380-P D. SCOTT NICKERSON, TIM M. RANKIN, Sheridan, WY, Tucson, AZ University of Michigan Intensive Type 2 Diabetes Program The U.S. diabetic foot ulcer (DFU) incidence is 3 to 4% of 22.3 million di- ISRAEL HODISH, MARTHA M. FUNNELL, Ann Arbor, MI agnosed plus 6.3 million undiagnosed diabetes cases, 858,000 cases total. Type 2 diabetes is a group of conditions with a progressive course. For Recurrences comprise around 50% of DFU. Annual recurrence risk is 30%. At most patients the clinical course aggravates after the fi rst decade. Patients least 6 reports show that nerve decompression (ND) by external neurolysis become resistant to multiple pharmacological agents and become increas- of entrapped nerve trunks reduces neuropathic DFU (nDFU) recurrence by ingly insulin defi cient. By that time, many have developed complications and >80%, from 30%/yr to <5%/yr, e.g. Figure 1, n=42. ND might preclude large individual annual expenses grow exponentially. medical expenses and societal costs by minimizing DFU recurrences. Cost/ Attainment and maintenance of therapy goals require frequent monitoring benefi t of ND implementation for nDFU recurrence is calculated and com- and therapy modifi cations (particularly with insulin therapy). Unfortunately, pared to the current $6.171 billion annual DFU expense. high workload and a shortage of specialists hinder the implementation of Literature review identifi ed best estimates of annual nDFU incidence, regular monitoring and therapy adjustments in routine clinical practice, and recurrence risk, medical management expense and non-economic costs patients are seen only 2-3 times per year. for DFU. Calculations assume widespread application of bilateral ND after We have implemented an intensive type 2 diabetes program, which em- wound healing to the nDFU problem, using Center for Medicare Services data ploys frequent monitoring and therapy adjustments while seeing patients of $1,143 cost for unilateral leg ND. Universal adoption of ND after nDFU once a year for face-to-face visits. Technology has been developed to man- healing could reduce total annual DFU occurrences by at least 21% in the age data and day-to-day operations. The program has been tested in a ran- third year and 24% by year 5, representing calculated cost savings of $1.296 domized controlled trial, aiming to recruit N=60 patients. Participants have billion (year 3) to $1.481 billion (year 5). Selective application of ND to highest been randomized to either the intensive type 2 diabetes program or the usual risk diabetic polyneuropathy (DSPN) cases might achieve further savings. By endocrinology clinic and followed for a year. Comparators have included clin- forestalling recurrences to shrink DFU incidence, ND has potential to reduce ical parameters, hospital visits, clinic retention, patients’ satisfaction and U.S. treatment expense and societal cost by $1 billion/yr or more. resource utilization. Until December 2014, 30 patients were recruited to the experimental group and 24 to the control. Average age of subjects in the intensive group was 55.5 (±9.2) years and average duration of diabetes 10.4(±6.1) years. Thus far, subjects in the experimental group have been followed for 9.8(±1.6) months. In this group, face-to-face clinic visits have occurred 1.1(±0.3), yet therapy adjustments have been done in average 10(±5.4) times per patient by either email or phone exchanges. A1C in the intensive group has improved from 9.5% (±1.0) to 7.9%(±1.2). Preliminary results indicate that the program is effective and well re- ceived by patients. It has the potential to improve outcomes and ease the burden on both patients and providers. Supported By: University of Michigan

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A358 PEDIATRICS—OBESITY AND TYPE 2 DIABETES

PEDIATRICS—OBESITY AND TYPE 2 DIABETES & 1383-P Subclinical Cardiovascular Disease Is Inversely Associated with Guided Audio Tour: Spectrum of Pediatric Diabetes—Obesity, Cerebral Blood Flow in Adolescents with Type 2 Diabetes Type 2 Diabetes, Cystic Fibrosis-related Diabetes, and More (Posters: 1381-P CASSANDRA C. BRADY, LAWRENCE M. DOLAN, JENNIFER VANNEST, SCOTT to 1387-P), see page 17. HOLLAND, JANE KHOURY, GREGORY R. LEE, AMY S. SHAH, Cincinnati, OH Adolescents with type 2 diabetes (T2DM) have evidence of subclinical cardiovascular disease measured by carotid intima media thickness (cIMT). & 1381-P Whether subclinical cardiovascular disease is associated with cerebrovas- Maternal Weight Status during Pregnancy Infl uences Breast Milk cular changes is not known. Therefore, we assessed the relationship be- Oligosaccharide and Amino Acid Content tween cIMT and cerebral blood fl ow (CBF) in adolescents with T2DM. ELVIRA M. ISGANAITIS, TUCKER J. MATTHEWS, DAVID A. FIELDS, Boston, MA, We recruited 20 adolescents with T2DM (mean age 16.7±1.9 years) with- Oklahoma City, OK out prior history of neuropsychological disease or abnormal brain imaging. Maternal obesity is a risk factor for offspring obesity and metabolic syn- CBF was obtained via magnetic resonance imaging (MRI) using pseudo-con- drome. This is a major public health concern given ~50% of pregnant women tinuous arterial spin labeling. cIMT, a validated marker of early atheroscle- are either overweight or obese. Whether altered breast milk composition rosis, was measured in the common carotid by high resolution ultrasonog- contributes to mother-child transmission of obesity risk is poorly under- raphy. Associations between cIMT and CBF were determined using Pearson stood. We hypothesized that maternal weight status would alter breast milk correlation coeffi cients. nutrient content. Mean hemoglobin A1c was 7.9±2.2%. Mean duration of T2DM was 2.8±2.2 We enrolled 35 mother-infant pairs from Oklahoma University Health Sci- years. Mean BMI was 37.8±4.7 kg/m2. There was a signifi cant inverse cor- ences Center. Participants were non-diabetic and grouped by maternal pre- relation between increased common cIMT and decreased CBF in the brain pregnancy BMI <25 (normal) or ≥25 kg/m2 (overweight/obese, “ov-ob”). A both globally and in 19 major regions of the brain including bilateral areas in complete expression of breast milk was collected at 1 and 6 months postpar- frontal, occipital, parietal and temporal lobes (all p<0.05). tum. Milk content of 274 metabolites was quantifi ed by LC-MS (Metabolon) We show for the fi rst time a relationship between subclinical cardiovas- and analyzed (JMP10, MetaboAnalyst). Primary exposures were maternal cular and cerebrovascular changes in adolescents with a short duration of pre-pregnancy BMI and gestational weight gain (GWG); primary outcomes T2DM. Whether these fi ndings suggest an increased risk for premature cere- were breast milk metabolites at both 1 and 6 mo. postpartum. POSTERS brovascular disease is not known. Therapeutics

Pre-pregnancy BMI differed between the normal and ov-ob group (nor- Supported By: Cincinnati Diabetes and Obesity Center; Endocrine Fellows Clinical Diabetes/ mal: 21.8 ± 2.1, ov-ob: 32.0 ± 6.6 kg/m2, P<0.0001). Maternal age, race, and Foundation income were similar, but parity and birth weight tended to be higher in the ov-ob group. At 1 mo. postpartum, 9 breast milk metabolites were altered in the ov-ob group (P<0.05); 3 oligosaccharides previously linked to mucosal & 1384-P immunity correlated with maternal BMI, including lacto-N-fucopentaose 2/3 Metabolic Syndrome among Pima Indian Children and Risk of Type (r= 0.46, P=0.001), lacto-N-fucopentaose 1 (r= -0.42, P=0.02), and 3-fucosyl- 2 Diabetes lactose (r= 0.39, P=0.03). At 6 mo. postpartum, 16 metabolites were altered KEVIN M. WHEELOCK, MADHUMITA SINHA, GUDETA D. FUFAA, WILLIAM C. in the ov-ob group (P<0.05), including reductions in several amino acids (glu- KNOWLER, ROBERT G. NELSON, ROBERT L. HANSON, Phoenix, AZ tamine, ornithine, asparagine). GWG had a striking effect on milk composi- We assessed if Metabolic Syndrome (MS) components predicted type 2 tion at 6 mo., with 48 metabolites correlated with GWG (P<0.05), including diabetes mellitus (T2DM) in Pima Indian children aged 10-18 years at base- many positively correlated long-chain fatty acids and lysolipids. line examination. Of 4890 participants (47% male) followed for a median of In conclusion, maternal BMI and weight gain during pregnancy infl uence 11.7 years (IQR 5.3 - 21.7), 1123 (25%) developed T2DM. After multivariable breast milk composition, a potential mediator of mother-child transmission adjustment by Cox regression, Body Mass Index (BMI, percentile) and 2-hour of obesity risk. plasma glucose predicted incident T2DM. Table. Unadjusted and Adjusted Incidence of T2DM. & 1382-P Characteristic Hazard Ratio Hazard Ratio Prevalence of Prediabetes in U.S. Adolescents and Young Adults (95% Confi dence Interval) (95% Confi dence Interval) GIUSEPPINA IMPERATORE, YILING J. CHENG, DEBORAH B. ROLKA, CATHERINE Univariate Models Multivariate Model COWIE, ANN L. ALBRIGHT, EDWARD W. GREGG, Atlanta, GA, Bethesda, MD adjusted for all other variables Pre-diabetes (pre-DM) includes impaired fasting glucose (IFG), impaired Age (per year) 1.07 (1.04 - 1.10) p<0.0001 1.06 (1.03 - 1.10) p<0.0001 glucose tolerance (IGT) or increased A1c (IA1c). All of these categories in- Sex 1.17 (1.04 - 1.32) p=0.0111 1.07 (0.95 - 1.20) p=0.2841 crease the risk of type 2 DM. Recent national estimates on the prevalence Body Mass Index 1.11 (1.10 - 1.13) p<0.0001 1.10 (1.08 - 1.12) p<0.0001 of pre-DM in U.S. youth and young adults are lacking. We estimated the (per 5 percentile) prevalence of pre-DM among U.S. adolescents (aged 12-18 yrs) and young adults (aged 19-34 yrs) by sex, race/ethnicity, and body mass index (BMI) 2-Hour Oral Glucose 1.57 (1.49 - 1.66) p<0.0001 1.44 (1.36 - 1.53) p<0.0001 Tolerance Test status. The study included 4,028 non-pregnant participants aged 12-34 yrs (per 30 mg/dL) without DM from the 2005-2012 National Health and Nutrition Examination survey in whom fasting (FPG) and 2-hour post-load plasma glucose (2-hrPG), Mean Arterial Pressure: 1.20 (1.14 - 1.27) p<0.0001 1.00 (0.94 - 1.07) p=0.9136 MAP (per 10 mm Hg) and A1c were measured. We defi ned IFG as FPG ≥100 – ≤ 125 mg/dL, IGT as 2-hrPG ≥140 – < 200 mg/dL, and IA1c as A1c ≥5.7 – <6.5%. Obesity was Serum Cholesterol (per 30 mg/dL) 1.12 (1.05 - 1.19) p=0.0007 1.03 (0.97 - 1.10) p=0.3607 defi ned as age and sex-specifi c BMI ≥95th percentile (adolescents) or ≥30 Utility of dichotomizing variables for risk stratifi cation was assessed: kg/m2 (adults). We calculated predictive margins using logistic regression presence of obesity (BMI >90th %ile) resulted in increased risk for T2DM, models, adjusting for age, sex, obesity, and race/ethnicity. Pre-DM preva- addition of MS risk clusters (impaired 2-hour OGTT, hypercholesterolemia, lence was 17.8% (95% CI 15.5%-20.4%) among adolescents, and 23.6% and elevated MAP) resulted in even higher risk. Maximizing strategies of (21.4%-26.0%) among young adults. The largest proportion of pre-DM was weight control through physical activity and dietary modifi cation in children due to IFG (prevalence 11.7% and 15.6%, respectively, among adolescents with obesity may lower risk of T2DM. and young adults). In multivariable analysis, pre-DM prevalence was higher among males than females (26.3% vs. 17.0%; Prevalence Ratio [PR]: 1.6 [95% CI 1.4-1.9]), among obese than normal weight individuals (33.9% vs. 16.1%; PR 2.0 [1.7-2.4]), and among non-Hispanic blacks (24.9%) and Hispan- ics (25.2%) than non-Hispanic whites (19.2%) (PR 1.3 [1.1-1.6] for both non- Hispanic blacks and Hispanics). In the U.S., approximately 1 in 5 adolescents and 1 in 4 young adults have pre-DM, corresponding to 5.3 million adoles- cents and 14.6 million young adults. Prevalence is higher in males, minorities, and obese people. Longitudinal studies are needed to better understand the natural history of pre-DM categories in youth and young adults.

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A359 PEDIATRICS—OBESITY AND TYPE 2 DIABETES

tion between POPs tertiles and biomarkers of metabolic function. Compared with the lowest tertile of β-HCH, participants in the third tertile had decreased HOMA- β, after adjustment of age, sex, WHO BMI z-score, Ponderal Index (PI), and mother’s education [β: -0.18; 95% confi dence interval (CI): -0.40, -0.007; P: 0.04 for linear trend]. Similar associations with HOMA- β were obtained for p,p’-DDE and trans-Nonachlor. The third tertile of p,p’-DDE was signifi cantly negatively associated with insulin [β=-0.12; 95% CI: -0.23,-0.01; P=0.034 for linear trend). No signifi cant relationships were found between serum concen- trations of POPs and HOMA-IR. Similar patterns across tertiles were observed for sum of fi ve marker PCB congeners and specifi c PCB congeners; PCB153 and PCB180. This study suggests that POPs exposure among children might affect insulin secretary function, which may possibly lead to an increased risk of developing diabetes. Supported By: Ministry of Food and Drug Safety (13162KFDA891); National Research Foundation of Korea (2011-0029348)

& 1387-P Exercise Capacity and Glucose Tolerance in a Pediatric Cystic Fi- brosis Population without Diabetes KARLA FOSTER, BARBARA CHINI, JOSEPH CRISALLI, NANHUA ZHANG, GARY MCPHAIL, DEBORAH A. ELDER, Cincinnati, OH Objective: To examine the relationship between glucose tolerance and ex- & 1385-P ercise capacity in pediatric Cystic Fibrosis (CF) patients without diabetes. Obesity in Youth: Distinguishing Characteristics between Meta- Research Design and Methods: A retrospective chart review on all CF bolically Healthy vs. Unhealthy Adolescents patients at Cincinnati Children’s Hospital Medical Center who performed a

POSTERS SOJUNG LEE, INGRID LIBMAN DE GORDON, SILVA A. ARSLANIAN, Pittsburgh, cardiopulmonary exercise test (CPET) and two-hour oral glucose tolerance Therapeutics PA test (OGTT) from June 2011 to August 2014. Data were included if CPET and Clinical Diabetes/ Although obesity is often associated with adverse cardiometabolic risk, OGTT were performed within one year of each other. Data were excluded if a subgroup of obese individuals is protected against obesity-related comor- patients had diabetes at testing or failed to meet maximal effort criteria on bidities despite having excess adiposity. In this study, we examined whether the CPET. CPETs were performed on the cycle ergometer using the Godfrey body composition characteristics, particularly ectopic fat deposition, are protocol (10-20 W/min). Maximal effort on CPET was defi ned as meeting different between metabolically healthy obese (MHO) versus metabolically one of the following: maximum heart rate >85% age-predicted maximum, unhealthy obese (MUO) adolescents. Participants consisted of 73 black and respiratory quotient >1.1 or ventilator limitation of <11% or <11 liters. Peak 48 white obese adolescents (BMI >95th, 12-18 years) who underwent a 3-h watts % pred represented maximum workload achieved. hyperinsulinemic (80 mU/m2/min)-euglycemic clamp. Using race-specifi c cut- Results: Data for 81 CPETs and OGTT on 58 patients were included in the points of insulin-stimulated glucose disposal (Rd), participants in the highest analysis. Patients were dichotomized into two groups based on EC: Low EC quartile of Rd were classifi ed as MHO, while participants in the lowest three if VO2peak <80% of predicted and Normal EC if VO2peak >80% of predicted. quartiles of Rd were classifi ed as MUO. Total and abdominal fat were as- There was no difference in mean age, sex or BMI between the Low and sessed by DEXA and MRI, respectively, liver fat by 1H-MRS, and mid-thigh Normal EC groups. There was a difference in lung function (FEV1 % pred) skeletal muscle density by CT. In both races, MHO adolescents had lower between the groups. Patients with Low EC had a higher incidence of indeter- (P<0.05) waist circumference, but in blacks this was associated with lower minate glucose tolerance (1-hour glucose >200 mg/dl; p<0.01). There was a visceral fat (46.8 ± 11.0 cm2 vs. 61.4 ± 26.4 cm2, P<0.05), while in whites with trend for patients with Low EC to have higher incidence of impaired fasting lower subcutaneous fat (380.8 ± 169.1 cm2 vs. 481.6 ± 119.8 cm2, P<0.05). glucose and impaired glucose tolerance. Two-hour glucose values correlated In whites but not blacks, MHO adolescents had three-fold lower (1.5 ± 1.5% with peak watts % pred (r=-0.29, p=0.009). Peak watts % predicted was vs. 4.9 ± 4.9%, P<0.05) liver fat than MUO youth. By contrast, black MHO marginally signifi cant in predicting 2-hour glucose values. adolescents, but not whites had higher skeletal muscle density (52.8 ± 2.0 Conclusion: Pediatric CF patients who present with low exercise capacity HU vs. 51.0 ± 2.6 HU, P<0.05) than MUO adolescents. Independent of race, had a higher prevalence of glucose impairment compared to patients with no differences in cardiorespiratory fi tness were found between MHO and normal exercise capacity. CPET may be used as a tool tool to identify those MUO. Our fi ndings indicate that in obese adolescents, metabolic health is with glucose impairment. driven by racial contrast in ectopic fat deposition. In whites increased liver fat is associated with the unhealthy obese phenotype, while in blacks it is 1388-P increased skeletal muscle fat. In both races, the MHO phenotype is associ- Elevated Monocyte Counts in Obese Children at Rest and in Re- ated with lower levels of abdominal fat. sponse to High-Fat Feeding and Exercise Challenges Supported By: American Diabetes Association (7-08-JF-27 to S.L.); National GOUTHAM GANESAN, ABRAHAM S. CHIU, SCOTT GRAF, MICAELA MARTINEZ, Institutes of Health (1R21DK083654, 1R01HL114857, UL1RR024153) FADIA HADDAD, PIETRO GALASSETTI, Irvine, CA In dysmetabolic states such as obesity and diabetes, elevated monocyte & 1386-P (Mc) numbers and activity are increasingly believed to play an important Association Between the Level of Pops Exposure and Insulin Secre- pro-atherogenic role. Acute and chronic Mc elevations have been reported tion among Children Ages 8 to 9 in obese adults, at rest and in response to pro-infl ammatory stimuli (high- SU HYUN PARK, HYESOOK PARK, YOUNG SUN HONG, Seoul, Republic of Korea fat feeding, intense exercise), but despite the alarming increase in pediatric Persistent Organic Pollutants (POPs), as known as endocrine disruptors, have obesity, little is known about these processes in children. Therefore, in 7 been suggested as a possible risk factor for diabetes. The aim of this study was healthy (HC, BMI <85%), 7 overweight (OW, BMI 85-95%), 11 obese (Ob, BMI to examine the relationship between glucose metabolism and the body con- >95%) children (ages 10-17), during 3 study visits, we assessed Mc profi les centration of POPs among children. Data were collected from the Ewha Birth in fasting, resting conditions; in response to high fat or placebo feeding (1.5g & Growth Cohort Study, an ongoing longitudinal birth cohort study constructed fat/kg or a non-caloric control); and after a standardized 30-min cycling ex- 2001 through 2006. In 2011 and 2012, blood samples of 148 children aged 8 to ercise challenge (2 min at 80% peak O2 uptake + 1 min rest x10). Blood was 9 were collected and separated from peripheral venous blood, and stored at collected at baseline, at the end of, and 1 & 2 hours after each intervention. -70ºC until transport for analyses. A total of 51 POPs were measured by the On average, fasting Mc counts (cells/ul) were signifi cantly elevated in Ob isotope dilution method with gas chromatography high resolution mass spec- vs. HC (590±30 vs. 400±70, p<.05); this difference persisted after high-fat trometry (GC-HRMS). A total of six POPs (PCB 138, 153, β-HCH, p,p’-DDE, and feeding (2-hour post: Ob, 650±60, HC, 470±80, p<.05), and in the post exer- trans-Nonachlor) were included and analyzed for this study. Fasting plasma cise state, where Mc increased signifi cantly in both groups (Ob, 960±60; HC, glucose and insulin concentrations were measured, as well as HOMA-IR and 710±100, p<.05). Our data indicate that Mc counts are elevated in obese chil- HOMA-β were calculated. These were log-transformed due to their skewed dren in multiple physiological situations, possibly contributing to the early distributions. Multivariate linear regression was used to examine the associa- pro-atherogenic milieu associated with this condition.

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A360 PEDIATRICS—OBESITY AND TYPE 2 DIABETES

1390-P Association of rs3856806 Polymorphism of PPARγ Gene as a Risk Factor for Obesity in Mexican Children JOSÉ DE JESÚS PERALTA ROMERO, ALDO ULLOA VALDEZ, ANA I. BURGUETE, JORGE GUTIERREZ CUEVAS, FERNANDO SUAREZ SANCHEZ, JAIME GOMEZ ZAMUDIO, ADÁN VALLADARES SALGADO, MIGUEL CRUZ, Mexico City, Mexico, Cuernavaca, Mexico The prevalence of overweight and obesity are 34.4% in Mexican children. Reports showed association of peroxisome proliferator-activated receptor gamma (PPARγ) gene variants with obesity, insulin resistance, type 2 diabe- tes and metabolic syndrome. However, replication studies in other popula- POSTERS tions not always variants are associated with metabolic diseases. The aim Therapeutics of the study was to investigate the association of rs7793693 and rs3856806 Clinical Diabetes/ polymorphisms of PPAR gene with obesity in Mexican children population. Supported By: National Institutes of Health (P01HD048721-061, K24DK085223- γ We study 200 obese and 200 normal weight unrelated children, 6-12 years 01A1, UL1TR000153); Newkirk Center for Science and Society old, consent and assent letter were signed. Several questionnaires were documented about metabolic diseases, anthropometric measurements and 1389-P biochemical analysis were performed. DNA genotyping was performed by Waist Circumference Percentiles in Indigenous School Children Taqman probes with Open Array software. Data were analyzed by logistic from Northwestern Argentina regression models adjusted for age and sex. Depending on continuous or VALERIA HIRSCHLER, CLAUDIA MOLINARI, GUSTAVO MACCALLINI, MILVA SAN- discrete variables, appropriate statistical tests were used accepting statis- CHEZ, CLAUDIO GONZALEZ, Buenos Aires, Argentina tically signifi cant differences if p value = <0.05 using STATA. Central obesity is associated with increased risk for type 2 diabetes. The Waist circumference was signifi cant when comparing the groups. Systolic objective of this study were 1- to develop waist circumference (WC) percen- and diastolic blood pressure were signifi cant in children obesity children. tiles and to compare with NHANES data 2- to determine if WC could iden- Biochemical parameters showed statistically signifi cance in fasting glucose tify indigenous children with dyslipidemia. A cross-sectional study of 1232 and insulin measured by HOMA-IR in obese children. Lipids were elevated children (606 M), 5-14y, was performed from 2011to 2014 in an indigenous in children with obesity. All polymorphisms studied were in Hardy-Weinberg community. Anthropometric measures, glucose, and lipids were measured. Equilibrium. No association with obesity in rs7793693, whereas rs3856806 Sex-specifi c reference percentiles were computed using the LMS method polymorphism had a signifi cant risk effect in the dominant model (OR of 1.65, and compared with NHANES 2007-2010 WC percentiles. Compared with the CI95% 1.01-2.70, p=0.044). This association was confi rmed by Log-additive 90th NHANES, WC values in indigenous children were lower by 11.05 cm (OR of 1.68, CI 95% 1.06-2.65, p=0.024). for girls and 12.66 cm for boys (Figure). The prevalence of low HDL-C was This study is the fi rst to investigate the association of rs7793693 and 11.8% in children with WC<=50th; 10.3% with 50th90th. The prevalence of high triglyc- polymorphism of PPARγ is associated with risk to obesity and could be used erides was 19.5% in children with WC<=50th; 19.9% with 50th90th. Multiple logistic Supported By: SSA-IMSS-ISSSTE-CONACYT 2013 (SALUD-2013-01-201471) regression analyses showed that high triglycerides (>=150mg/dL) were sig- nifi cantly associated with WC [OR, 1.05 (95% CI 1.03-1.08)], and low HDL-C 1391-P (<=35 mg/dL) was signifi cantly associated with WC [OR, 1.04 (95% CI 1.01- Type 2 Diabetes in Youth: Not an Epidemic—A Comparison of Pa- 1.06)] adjusted for age and gender. There was a signifi cant association be- tients with New Onset Diabetes in 2000 and 2014 tween WC and dyslipidemia. In this community WC values were lower than LINDSEY WALDMAN, MARINA GOLDIS, ELIZABETH BURTMAN, DENNIS CHIA, those in NHANES and seem to be lower than in western countries. MOLLY REGELMANN, ELIZABETH WALLACH, ROBERT RAPAPORT, New York, NY The rise in obesity rates in childhood was expected to result in a similar increase in the incidence of type 2 diabetes (T2DM) in youth. The objective of this study was to compare types of new onset Diabetes (DM) seen in an urban pediatric endocrinology clinic in 2000 and 2014. Retrospective chart review of a similar number of children diagnosed con- secutively with new onset DM from 2000-2001 and June 2012-June 2014 were compared. The diagnosis of diabetes was based on clinical and labora- tory grounds including the presence of DM related autoantibodies (DRAB). Statistics included chi-square analysis. We compared 94 patients diagnosed with new onset DM in 2000 (ADA abstract 2003) with 97 patients diagnosed by June 2014. The mean age of the patients diagnosed in 2000 was 10.7 years. 55% were female and 43% had BMI >85th%. 51% of those tested, had at least 1 positive DRAB. 66 patients (70%), mean age 8.7 years, 51% female were diagnosed with T1DM. 19 patients (20%), mean age 15.1 years, 79% female were diagnosed with T2DM and 9 patients (10%) were diagnosed with un- known type (features of both).

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A361 PEDIATRICS—OBESITY AND TYPE 2 DIABETES

The mean age of the patients consecutively diagnosed by June 2014 in the diabetes category, 80% were classifi ed with type 2 diabetes by the was 11.1 years. 55% were female and 38% had BMI >85th%. 59% of those OGTT. In the type 2 diabetes category, the AUC for HbA1c to diagnosed was tested, had at least 1 positive DRAB. 57 patients (59%), mean age 9.2 years, 0.968. The optimal threshold of HbA1c was 6.1% in identifying type 2 diabe- 49% female were diagnosed with T1DM. 24 patients (25%), mean age 14.3 tes, with a specifi city of 99.1% and sensitivity of 88.9%. For pre-diabetes, years, all female, were diagnosed with T2DM. 9 patients (9%) were diag- the AUC for HBA1c was 0.683. The optimal threshold was 5.5%, with a nosed with medication-induced DM, 6 (6%) with unknown type and 1 (1%) specifi city of 67.4% and sensitivity of 61.9%. with monogenic diabetes. The ADA suggested that an HbA1c of 5.7% and 6.5% may not serve us Comparing 2000 to 2014, no signifi cant differences were found in percent- to make the diagnosis of diabetes or pre-diabetes in adolescents and the ages of those diagnosed with T1DM (p=0.098), T2DM (p=0.45) or patients youths, especially in Chinese population. with BMI >85th% (p=0.44). In patients consecutively diagnosed with diabetes at an urban pediatric 1394-P endocrinology clinic, no signifi cant differences were found between the A Decade Trend of Childhood Obesity in a Developing Country, 2001 proportion of patients diagnosed with T2DM between 2000 and 2014. The to 2011 percentage of patients with diabetes and BMI >85th% also did not differ ANA MAYRA OLIVEIRA, LORENA MASCARENHAS VENEZA, CRISLAINE CAR- between the two time periods. NEIRO MARQUES DA SILVA, ALANNE LOUISE CARDOSO DE OLIVEIRA, ALINE DA SILVA SANTOS, ATILA OLIVEIRA, ANA LUISA OLIVEIRA, MARA SUELY SANTOS 1392-P TEÓFILO CARNEIRO, MARCELE SCHETTINI, ANTONIO CESAR OLIVEIRA, Feira de Effi cacy of “Sacbe,” a Clinical Education Program, to Decrease Santana, Brazil, Salvador, Brazil, Campinas, Brazil Weight and Body Mass Index in Children/Adolescents with Risk Childhood obesity is now epidemic and its prevalence is growing up Factors of Type 2 Diabetes around the world. Our goal is to analyze the decade trend of epidemiological ANA L. RODRIGUEZ-VENTURA, Mexico City, Mexico characteristic of weight in youth. Temporal cross-sectional analysis of the Before the poor success of interventions to decrease overweight/obesity years 2001 and 2011 was done with children aged 5 to 9 years randomly and in children, it is requiered integral interventions. To determine the effi cacy of proportionally selected from public and private schools in the urban area of a clinical education program (Sacbe), we mixed different strategies already Feira de Santana, Bahia, Brazil. Overweight and obesity were defi ned using published (DPP and TODAY studies, sessions of groups, active participation body mass index (BMI) equal or above the 85th and the 95th percentiles for

POSTERS of parents) and considered sociocultural barriers to lose weight. Children age and gender, respectively. Blood pressure was measured following the Therapeutics with overweight or obesity and 2 or more risk factors to develop type 2 criteria of the update on the 1987 Task Force Report on High Blood Pressure Clinical Diabetes/ diabetes, according ADA recommendations. We recorded anthropometric in Children and Adolescents. A total of 1,413 children were studied being 699 measures, demographic, clinical, nutritional and lifestyle habits data of chil- (15.6±2.5 BMI; 366 [52%] girls; 7.1±1.3y) and 714 (16.6±3.0 BMI; 348 [48.9%] dren/adolescents and their parents. Fifty one children and 61 parents par- girls; 7.6±1.4y) in 2001 and 2011 respectively. The excessive weight preva- ticipated, 63% was female sex, media age was 14.3+3 years, 35% presented lence increased signifi cantly from 2001 to 2011 (overweight [9.2%, 15.5%; overweight and 65% obesity, after the fi rst 3 months, overweight increased p= 0.019] and obesity [4.4%, 7.2%; p=0.134] ) and normal weight decreased to 54.5% and obesity decreased to 42.5%, 3% achieved a normal BMI; 73% (86.4%, 77.4%; p=0.002). The children were also classifi ed by type of school lost weight at the fi rst month and 57.9% at the 3rd. month; BMI and weight into groups, 1 (private) and 2 (public). In both groups comparing 2001 and decreased signifi cantly (p=0.001). Eighty two percent of parents was female 2011, the rate of excessive weight increased (normal weight [84.2%, 68.6%], sex, media age was 45.8+9.4 years, 90% had overweight or obesity (38% y overweight [9.9%, 19.9%] and obesity [6.0%, 11.5%] for group 1 and (normal 52%, respectively) and decreased 10% (41 y 39%, respectively), 75% lost weight [88%, 81.7%], overweight [8,7%; 13.3%] and obesity [3.4%, 5.0%] weight in the fi rst month and 80% in the 3rd. month; BMI and weight also for group 2; p< 0.001 for all). There was a trend towards raised prevalence decreased signifi cantly. Their habits improved (lower calories, eating more of obesity, more expressive in those from private schools, probably due to vegetables and less fast food) but some others remained without signifi cant socioeconomic and cultural factors. changes (hours TV watching, few hours for physical activity). This program “Sacbe” has been effective, but it will be necessary to 1395-P achieve one year of follow-up and analyze all variables, including metabolic Severe Obesity Associated with Severe Hyperinsulinism and T2D in parameters that were also determined. The active participation of parents a Family with Mutation in SH2B1 Gene and the inclusion of sociocultural barriers inside the Sacbe program may ROSANGELA ARTUSO, ALDESIA PROVENZANO, BENEDETTA MAZZINGHI, VIVI- explain these promising results. ANA PALAZZO, SILVIA ROMANO, STEFANO STAGI, SABRINA GIGLIO, Florence, Supported By: National Council of Science and Technology of Mexico Italy Genetic sequencing has become a critical part of the diagnosis of certain 1393-P forms of familiar or isolated diabetes. Despite great advances in the speed ADA HbA1c Diagnostic Criteria Fail to Identify Prediabetes and Dia- and cost of DNA sequencing, determining the pathogenic variants remains a betes in a Population of Chinese Adolescents and Young Adults at challenge. MODY is a form of monogenic diabetes caused by mutations oc- High Risk for Diabetes curring in different genes with a slightly different form of diabetes. Genetic SHAN GAO, MING LI, XIAOXUE QU, YONGHUI WANG, XIUJUAN ZHANG, XIU- testing for MODY has become a routine procedure allowing to set up proper JUAN ZHANG, STEVEN M. WILLI, Beijing, China, Philadelphia, PA treatment and discriminate from type 2 diabetes (T2D), whose symptoms of- Introduction: In 2010, the American Diabetes Association (ADA) recom- ten overlap. We analysed, in the last 2 years, about 100 Italian families with mended HbA1c value of 5.7-6.4% was defi ned as pre-diabetes and HbA1c MODY/T2D diagnosis by high-throughput technology. We identifi ed a novel value of 6.5% was selected as the diagnostic cut off for diabetes. Current missense mutation in SH2B1 gene in family with history of severe MODY/ researches for identifying pre-diabetes and diabetes has been largely stud- T2D. The proposita (16 years-old) presented severe obesity and secondary ied in adult populations, we have to think whether the criteria used for adults amenorrhea. The father and the grandfather have a severe obesity and T2D best serve us to make the diagnosis of diabetes or pre-diabetes in adoles- (from 27 and 22 years respectively). BMI was 43.8 Kg/m2. Basal hormonal in- cents and the youths, especially in Chinese population. vestigation showed normal thyroid function, adrenal function, but severe hy- Objective: The aim of this study was to assess HbA1c for the diagnosis of perinsulinism (fasting insulin 69.5 µU/ml). Diffuse hepatic steatosis as well pre-diabetes and diabetes in a population of Chinese adolescents and young as a sonographic pattern suggested a polycystic ovary syndrome. The oral adults at a high risk of diabetes. glucose tolerance test showed an impaired glucose tolerance with marked Research Design and Methods: The study cohort consisted of 559 indi- insulin resistance (respectively, peak insulin level 564 µU/mL; 120’ insulin viduals, recruited from the cohort of Beijing Child and Adolescent Metabolic level 435 µU/mL). As the father, only liraglutide and metformin treatment Syndrome (BCAMS) study, without a diagnosis of diabetes at baseline, with was associated with signifi cant weight loss (after 3 months BMI was 40.1 a follow-up time of 10 years. All subjects underwent an oral glucose tol- Kg/m2). Menstrual cycle normalized after 2 months. erance test (OGTT) and HbA1c measurement. ROC curve analysis was per- SNPs in SH2B1 have been shown to be associated with leptin resistance formed for evaluating HbA1c screening effi cacy. and obesity as well as chromosomal deletions that eliminate the gene, are Results: Subjects were stratifi ed according to HBA1c categories: 85.5% also associated with severe obesity and insulin resistance. This approach with normal glucose tolerance (HBA1c<5.7%), 13.3% at risk for diabetes may help in understanding the molecular aetiology of diabetes and in provid- (HBA1c 5.7-6.4%), and 1.2% with diabetes (HBA1c>6.5%). In the at risk for ing a more personalized treatment for each genetic subtype. diabetes category, 28.9% were classifi ed with prediabetes or diabetes, and

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A362 PEDIATRICS—OBESITY AND TYPE 2 DIABETES

Next-generation sequencing technologies are the perfect applications to 1398-P study of the genetic etiology of complex diseases Generic and Diabetes Disease-specifi c Quality of Life in Newly Di- agnosed and Established Pediatric Patients with Type 2 Diabetes 1396-P Mellitus: Data from the Sitagliptin Pediatric Study Program An SGLT2 Inhibitor Used as Add-on Resolves Glucotoxicity and En- R. RAVI SHANKAR, JAMIE BRIDGES, MARY ANNE RUTKOWSKI, PHILIP ZEITLER, hances the Effi cacy of Conventional Antidiabetic Therapy KIMBERLY G. BRODOVICZ, SAMUEL S. ENGEL, Whitehouse Station, NJ, Denver, YUKIKO TANIGUCHI, TETSUROU OHNISHI, YUTAKA MORI, Higashimurayama, CO Japan, Katsuura, Japan, Komae, Japan The PedsQL™ assesses health-related quality of life (HRQoL) in pediatric Objective: We compared changes in diurnal glycemic fl uctuations with an patients. We administered the Generic Core Scale (GCS) and the Diabetes SGLT2 inhibitor as monotherapy versus add-on to conventional anti-diabetic Disease-Specifi c Scale (DDSS) to 15 patients with newly diagnosed (ND) therapy. and 22 with established type 2 diabetes (T2DM) (ED) and their caregivers Methods: Ipraglifl ozin (IPRA) 50 mg/day was administered to 13 type 2 to understand the impact of T2DM on QoL in youths and their families. Data diabetic patients admitted for glycemic control (monotherapy, n=6; add- are presented as ND vs. ED. Compared to patients with ED, ND patients on to conventional therapy, n=7 oral hypoglycemic agents including DPP-4 were younger (mean 13.7 vs. 14.5 years), had a higher percentage of females inhibitors, n=2; basal-bolus insulin therapy, n=5) and CGM data for diurnal (68% vs. 59%), and had higher BMI (BMI: 33.3 vs. 29.6 kg/m2). Baseline A1C glycemic fl uctuations were compared in these patients at baseline and after was similar (8.2 vs. 8.2%). In the GCS in both groups, the highest scores 2 weeks of treatment. (better QoL) reported by patients were in the domains of physical function Results: 1. Monotherapy outcome: In patients on diet therapy alone, di- (77.5, 75.8) and social function (75.3, 86.3) and the lowest scores (poor QoL) urnal glycemic fl uctuations were primarily characterized by postprandial were for school function (68.1, 69.5). Scores from caregivers were gener- hyperglycemia at baseline, but by the presence of postprandial glycemic ally consistent with the pattern reported by patients. In both patients and increases, despite decreases in nighttime glucose levels, after 2 weeks of caregivers, the total scores for GCS were comparable between ND and ED, treatment with IPRA as monotherapy, which was associated with signifi cant but scores from caregivers were lower compared to patients. In the DDSS, decreases in mean glucose levels (P < 0.05) but no signifi cant changes in the patients reported the highest scores (lower problems) for the domains of glycemic variability parameters. 2. Add-on treatment outcome: In patients treatment adherence (78.2, 78.6) and communication (75, 81.4) and lowest receiving conventional anti-diabetic therapy, diurnal glycemic fl uctuations scores (higher problems) for the diabetes domain (DD) (63, 65). Caregivers also reported lowest scores for the DD (59.7, 59.8), and highest for commu- were primarily characterized by fasting hyperglycemia at baseline, but by POSTERS decreases in pre-meal and nighttime as well as postprandial glucose levels nication (82.9, 75). In addition, low scores were reported by caregivers of ED Therapeutics after 2 weeks of treatment with IPRA as add-on, which an examination of for the worry domain (56.1). In both patients and caregivers, the total scores Clinical Diabetes/ the glycemic variability parameters showed were associated with signifi - for DDSS were comparable between ND and ED, but scores from caregiv- cant decreases in mean glucose levels (P < 0.05) as well as in the glycemic ers were lower compared to patients. This preliminary report suggests that variability parameters (P < 0.05). HRQoL and problems related to T2DM were not different between ND and Conclusions: The reason that IPRA as add-on, but not as monotherapy, ED patients. The pattern for GCS is generally similar to previous reports, but helped narrow the range of glycemic fl uctuations may be accounted for as data from DDSS and comparisons of ND to ED patients are unique. follows: improvements in hyperglycemia with IPRA resolved glucotoxicity Supported By: Merck & Co., Inc. on β cells, improved insulin secretion and sensitivity, thus enhancing the effi cacy of the conventional anti-diabetic therapy used. SGLT2 inhibitor may 1399-P thus be positioned as a “glucotoxicity-resolving agent.” Adherence to Clinic Visits Is Not Improved by Insulin Use in Met- formin-treated Children and Teens with Type 2 Diabetes 1397-P DAVID W. HANSEN, LISA E. REIN, SUSANNE M. CABRERA, Milwaukee, WI Obesity-Risk Behaviors in Korean American Children and Their As- The incidence of type 2 diabetes (T2DM) is increasing in children and sociations with Body Mass Index (BMI) teens. Many have comorbidities at diagnosis and are at high risk of develop- MYOUNGOCK JANG, MARGARET GREY, LOIS SADLER, SANGCHOON JEON, ing future complications. Unfortunately, these children are often socioeco- SOOHYUN NAM, HEE-JUNG SONG, ROBIN WHITTEMORE, Orange, CT, College nomically disadvantaged and have poor rates of clinical follow-up. Guide- Park, MD lines recommend clinic visits every 3 months and insulin initiation for HbA1c Korean American (KA) children have an increased risk of becoming over- >9%, but suggest that initiation of insulin at an earlier time may enhance weight; however, there is limited research about obesity-risk behaviors in the patient’s perception of disease severity and increase compliance. We KA children. Therefore, the purpose of this presentation is to describe the sought to determine if children and teens treated with insulin + metformin diet, physical activity, and sedentary behavior of KA children and to examine would have higher rates of adherence to clinic visits versus those treated the relationships among these behaviors and body mass index (BMI). A cross with metformin alone, as defi ned by visit rate (visits/yr, goal of 4/yr). If so, sectional study was conducted in the Northeast of the United States. Chil- we reasoned that earlier use of insulin may be a useful tool in increasing dren completed well-validated self-report questionnaires and their height adherence. Charts were reviewed of all 219 children ≤ 18 years of age with and weight were measured. Data were analyzed with bivariate and multi- initial diagnosis of T2DM in our diabetes clinic over 10 yrs. Of these, 18% variate analyses using multiple linear regression. A total of 120 KA children were excluded as they never returned after initial visit. In sum, 179 subjects [mean age 11.8±2 years; 50.8% boys; mean BMI 19.4± 3.4 adjusted for age with ≥ 2 visits (mean age 13.53 years, BMI 34.8, 35% male, 56% African and gender; 26.9% overweight or obese] participated in the study. KA chil- American, 26% Hispanic, 13% white, 5% “other”, 68% public insurance) dren consumed fruits/vegetables 4±2.4 times and sweets 1.2±1.0 times per were included in analysis with a mean follow-up period of 854 ± 569 days. day. They engaged in more than a half hour of vigorous physical activity Subjects were listed as receiving metformin or metformin + insulin (basal ± (VPA) 3.1± 2.0 days and outdoor play 2.3± 2.3 days per week. They reported bolus) at each visit. The visit rate and HbA1c per therapy were analyzed by 2.4± 2.1 hours of screen time each day. Sixty-four percent of KA children did Poisson and linear regression, respectively. There was no difference in the not meet established recommendations of 5 fruits/vegetables per day; 44% visit rate of metformin versus metformin + insulin subjects (2.36 vs. 2.41, p = did not meet recommendations for 3 days per week of VPA; and 61% did not 0.99). Within subjects, moving from metformin to metformin + insulin did not meet recommendations for < 2 hours of recreational screen time per day. improve the visit rate. HbA1c was lower in metformin versus metformin + Fruit/vegetable intake was negatively associated with child BMI after con- insulin treated subjects (7.6% vs. 8.6%, p = 0.0001). Our results suggest trolling for age and gender (p=.03). Screen time was positively associated adherence to clinic visits is not improved by the use of insulin in metformin- with child BMI after controlling for age and gender (p<.01). However, neither treated children and teens with T2DM. Clinicians should be cautious of using VPA nor outdoor play was associated with child BMI. There is much room for insulin primarily in hopes of enhancing adherence to clinical follow-up. improvement in the obesity-risk behaviors of school-aged KA children. More research is needed on the individual, family, and environmental factors con- tributing to poor health behaviors, overweight, and obesity in KA children to determine appropriate interventions.

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A363 PEDIATRICS—TYPE 1 DIABETES

PEDIATRICS—TYPE 1 DIABETES & 1402-P Rural vs. Urban Quality of Care (QOC): A Pilot Study Guided Audio Tour: New Directions in Pediatric Type 1 Diabetes (Posters: CONNOR MITROVICH, JOYCE P. YI-FRAZIER, MICHAEL PASCUAL, NEIL PANLASI- 1400-P to 1406-P), see page 17. GUI, NATALIE BEAUREGARD, KATHERINE COCHRANE, CATHERINE PIHOKER, FAISAL S. MALIK, KATHALEEN BRIGGS EARLY, Seattle, WA, Yakima, WA Equitable QOC is challenging particularly for families of youth with type 1 & 1400-P diabetes (T1D) in rural areas. This study compared rural and urban caregiv- Telehealth for Management of Type 1 Diabetes in High Risk Ado- ers’ perceptions of QOC. We recruited 34 rural and 27 urban (defi ned by zip lescents code) caregivers of youth with T1D ages 2-18 seen at a pediatric tertiary ERINN T. RHODES, JONATHAN FINKELSTEIN, GRETCHEN WALDMAN, JESSICA care center. Participants described QOC: patient-provider communication POST, LAUREN MEDNICK, NISSA ASKINS, ERICA DENHOFF, JEAN POTTER, PA- (PPC), diabetes education, and healthcare providers seen. Chart review of TRICE MELVIN, JOSEPH WOLFSDORF, Boston, MA the previous 12 months included insulin regimen, A1C, and diabetes-related Optimal glycemic control of type 1 diabetes (T1DM) is particularly diffi cult hospitalizations. Chi-squared or t-tests were used to compare groups on all to achieve during adolescence. Telehealth interventions allow for more fre- measures. There were no differences on demographics (education, race, in- quent interaction and collaborative diabetes management between patient come) except for insurance type (56% of rural on public insurance vs. 15% and provider, which may improve diabetes self-management and health out- of urban, p=.001). On a scale of 4-16 (higher scores mean better PPC), rural comes. Between June 2013 and May 2014, adolescents aged 13 to 17 years participants rated PPC lower than the urban group (13.0±3.0 vs. 14.4±2.2, with T1DM for at least 1 year and an HbA1c >8% were enrolled in a ran- p=.04). When asked whether 7 areas of diabetes care (i.e., treating hypo/ domized controlled trial of a telehealth intervention. The telehealth arm (TH) hyperglycemia) were addressed, 65% endorsed all 7 (no group differences). included separate, monthly videoconference “visits” with a diabetes nurse Similarly there were no differences in rates of seeing various healthcare educator (DNE) and a social worker (SW) for 6 months focusing on diabetes disciplines (i.e., dietician, social work). self-management and social support (12 “visits” total) along with a diabetes Of the clinical measures, 4% urban versus 33% rural had been hospital- action plan and usual diabetes care. The control arm (CT) received usual ized one or more times for a diabetes-related problem such as DKA (p=.005). care as prescribed by the diabetes team and study participation reminder The urban group averaged more clinic visits than the rural group (4.1±0.8 vs. cards twice per month. The primary outcome was change in HbA1c from 3.6±0.7, p=.01). No differences were found in A1c (9.0±1.8 rural vs. 8.5±1.6

POSTERS baseline to 6 months obtained during a clinic visit. A generalized estimating Therapeutics urban) or insulin regimen (47% of rural on pump vs. 52% of urban).

Clinical Diabetes/ equations model for repeated measures compared outcomes between arms Lastly, we asked rural participants why they traveled so far for care: 33% re- in an intention-to-treat analysis. A total of 32 subjects (16 per arm) partici- ported “no other option,” and 44% cited “it is worth it to receive the best pos- pated in the study. Subjects were 14.3±1.5 years old, 56% female, and 81% sible care.” However, 67% of respondents noted that travel was a hardship, white. Baseline HbA1c were (mean±SD) CT 9.36±1.6 vs. TH 9.01±1.1, p=0.46. particularly in regards to the fi nancial impact of travel and time off work. In the TH arm, 88% completed at least 1 DNE visit and 75% completed at Although these results indicate high perceived QOC in both groups, there least 5 DNE visits; 81% completed at least 1 SW visit and 69% completed were more hospitalizations and perceived burden for those who live in rural at least 5 SW visits. Follow-up HbA1c (at 6 months) was available for 13/16 areas. Strategies to address local support for families living in rural areas CT and 15/16 TH subjects. There was no difference in the change in HbA1c may be benefi cial. between arms (CT 0.082±0.31 vs. TH 0.354±0.32, p=0.55). The study dem- Supported By: Pacifi c Northwest University of Health Sciences (to K.B.E.) onstrated that a telehealth intervention with up to 12 visits over 6 months is a feasible method of increasing interaction between adolescents and their diabetes team. Although there was no effect on HbA1c, additional analyses & 1403-P will examine the intermediate impact of increased interaction on diabetes Glucose Levels Assessed by Continuous Glucose Monitoring (CGM) self-management and inform the design of larger, more defi nitive trials. across the Pediatric Age Range in Youth with Type 1 Diabetes (T1D) LORI M. LAFFEL, TIMOTHY S. BAILEY, ANDREW J. AHMANN, EVA TSALIKIAN, PETER CHASE, Boston, MA, Escondido, CA, Portland, OR, Iowa City, IA, Denver, CO & 1401-P Glycemic control remains suboptimal in the majority of youth with T1D; Screening with Diabetes-Specifi c Questionnaires Can Assist in evaluating glucose levels with CGM may help improve A1c without severe Timely Detection of Psychological Problems in Young Adults with hypoglycemia. To assess glucose extremes and mean glucose levels by time Type 1 Diabetes Transitioning to Adult Care of day, we performed CGM in youth ages 2-17 using the Dexcom G4 Plati- SHEILA M. QUINN, JODIE M. AMBROSINO, KATE WEYMAN, ELIZABETH A. num CGM system with the 505 advanced software algorithm. 77 youth (51% DOYLE, WILLIAM V. TAMBORLANE, ANIA M. JASTREBOFF, New Haven, CT male) from 5 U.S. sites wore 1 CGM either on the abdomen or upper buttocks The coexistence of type 1 diabetes (T1D) with mental health conditions for 7 days, calibrating the device daily with a single, uniform BG meter. We such as disordered eating, depression, and anxiety contributes to poor gly- compared CGM data by age groups [preschool (2-5), school age (6-12) and cemic control and increased morbidity in young adults (YA). In this study, we adolescent (13-17)] according to time of day, encompassing overnight (10P- tested the hypothesis that screening for these problems would aid in their 6A) and meal times [breakfast 6A-11A, lunch 11A-4P, supper 4P-10P]. Mean early identifi cation in young adults transitioning from pediatric to adult care. A1C was 8.2±1.1%, 7.8±1.2% and 8.8±1.6% (p=0.08); and 50%, 69% and 60% Forty-three YA with T1D (47% male, mean age 19.7 +/- 1.4y; mean duration used pump therapy (p=0.55); respectively, in the 3 groups. of T1D 10.5 +/- 4.8y; mean HbA1c 8.5+/- 2.0%; mean BMI 25.5 +/- 4.6 kg/m2) CGM performance was similar across age groups; compared to YSI refer- enrolled in the Yale T1D Transition Clinic completed the Diabetes Eating ence in the 6-12 and 13-17 y/o age groups, MARD was 10%; compared to Problem Survey-Revised (DEPS-R), the Diabetes Distress Scale (DDS), and meter BG reference in all 3 groups, MARD was 12.5%. During the 7-day CGM Patient Health Questionnaire (PHQ-8), a measure of depression. Each sub- session, mean glucose level and proportion >240 mg/dL were highest in the jects’ medical records were reviewed to determine if clinicians noted similar 2-5 y/o; proportion <70 mg/dL was lowest in the 2-5 y/o. All age groups ex- symptoms during the 12 months prior to questionnaire completion. Question- perienced substantial hyperglycemia with ~1/5 to 1/3 CGM values >240 mg/ naire results revealed 23.5% reporting disordered eating, 7.1% diabetes-dis- dL. The new CGM algorithm yielded improved accuracy and opportunities to tress, and 9.5% depression. Medical record review revealed 0% diagnosed target times of hypo- and hyperglycemia to improve A1c in T1D youth. with disordered eating, 11.9% diabetes-distress/anxiety, and 2.3% depres- sion. Concordance with questionnaire responses was highest for detection of diabetes distress, lowest for disordered eating. HbA1c positively correlat- ed with all 3 indices with statistical signifi cance. Even though HbA1c levels were higher in patients with vs. without disordered eating (p<0.001), BMI did not differ between the two groups (p=0.51). In the transition from pedi- atric to adult care, screening with diabetes-specifi c measures may assist in earlier detection of psychological symptoms, especially disordered eating, thus potentially creating opportunity for timely intervention contributing to improved metabolic control.

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A364 PEDIATRICS—TYPE 1 DIABETES

In summary, 55% of participants used IR to assist with diabetes man- & 1404-P agement independent of socioeconomic factors. Nutrition IR was the most Cross-Cultural Comparison of Physical Activity in Young Children commonly used, and use was associated with lower A1c levels. Given the Genetically At-Risk for Type 1 Diabetes prevalence of IR use, providers should be familiar with available resources. KERRY L. MCIVER, RUSSELL R. PATE, MARSHA DOWDA, JIMIN YANG, MARTHA BUTTERWORTH, SUZANNE B. JOHNSON, Columbia, SC, Tampa, FL, Tallahassee, FL & 1406-P Cross-cultural differences in physical activity (PA) among adults are well Health-Related Quality of Life (HRQoL) in Teens with T1D: Parent documented but less is known about these infl uences on PA in young children. vs. Teen-Report There is limited information about PA in children who are genetically at-risk ARIANA CHAO, SUSAN DUMSER, KATHRYN MURPHY, KARL E. MINGES, ROBIN for the development of type 1 diabetes (T1D). The prospective Environmental WHITTEMORE, MARGARET GREY, New Haven, CT, Philadelphia, PA Determinants of Diabetes in the Young (TEDDY) study enrolled children with HrQoL is an important clinical and research outcome. Proxy-reporting T1D high risk genotypes in the U.S., Finland, Germany and Sweden. PA was by parents is common; however parent and teen perceptions may differ. measured with an ActiGraph accelerometer (GT3X+) in 54% of study partici- The purpose of this study is to compare parent and teen reports in HrQoL pants at their 5-year-old visit. Minutes of moderate-to-vigorous physical activ- domains (ambulation, cognition, dexterity, emotion, hearing, pain, speech, ity (MVPA) per day were determined using age-specifi c cutpoints. Cultural and vision) and to identify clinical and demographic variables associated with gender differences in minutes of daily MVPA were examined using ANOVA. discrepancies in these domains. Complete data were available on 1504 participants. Girls were less active than This analysis was based on baseline data from 124 parents and teens boys in all countries (P<0.0001). Cross-cultural comparisons show signifi cant enrolled in an Internet-based RCT. All teens had T1D (11-14 yrs; mean A1C differences in MVPA between children in the U.S. and those in European coun- 8.2+1.4%; mean diabetes duration 5.0+3.47 yrs 63% female; 83% white). tries (P<0.0001). There were no signifi cant differences between activity levels Parents (77.4% mothers) and teens completed the Health Utilities Index and of children within the U.S. or within European countries. The results suggest teens completed additional baseline surveys online. A1C was obtained from cultural infl uences on PA in young children that could impact development of chart review. We used intraclass correlations (ICC) and multivariate general T1D in those genetically at-risk. The TEDDY Study will continue annual assess- linear models with the independent variables of gender, race, age, parent ment of PA in children as part of the efforts to identify environmental factors proxy (mother or father), A1C, diabetes duration, depressive symptoms, and associated with the development of T1D. perceived stress.

There was low between- and within-group variability for ambulation, dex- POSTERS terity, hearing, speech, and vision thus ICCs were not calculated. Parent-teen Therapeutics agreement on HrQoL ranged from .30 to .36 for the other domains. The level Clinical Diabetes/ of discrepancies in each domain ranged from 4.8% to 41.9%. The highest dis- crepancies were in emotion (41.9%), cognition (37.1%), and pain (34.7%) and overall, parents reported better HrQoL than teens. Discrepancies in emotion and cognition were associated with depressive symptoms (p<.05) and dis- crepancies in pain were associated with teen gender (p=.04). There was high agreement between parental and teen reports of ob- servable behaviors; however, there were discrepancies for internal states. Parental underreporting of some internal state domains was more likely in teens with high depressive symptoms and females. Teens self-report of HrQoL should be obtained when possible. Supported By: American Diabetes Association (1-12-SAN-10 to M.G.); National Institute of Nursing Research-National Institutes of Health (F31NR014375); Na- tional Institute of Diabetes and Digestive and Kidney Diseases-National Institutes of Health (T32DK07718)

1407-P Identifi cation of Diabetic Retinopathy Using Telemedicine in an & Underserved Pediatric Diabetes Population 1405-P ANDREINA MILLAN-FERRO, KRISTEN M. HOCK, MORELLA GROSSMANN, LLOYD Use of Internet Resources (IR) for Nutrition Is Associated with More M. AIELLO, JERRY D. CAVALLERANO, LLOYD PAUL AIELLO, PAOLO S. SILVA, Bos- Optimal Hemoglobin A1c in Pediatric Patients with Type 1 Diabetes ton, MA, Caracas, Venezuela, Bolivarian Republic of (T1D) A telemedicine (TM) program for diabetic retinopathy (DR) was deployed PRIYA PRAHALAD, JENISE C. WONG, San Francisco, CA at the Endocrine Unit of the Children’s Hospital in Caracas, Venezuela in 2006 IR, such as websites and mobile applications, are available to assist pa- providing retinal evaluation in an area of limited eye care access. Medical tients with T1D management. IR usage and their association with clinical history, patient education, nonmydriatic (NM) retinal imaging and counsel- outcomes are unknown. A cross-sectional survey of 117 participants at 2 ing on evidence-based follow-up (FU) care were performed. Records from sites was performed to assess IR use for T1D management and the associa- 11/06/2006 - 11/07/2014 were reviewed for demographic data, DR severity, tion between IR use and clinical factors. The study population was divided and medical history including hemoglobin A1C (A1C). into caregivers of children with T1D and patients 13-26 years. Participants TM cared for 535 type 1 diabetes (DM) patients (pts). At initial imaging all were classifi ed as “users” if they self-reported IR use ≥1 time a month for were ≤18 yrs [10.5±3.8 yrs, mean ± SD], 46% male, DM duration 2.6±3.4 yrs, 3 months for T1D management. IR were categorized as educational, nutri- age at DM Dx 7.8±3.8 yrs. A1C was available for 340 (63.5%) 9.8 ±2.5% and tional, activity-based, peer support, and device-related. Logistic regression was ≥7.5% in 276 (81%). TM was the 1st eye exam for 246 (46%) pts with was used to determine the association of demographic and clinical factors 7 (1.3%) having ungradable images. DR existed in 28 (5.2%) pts (25 mild, 2 with “user” status, and linear regression was used to look for the associa- moderate, 1 proliferative DR). tion of use of specifi c categories of IR and A1c. All pts were offered retinal imaging. Based on current ADA initial eye In this study, 99% of participants had internet access, and 65% of care- exam recommendations (IEER) (age ≥10yrs and DM ≥3yrs), 145 (27%) met givers and 45% of patients were “users” of IR. Multivariate analysis did not IEER and 390 (73%) did not. In pts meeting IEER, DR was present in 24 show associations between demographic factors (age, ethnicity, education (16.6%). DR only existed in 4 (1%) without IEER. level, income, and gender) or clinical factors (T1D duration and mode of in- FU occurred for 320 (60%) pts [3.2±2 yrs], and 315 (98.4%) had gradable sulin delivery) and “user” status in the caregiver group. In the patient group, studies at both baseline and FU. Of IEER pts, 85 (60%) had FU and 40 (47%) there was an association between pump use and “user” status when adjust- developed DR compared to pts without IEER, 230 (59%) had FU and 18 (7.8%) ing for age, T1D duration, and gender (OR = 7.3; 95% CI 1.3, 41.8; p = 0.025). developed DR (p<.0001). Pts with IEER were older (14±2.3 yrs vs. 8.8±3.1 yrs, The most commonly used category of IR was nutritional, which was used p<.0001), had DM for longer (median 7.5 yrs, IQR 5.5 vs. median 1.5 yrs, IQR by 60% of all “users.” Nutrition IR users had a lower mean A1c of 1.1% less 1.9, p<.0001), and were pubescent (95% vs. 39%, p<.0001); at FU 4 (1.7%) in caregivers (95% CI -1.9, -0.1, p = 0.024) and 1.4% less in patients (95% CI developed DR prior to IEER. There were no differences in DM onset, gender -2.2, -0.5; p = 0.002) compared to “non-users” after controlling for possible or A1C. confounders.

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A365 PEDIATRICS—TYPE 1 DIABETES

NM retinal imaging may increase DR exam, provide low ungradable rates 1410-P and identify DR progression over time in an underserved pediatric DM popu- Health Care Transitions in Young Adults with Type 1 Diabetes lation. Age, DM duration of ≥3 yrs and puberty were the primary risk factors (T1D): Perspectives of Adult Endocrinologists and Adult Diabetes for DR in this cohort. Educators Supported By: Fundación M.M.G. GABRIELA H. TELÓ, LORI M. LAFFEL, KATHARINE C. GARVEY, Boston, MA The young adult period presents challenges for patients with T1D, and 1408-P lack of effective transfer from pediatric to adult care contributes to adverse A Randomized Crossover Study of the Effi cacy and Safety of outcomes. To understand the perspectives of adult endocrinologists (AEs) Switching from Insulin Glargine to Insulin Degludec in Children and adult diabetes educators (ADEs), we fi elded a web-based survey to as- with Type 1 Diabetes sess clinical resources and barriers to young adult T1D care in 418 AE (AMA TATSUHIKO URAKAMI, YUSUKE MINE, REMI KUWABARA, MASAKO AOKI, MI- Masterfi le, response rate 13%, 46 states) and 476 ADE (AADE Database, SAKO OKUNO, JUNICHI SUZUKI, Tokyo, Japan response rate 14%, 49 states). More ADEs were female (96% vs. 43%) and We evaluated the effi cacy and safety of insulin degludec (IDeg) compared >55 years (40% vs. 32%); more AEs practiced in an academic setting (42% with insulin glargine (IGlar) in children with type 1 diabetes (T1DM). The vs. 16%) [all p<.01]. Over 50% of AEs and ADEs endorsed care barriers in study subjects consisted of 18 Japanese children, 11 males and 7 females, case vignettes involving depression, eating disorders, substance abuse, and age 11.7±2.1 (7.0-14.0) years, with T1DM. All subjects were non-obese with developmental disability. AEs and ADEs reported need for more access to BMI of 20.9±4. All the subjects previously used quick-acting insulin before mental health resources (54% vs. 49%). ADEs were more likely than AEs each meal as bolus insulin, and IGlar once per day at bedtime as basal insu- to report often/always communicating with pediatric providers regarding lin. By use of a randomized crossover design, we compared fasting plasma transfer (35% vs. 12%, p<.0001) and less likely to report pediatric record glucose (FPG) and HbA1c levels, and frequency of hypoglycemia with plasma review (22% vs. 36%, p<.0001). More ADEs vs. AEs felt that communica- glucose level<70 mg/dL at the 12th week after using IGlar and IDeg. IDeg was tion with pediatric providers was important/very important (74% vs. 36%, initially injected at the same dose as IDeg given once per day at bedtime, and p<.0001). While <5% of AEs and ADEs reported participation of their young the dose was titrated to attain self-monitored FPG levels between 90-140 adult patients in transition programs, 62% of ADEs vs. 35% of AEs (p<.0001) mg/dL during the 12-week study period. FPG and HbA1c (NGSP) levels at endorsed the importance of transition programs. In thematic analysis the 12th week after using IGlar and IDeg were 134.9±24.7 and 133.8±17.0 of free-text comments (n = 141 for AEs, 170 for ADEs), AEs and ADEs em- phasized the theme of “competing demands and non-adherence in young POSTERS mg/dL for FPG, 7.8±0.7 and 7.8±0.8% for HbA1c, respectively. There were Therapeutics no signifi cant differences of FPG and HbA1c levels between with IGlar and adults.” Many AEs criticized “divergent approaches to care by pediatric vs. Clinical Diabetes/ IDeg. Frequency of overall hypoglycemia was similar (4.2±3.1 vs. 3.4±2.5 epi- adult providers,” a theme rarely reported by ADEs. These results highlight sodes/mo) in the two basal insulin analogues, but nocturnal hypoglycemia modifi able factors that may aid transfer of care for young adults with T1D, from 22:00 to 6:59 was signifi cantly lower with IDeg than with IGlar (1.8±1.9 including enhanced communication between pediatric and adult providers vs. 0.8±1.0 episodes/mo, P<0.05). No severe hypoglycemia occurred during to overcome perceived divergent approaches to care, development of transi- the study period. The daily basal insulin dose was not signifi cantly different tion programs featuring the diabetes educator role, and increased mental between with IGlar and IDeg (0.48±0.15 vs. 0.44±0.16 kg/day). These results health access for young adults. suggest that IDeg given once at bedtime provides similar glycemic control to Supported By: National Institute of Diabetes and Digestive and Kidney IGlar while lowering a risk of nocturnal hypoglycemia than IGlar in children Diseases; William Randolph Hearst Foundation; National Institutes of Health with T1DM. (P30DK036836)

1409-P 1411-P Diabetes Community Care Ambassador Program: A Preliminary Report Biomedical Predictors of Consistent Continuous Glucose Monitor- FAISAL S. MALIK, JOYCE P. YI-FRAZIER, CRAIG E. TAPLIN, CHRISTIAN L. ROTH, ing in Youth with Type 1 Diabetes ANNE C. DULONG, LISA SCHMIDT, CAROL JENKINS, ANNETTE E. QUAYLE, ME- ELISA GIANI, GABRIELA H. TELÓ, ZIJING GUO, MICHELLE L. KATZ, LISA K. VOLK- LINDA H. MACMILLAN, CATHERINE PIHOKER, Seattle, WA ENING, LORI M. LAFFEL, Boston, MA The Diabetes Community Care Ambassador (DCCA) Program is a pilot Consistent continuous glucose monitoring (CGM) appears necessary to study designed to address barriers in the current diabetes care model and derive glycemic benefi ts in patients with type 1 diabetes (T1D). However, improve the health of children with poorly controlled diabetes by extending sustained CGM use is challenging in children and teens with T1D. To assess the clinical care model into relevant and convenient settings for families, factors associated with consistent CGM use, we assessed demographic including the home, school, and community through the use of non-medical and diabetes characteristics at baseline and after 6 months of CGM use personnel. In this model, DCCAs assess and coach families and school care- in 61 youth with T1D (52% male, 7% non-white). Youth were aged 12.7±2.9 givers on self-management skills through home visits, school visits, and com- years (range 8-17 years) with mean T1D duration 6.3±3.8 years, daily insulin munity support groups. Each DCCA is hired from within the local community dose 0.9±0.3 units/kg, and blood glucose (BG) monitoring frequency 7.0±2.6 and trained extensively in diabetes self-management by certifi ed diabetes times/day; 80% were pump-treated. Mean baseline A1c was 7.9±0.9% and educators and physicians. They work closely with the participant’s primary 33% met the ADA target A1c of <7.5%. At 3 months, mean CGM use was diabetes team and are also supported by a Medical-Legal Partnership attor- 99.6±49.0 hours/week (median 114.4); at 6 months, mean CGM use was ney to help overcome legal barriers identifi ed. Both patient and parent must 82.5±55.6 hours/week (median 93.7). Eight youth had stopped using CGM consent and engage in the intervention for 9 months. by 3 months; by 6 months, 4 more youth (total n=12, 20%) had stopped using Initial aims include assessment of feasibility and impact on glycemic con- CGM. Approximately 1/3 of youth (n=22, 36%) were using CGM consistently trol. Of 342 eligible participants (T1 or T2 patients ages 3-19 in 3 counties, (6-7 days/week) at 6 months. Consistent CGM use at 6 months was associ- A1c ≥ 8.5% and/or ≥ 1 episodes of DKA in last year, duration of diabetes ated with more frequent BG monitoring (p<.05) and lower A1c (6-7 days/ ≥ 1 year, English or Spanish-speaking), 109 enrolled (32%) and are refl ec- week: 7.5±0.6% vs. 0-5 days/week: 7.9±0.9%, p=.02). Youth using CGM 6-7 tive of our patient population (1/3 public insurance, 2/3 white race). The days/week had a 4.2 times greater odds of meeting the ADA target A1c of enrollment rate suggests that the intervention is feasible, though the lower <7.5% than those using CGM 0-5 days/week (59% vs. 26%, p=.01). Provider- than anticipated number may refl ect the intensity of the intervention and reported missed insulin dosing was less likely to occur in youth using CGM exclusion of families with known or identifi ed mental health comorbidities 6-7 days/week than in those using CGM 0-5 days/week (18% vs. 47%, p=.02). through PHQ-9 screening. While 17% of participants were lost to follow up These data confi rm that greater CGM use is effective in optimizing glycemic before their fi rst home visit, retention for families that had an initial home control in pediatric patients with T1D. CGM use overall was related to great- visit is currently 96% (n=87/91), indicating high engagement. Of the 55 par- er management adherence, more frequent BG monitoring, and less missed ticipants enrolled for ≥ 4 months and participating in ≥ 2 home visits (mean insulin. In pediatric patients, consistent CGM use appears to be associated A1c of 9.8±1.7% before the fi rst home visit), A1c fell by 0.43% (p=.014). At with greater BG monitoring frequency rather than decreased BG monitoring the study’s conclusion, the impact on quality of life, cost-effectiveness and frequency, suggesting that attention to CGM data leads to greater treatment medical-legal issues will also be evaluated. adherence with more BG checks and insulin administration. Supported By: Washington State Offi ce of the Attorney General Supported By: National Institutes of Health (R01DK089349, P30DK036836, K12DK094721)

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A366 PEDIATRICS—TYPE 1 DIABETES

1412-P 1414-P Serum Protein Glucosepane and Skin Intrinsic Fluorescence Are Transitioning from Pediatric to Adult Care: Patient and Provider increased in Youth with Type 1 Diabetes Viewpoints RUBY JOSHI BATAJOO, RACHANA DAHIYA, LYNNE MEADEMA-MAYER, JOHN NICOLE JOHNSON, STEPHANIE T. MELTON, ASHLEY WINGERT, Tampa, FL MAYNARD, SAFFAR MANSOOR, MARYANN O’RIORDAN, DAVID R. SELL, VIN- During transition young adults face changing lifestyles, and diabetes CENT M. MONNIER, ROSE A. GUBITOSI-KLUG, Cleveland, OH, Albuquerque, NM clinical experiences, which can affect self-care. To explore patient needs, Advanced glycation end products (AGEs) have been shown to be associ- a study was conducted assessing patients’ and health care providers’ per- ated with microvascular complications of diabetes. This study was done to spectives (HCP). This study 1) assessed experiences and perspectives of evaluate whether AGEs and skin intrinsic fl uorescence (SIF), used as a surro- adults with diabetes concerning their transition from pediatric to adult care gate marker for skin AGEs, are increased in youth with type 1 diabetes (T1D) and 2) identifi ed the transition practices of diabetes HCPs. and to determine timing and factors that contribute to their formation. Surveys were conducted with 188 adults ages 18-40, and with 72 HCP. This was a cross sectional study of 101 youth age 4-22 yrs, including 70 Over half of patients (67%) described their transition experience as “fair” or patients with T1D and 31 age-matched controls without diabetes. Using the “poor.” To improve the transition experience, patients felt inclusion in a so- Scout-DS machine, SIF was measured via fl uorescence excited at 459 nm (SIF- cial diabetes group and access to insurance/diabetes policy resources would 459), using the intrinsic correction coeffi cients Kx 0.4, Km 0.9. Glucose-derived be highly benefi cial. Overall, participants (47%) expressed an unmet need for fructose-lysine (Amadori product) and the AGE glucosepane, were measured lifestyle management help regarding real life situations. For instance, pa- by liquid chromatography/mass spectrometry (LC/MS/MS) using isotope di- tients reported facing a variety of challenges that affected self-care not dis- lution method. These values were correlated with anthropometric measure- cussed with their HCP including: sexual issues (28%), depression or anxiety ments, pubertal status, duration of diabetes and hemoglobin A1c (A1c). (17%), eating disorders (11%) and workplace challenges (11%). This indicates We found that serum glucosepane and fructose-lysine were both signifi - that psycho-social factors may not be adequately addressed in the clinical cantly elevated in T1D as compared to controls (p<0.0001). Mean glucosepane setting as less than half of HCPs (45%) reported screening for mental health was 43.5 + 13.6 pmol/mg protein in T1D as compared to 19.7 + 5.4 pmol/ issues related to diabetes during transition. mg protein in controls. Mean fructose-lysine was 1127.0 + 526.5 pmol/mg Both patients and HCPs expressed concerns regarding poor patient-pro- protein in T1D and 486.2 + 215.0 pmol/mg protein in controls. Glucosepane vider communication and the barriers to independently managing diabetes was signifi cantly correlated with A1c (p =0.0007), but not with duration of self-care (e.g. insurance, ordering supplies). Only 6% of HCPs offered shared diabetes. SIF-459 was signifi cantly elevated in T1D as compared to controls offi ce visits between pediatric and adult care providers during transition, but POSTERS (p < 0.0001) and positively correlated with increasing age (p =0.03, r 0.25) all reported their greatest fear for patients was loss to follow-up. Similarly, Therapeutics and duration of diabetes in T1D (p =0.03, r 0.25). SIF-459 was elevated even patients desired greater access to their HCP and better communication. Clinical Diabetes/ in prepubertal children to similar extent as in pubertal children with T1D. Findings highlight the need for clinical and educational support for ado- We conclude that both glucose-derived serum AGEs and SIF are signifi - lescents as they transition to adulthood. Recommendations are made to cantly elevated in children with diabetes and this is seen even in prepu- enhance patient-provider communication with the goal of improving health bertal children. Early detection of AGEs may serve as novel biomarkers for outcomes and quality of life. early identifi cation and monitoring of youth at risk for developing long-term Supported By: Patterson Foundation complications. 1415-P 1413-P The Relation between Adolescents’ and Parents’ Reports of Self- Is Pancreas Volume a Marker of Type 1 Diabetes Disease Progres- Regulation Skills and Performance-based Measures in Late Ado- sion? A Preliminary Report lescents with Type 1 Diabetes BIMOTA NAMBAM, MICHAEL J. HALLER, DESMOND A. SCHATZ, JONATHAN CYNTHIA A. BERG, YANA SUCHY, DEBORAH WIEBE, SARA TURNER, TARA J. SHUSTER, JONATHAN J. WILLIAMS, RICHARD BEEGLE, MIRIAM CINTRON, QUEEN, JOEL WINNICK, JESSICA ANDERSON, AMY HUGHES, KARA DURRACIO, JESSICA FERGUSON, MARK A. ATKINSON, MARTHA CAMPBELL-THOMPSON, JONATHAN BUTNER, Salt Lake City, UT, Merced, CA, State College, PA Gainesville, FL Parent or adolescent reported diffi culties in self-regulation skills (execu- Pancreatic weight (PW) or volume (PV) is reduced in new-onset as well tive function, attention) have been related to poorer adherence and Hba1c as long standing type 1 diabetes (T1D) patients. Studies from the JDRF Net- in adolescents with type 1 diabetes. However, what is less clear is whether work for Pancreatic Organ donors with Diabetes (nPOD), suggest decreased these self-reports indicate that adolescents’ actual executive function and PW in T1D-associated autoantibody positive (Ab+) non-diabetic individuals attentional capacity relate to chronic illness management. The objective compared to those without Ab. As such, non-invasive measures of PV may of the present study was to examine whether teens’ and mothers’ reports provide important information regarding the natural history of T1D prior of self-regulation skills are predictive of performance-based measures of to diagnosis and serve as a surrogate marker for disease progression. We such skills, while controlling for the infl uence of basic cognitive ability. hypothesized that PV is decreased in Ab+ fi rst degree relatives (FDR) and Two hundred late adolescents (M age=17.74) and their mothers completed recent-onset T1D subjects in comparison to Ab- controls and Ab- FDR. questionnaires assessing executive function (BRIEF), inattention and im- This prospective study included 4 groups between 8-45 years: T1D (n=16 pulsivity (CRS), and reward sensitivity. In addition, adolescents completed to date, goal 60) within one year of diagnosis; Ab+ FDR (n=10, goal 120); performance-based measures of executive function (DKEFS), attention Ab- FDR (n=16, goal 60); and Ab- controls (23, goal 60). Following a minimum (CPT), and reward sensitivity. Results indicated through separate regression 4-hour fast, all subjects underwent abdominal ultrasound (US) and magnetic analyses that both teens’ and mothers’ reports of executive function were resonance imaging (MRI). All images were read by a pediatric radiologist predictive of executive function performance over and above basic cogni- blinded to study group. Relative PV (RPV), defi ned as PV divided by body tive abilities, however, when entered into a single regression only teens’ weight (kg), was analyzed between the 4 groups utilizing ANOVA and t test- reports were uniquely predictive. Similar results were found for inattention. ing, with post-hoc Bonferroni correction. Effects of age, gender, and BMI However, for measures of impulsivity and reward sensitivity neither teens’ were adjusted using the RPV. nor mothers’ reports predicted performance-based measures. In conclusion, RPV by MRI in recent-onset T1D subjects was signifi cantly lower (p<0.05) teen and mother reports of executive function and inattention are refl ective when compared to the other 3 groups. This difference was not observed of performance-based measures, with teen reports providing unique infor- when analyzing RPV obtained by US. No differences in RPV were present mation over and above mother reports. These results hold implications for between Ab+ FDR, Ab- FDR, and Ab- control subjects using MRI or US. There researchers who frequently use parent (and sometimes adolescent) report was no signifi cant correlation between disease duration and RPV in new to evaluate self-regulatory capacities of children and adolescents, with the onset T1D. caution that by late adolescence individuals may be better reporters of such Recent-onset T1D subjects have reduced RPV via MRI when compared abilities than are parents. to non-diabetic subjects. Differences in RPV between controls, Ab+ FDR, Supported By: National Institute of Diabetes and Digestive and Kidney Diseases and Ab- FDR were not detected. As the cohort approaches the planned (R01DK092939) sample size, additional analyses will be required to determine if differences between Ab- and Ab+ subjects exist, and whether RPV can be used as an adjunct marker of T1D risk during the preclinical phase. Supported By: National Institutes of Health-National Institute of Diabetes and Digestive and Kidney Diseases; DARE

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A367 PEDIATRICS—TYPE 1 DIABETES

1416-P 1418-P Effect of Vitamin D Supplementation on Frequency of Partial Clini- Type 1 Diabetes-related Quality of Life in Rwanda cal Remission Period in Children and Adolescents with Newly Di- LAURIEN SIBOMANA, BERNARD RWABUFIGIRI, VEDASTE KABERUKA, CRISPIN agnosed Type 1 Diabetes GISHOMA, WILSON RUBANZANA, RACHEL G. MILLER, TREVOR J. ORCHARD, KATHRYN S. OBRYNBA, ROBERT HOFFMAN, Columbus, OH GRAHAM OGLE, DEBORAH V. EDIDIN, Pittsburgh, PA, Kigali, Rwanda, Sydney, Aus- Growing evidence suggests vitamin D (VD) may play a role in the natural tralia, Chicago, IL progression of type 1 diabetes (T1DM) by altering endogenous insulin secre- A pilot randomized clinical trial to assess two different approaches to tion and infl uencing systemic infl ammation. Newly diagnosed patients with insulin therapy in type 1 diabetic youth aged <26 years was recently com- T1DM may enter a period of partial clinical remission (PCR) or honeymoon pe- pleted in Rwanda. Fifty participants were randomized to basal glargine insu- riod characterized by recovery of beta-cell function with near normal insulin lin (G) and later prandial regular insulin (n=26, mean age 18yrs) versus NPH/ secretion, and attenuation of the autoimmune and infl ammatory response. regular (N/R) insulin twice daily (N=24, mean age 20yrs). To determine if VD supplementation increases frequency of PCR by increas- The primary outcome (glycemic control measured by HbA1c) was previ- ing endogenous insulin secretion and decreasing systemic infl ammation, ously reported as showing no treatment group difference. We now report on 35 patients with new onset T1DM (age 11.6±3.3y, BMI z-score -0.91±2.0, a secondary outcome - Diabetes Related Quality of Life (DRQoL) - which was mean±SD) were randomized to VD cholecalciferol 3000 IU (n=17) vs. P pla- assessed using an extension of the adolescent version of the DCCT DQoL by cebo (n=18) daily for 9m following diagnosis. Frequency of PCR defi ned by interviewing, in Kinyarwanda, the surviving 48 participants 6 months after insulin dose adjusted hemoglobin A1c (IDAA1c) ≤9 was determined in both the fi nal clinical visit. groups at 3, 6 and 9m. Beta-cell function was measured by fasting c-peptide There were no signifi cant differences between the two regimens for any (FCP) at diagnosis and 9m. Systemic infl ammation was assessed by c-reac- individual measures of impact, worry or satisfaction. However, more partici- tive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α). pants in the NPH/regular insulin group reported hypoglycemia as a problem 25-OHD was recorded at diagnosis and 9m. There was no statistical differ- (92% vs. 29% p<.0001), while glargine was rated as “very convenient” by ence in frequency of PCR between groups at 9m (VD 33% vs. P 14%), nor at 3 more participants (83% vs. 46% p=0.007). Glargine users also scored some- and 6m; although frequency of PCR was higher in VD at all time points. There what lower on the impact question as “To how often do you fi nd your diabe- were no differences in FCP, CRP, IL-6, TNF- α at diagnosis or 9m. 25-OHD tes prevents you from participating in school activities?” (p=0.08). values at diagnosis were similar between randomized groups at diagnosis Overall these youth appeared to be coping with their diabetes well with (VD 28.2±2.1ng/dL vs. P 27.3±2.2) (mean±SE) and at 9m (VD 35.0±4.0 vs. P 77% saying diabetes never or very seldom interfered with their family life, POSTERS Therapeutics 33.8±3.6). In all children, 25-OHD increased over time (p=0.016) with those though 37.5% were embarrassed by having to deal with their diabetes in Clinical Diabetes/ having lower 25-OHD at diagnosis having greatest degree of change. Our public. In general, responses were similar to those seen in the U.S., though study indicates VD supplementation does not signifi cantly improve frequen- defi nitive comparisons are complicated by assessing DRQoL in Sub-Saharan cy of PCR period in children and adolescents with newly diagnosed T1DM, Africa (SSA) using questions appropriate for the developed world. The lack without signifi cant changes in beta-cell function or systemic infl ammation; of a non-diabetic group for comparison is another major limitation. To our larger studies may be needed. knowledge this is the fi rst time DQoL has been assessed in East African youth and provides encouragement for the development of a SSA specifi c 1417-P DQoL instrument. Impact of A1c and zBMI on Blood Pressure (BP) Over Time in Pediat- ric Type 1 Diabetes (T1D) 1419-P MICHELLE KATZ, MING DING, GABRIELA H. TELO, CARLY E. DOUGHER, LORI M. Diabetes, Autoimmunity, and Psyche: Comorbidities Are Frequent LAFFEL, Boston, MA in Children High BP increases microvascular and macrovascular complication risk. OLGA KORDONOURI, SUSANA REBELO PACHECO, LAURA GALUSCHKA, MARY- There is a need to better understand BP changes during childhood and ado- AM FATH, TORBEN BIESTER, NICOLIN DATZ, KERSTIN SCHNELL, THOMAS DANNE, lescence in T1D. Hannover, Germany To study the impact of A1c and zBMI on BP changes, we assembled longi- Patients with type 1 diabetes (T1D) are at higher risk not only to develop tudinal data on a dynamic cohort of 640 youth (54% female), ages 8-18 years, other autoimmune diseases (AID), but also psychiatric disorders (PD) com- with ≥6 months of T1D duration. Mean follow-up was 7.1±2.3 years with pared to non-affected peers. Therefore, we investigated the prevalence of 24.3±9.7 observations per patient. We defi ned hypertension (HTN) as 2 con- these co-moridities in 594 children and adolescents with T1D (50.3% male; secutive BPs ≥95th %ile for age, height, and sex. Overall glycemic exposure 68% on CSII) treated in 2013 in our center. Patients were 13.0±4.1 y old, had resulted from the mean of the annual mean A1c values; to approximate adi- T1D for 5.3±4.7 y, required daily 0.79±0.31 units per kg body weight and had posity exposure, a mean zBMI measure resulted from the mean of the annual an A1c of 7.9±1.3% (mean±SD). mean zBMI measures. χ² analyses related HTN status to overall mean A1c 185/594 patients (31.1%; 42.2% male) suffered from at least one further and zBMI values. Longitudinal multivariate mixed effects models described AID (autoimmune thyroiditis: 153, celiac disease: 42, vitiligo: 7, autoimmune the impact of annual A1c and zBMI on systolic and diastolic BP z-scores, hepatitis: 1, rheumatoid arthritis: 2), while in 157 patients (26.4%; 50.3% controlling for baseline variables, age, T1D duration, and sex. male) a psychiatric and/or behavior disorder was diagnosed (ICD-10 F10-F19: At baseline, youth were 10.2±2.1 (X±SD) years old, with T1D duration 8, F30-F39: 35, F40-F49: 62, F50-F59: 80, F60-F69: 6, F70-F79: 13, F80-F89: 3.0±2.5 years, A1c of 8.6±1.6%, and 31% were overweight/obese; systolic (S) 33, F90-F99: 60). and diastolic (D) BP z-scores were -.04±0.86 and 0.29±0.64. At last observa- Patients with AID were more frequently females (p=.008), older (p=.003) tion, youth were 17.3±1.3, with T1D duration 10.1±3.6, A1c of 9.1±1.6%, 40% and had longer T1D (p<.001) than those without another AID. While treat- overweight/obese, and SBP and DBP z-scores of 0.18±0.91 and 0.25±0.64. ment modus (MDI/CSII), A1c, frequency of hypoglycemic episodes per month In the cohort, 16% had HTN at some point. Those with higher overall mean or severe hypoglycemia per year were not different, daily insulin require- A1c had greater likelihood of HTN; 8, 17, and 21% had HTN with A1c <8%, ≥8 ments (p=.033) and prevalence of lipodystrophy at injection sites (p=.026) and <9.5%, and ≥9.5%, respectively (p=.004). Overweight/obese by overall were higher in T1D patients with AID. mean zBMI also increased likelihood of HTN, 25% vs. 11% (p<.0001). In lon- Patients with PD were older (p<.001) and had worse glycemic control gitudinal models, increases in A1c predicted increases in SBP (β=0.02, p=.02) (p<.001) than those without a PD. Although their frequency of monthly hy- and DBP (β=0.02, p=.003) z-scores. Increases in zBMI predicted increases poglycemia was less (p=.002), the prevalence of severe hypoglycemia was in SBP (β=0.32, p<.0001) and DBP (β=0.15, p<.0001) z-scores. Baseline SBP higher (p=.034) in T1D patients with PD.Among young patients with T1D, (β=0.50, p<.0001) and DBP (β=0.30, p<.0001)strongly predicted subsequent every third is affected from another chronic autoimmune disease while ev- SBP and DBP. ery fourth may have additionally a psychiatric/behavioral disorder. Both co- Increases in A1c lead to small increases in SBP and DBP; zBMI and base- morbidities complicate diabetes treatment in different ways and represent line BP strongly infl uence BP changes. a huge challenge not only for patient/family, but also for the multidisciplinary Supported By: National Institutes of Health (K12DK094721, P30DK036836) diabetes team.

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A368 PREGNANCY—BASIC SCIENCE

1420-P Youth with T1D, self-identifi ed as black or white were recruited. At clinic Feasibility of Screening for Type 1 Diabetes and Celiac Disease in a A1c was drawn, MBG derived from averaged glucoses from home glucose Pediatric Clinic Setting monitor. Hemoglobin (Hb), hematocrit (Hct), mean corpuscular volume PATRICIA D. GESUALDO, KIMBERLY A. BAUTISTA, KATHLEEN C. WAUGH, LIPING (MCV), mean corpuscular Hb (MCH), MCH concentration (MCHC) platelets YU, JILL M. NORRIS, MARIAN J. REWERS, JUDITH BAXTER, Aurora, CO, Denver, (Plt), white cells (WBC), red cell distribution width (RDW) coeffi cient of varia- CO tion (RDWCV) and RDW standard deviation (RDWSD) from annual lab were Type 1 diabetes (T1D) or celiac disease (CD) develops in at least 2% of the analyzed. The infl uence of independent variables were tested on A1c in a general population. Early detection of disease-specifi c autoimmunity and multiple variable model. subsequent monitoring would be possible if autoantibody screening tests 84 patients (33 black and 51 white) were included. A1c was correlated were more widely available. Currently screening for T1D-specifi c islet auto- with MBG (r=0.64, p<0.0001), MCH (r=-0.25, p=0.0196), MCHC (r=-0.26, immunity is available only in a research setting with CD-specifi c autoimmu- p=0.019), RDWCV (r=0.5, P<.0001), and RDWSD (r=0.36, p=0.0009) There nity screening limited to those in high risk groups. This study assessed the were differences in variables between the races (Table), except for age, Hb feasibility of incorporating T1D and CD autoantibody screening into general and RDWSD. pediatric practice. Table. Patient engagement strategies, preference of blood collection method, Index Black White p blood volume per method, rate of auto-antibody detection in the general population, and parental satisfaction were assessed. Over fi ve weeks, re- HbA1c(%) 10.8±1.7 8.86±1.18 P<0.0001 search staff recruited 200 patients aged 2-6 from two pediatric practices in MBG (MG/DL) 260±86 197±43 P=0.0003 the Denver area to be screened for the transglutaminase antibody and six Hct (%) 40±3.70 41.6±3.0 P=0.0177 islet autoantibodies. MCV (fl ) 80.8±5.70 84.5±4.60 P=0.0028 Of the 765 parents approached, 200 (26%) completed the same day screen- ing. Of the 565 subjects who did not complete the screening, 345 expressed MCHC (g/dl RBC) 33.5±1.50 34.3±0.90 P=0.0060 interest, but were unable to make a participation decision. A fi nger stick, RDWCV(%) 13.5±1.10 12.6±0.60 P=0.0001 compared to a venous draw, was the preferred method of sample collection. MCH (PG) 27.10±2.43 28.98±1.87 P=0.0003 Both methods yielded suffi cient sample volume (500 ul) for autoantibody 2 determination. Islet autoantibodies or the transglutaminase antibody were The overall model was signifi cant R =0.58. MBG. Race, RDWCV, age all POSTERS detected in 11 subjects. Parents expressed satisfaction with all the results had infl uence on A1c. The A1c LS means for blacks and whites were 10.2% Therapeutics of this study suggest that it is feasible to conduct this type of screening in a and 9.2% respectively (p=0.0028). Other CBC indices were not signifi cant. Clinical Diabetes/ pediatric clinic. Such screening could lead to increased disease awareness A1c remains higher in blacks vs. whites even after infl uence of MBG and and the possible benefi ts that can accrue from early detection. CBC indices are removed. Factors besides MBG and RBC indices contribute Supported By: National Institutes of Health to higher A1c in blacks.

1421-P PREGNANCY—BASIC SCIENCE Motivational Interviewing in Adolescents with Type 1 Diabetes: A Randomized Control Trial SARAH TSAI, MARK A. CLEMENTS, STEPHEN DELURGIO, TIMOTHY APODACA, Guided Audio Tour: Epigenetic, Adipose, and Placental Pathways Under- Kansas City, MO pinning Fetal Programming and Potential Interventions (Posters: 1423-P to Motivational interviewing (MI) is a style of communication that fosters 1429-P), see page 15. collaboration between health care provider and patient. This project is a RCT designed to explore the impact of MI on improving adherence and glycemic control in adolescents with type 1 diabetes (T1D). & 1423-P This study was conducted in a clinical setting at a tertiary pediatric medi- Upregulation of Placental Toll-like Receptor 4 Refl ects Neonatal cal centre. Patients between the ages of 12-17, diagnosed with T1D more Adiposity than 1 year ago, and having an A1C value > 8.5% were eligible to participate. XIAOHUA YANG, MARY HAGHIAC, PATRICIA GLAZEBROOK, JUDI MINIUM, PAT- Participants were randomized to the MI group or the control group (CG). RICK M. CATALANO, SYLVIE HAUGUEL-DE MOUZON, Cleveland, OH The MI group received an interview performed by an MI-trained physician, TLR4-mediated infl ammation is central to the development of obesity and nurse practitioner or diabetes educator. This was followed by a booster ses- insulin resistance. The placental signals which facilitate fetal fat accretion sion at the next clinic visit and 2 post-MI follow-up visits. The CG received are not known. The aim of this study was to investigate the role of placental routine clinical care. TLR4-induced signals as potential mediators of excess fetal adiposity. Eighty patients enrolled in the study. Preliminary data is available on 40 Placenta were collected at term scheduled cesarean delivery in 39 nor- patients. The mean A1C at baseline was 10.2% in the control group and moglycemic women with a range of pre-gravid BMI (17.2 - 51.8) and pro- 10.4% in the MI group. The A1C rose in both groups following the fi rst MI cessed for isolation of trophoblast cells. TLR4 and cytokine expression were session. The A1C increase from baseline to visit 1 for CG is .50% and was assessed by immunofl uorescence, Western blot and RT-PCR. Neonatal body .16% for the MI group, p<.25, There was no difference in reported diabetes composition was assessed within 24h of birth using Pea Pod or anthropo- self-care measures between the groups as assessed by the “Self Care In- metrics. ventory - Revised Version” (SCI). The SCI for the CG increased by .32 points The neonates had a wide range of birth weight (2.6 - 4.4 kg) and pon- and by 2.33 for the MI group, p<.24. Diabetes self-effi cacy, as assessed deral indices (2.3 -3.6 g/cm3). Data were analyzed according to tertiles of by the “Self-Effi cacy for Diabetes Self-Management” questionnaire (SEF), neonatal fat mass (T1: 150-300g, T2: 410-510g, T3: 540-1030g). Neonates improved in the MI group compared to the control group, this result was in T3 had the highest birth weight, largest placentas and increased cord statistically signifi cant (p<0.05). If the differences in Group A1C, SCI, and SEF plasma leptin and insulin concentrations vs. T1 (p<0.001). Placental Il-6, IL-8 found in 40 patients hold for all 80 patients, they will be signifi cant (p<.05). and TLR4 expression was 1.5, 2 and 4 fold higher in T3 vs. T1 (p<0.001). There These results indicate that incorporating MI into a clinical setting for were strong positive correlations between birth weight (r=0.52, p=0.0009), adolescents with T1D improves short term self-effi cacy in diabetes manage- neonatal fat mass (r=0.53, p=0.0008), cord leptin (r=0.62, p<0.0001), cord ment. Whether MI leads to short term or long term improvement in glycemic insulin (r=0.50, p=0.0029) and placental TLR4 expression. The TLR4 activa- control has yet to be proven. tors palmitate and lipopolysaccharide (LPS) stimulated the expression of IL- 6, Il-8, and TLR4 in cultured trophoblast cells and this was associated with differential phosphorylation of NFkb in T1 vs. T3 (p<0.001). 1422-P In summary or we conclude that placental TLR4 expression correlates Differences in RBC Indices Do Not Explain Racial Disparity in HbA1c with anthropometrics and metabolic markers of fetal adiposity. These data in Children with Type 1 Diabetes (T1D) further suggest that placenta TLR4 signaling is enhanced in neonates with MAHMOUD A. HAMDAN, JAMES HEMPE, JODI KAMPS, STUART CHALEW, New excess adiposity. These observations suggest modulation of placental in- Orleans, LA nate immune pathways as functional links to excess fetal fat accretion. Blacks with T1D have higher A1c than Whites, even after adjusting for Supported By: National Institutes of Health (HD22965-19) mean blood glucose (MBG). We hypothesized that differences in RBC indices between blacks and whites account for non-MBG racial disparity in A1c.

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& 1424-P & 1426-P Epigenome-Wide DNA Methylation Changes in 9- to 14-Year-Old A Role for HKDC1 in Glycemic Control during Pregnancy Offspring of GDM Women and Controls from the Danish National ANTON E. LUDVIK, ANTHONY ANGUEIRA, BRIAN T. LAYDEN, Chicago, IL Birth Cohort Pregnancy is accompanied by a diverse range of metabolic adaptations LINE HJORT, LOUISE G. GRUNNET, ANDERS H. OLSSON, DAVID MARTINO, that maintain maternal and fetal glucose homeostasis. Women who are FRANK B. HU, CUILIN ZHANG, RICHARD SAFFERY, SJURDUR F. OLSEN, ALLAN A. unable to maintain normal glucose homeostasis during pregnancy develop VAAG, Copenhagen, Denmark, Parkville, Australia, Boston, MA, Rockville, MD gestational diabetes mellitus (GDM), resulting in detrimental health conse- Offspring of women with Gestational Diabetes Mellitus (GDM) are at high quences for both mother and fetus. In a previous report (Hayes et al., 2013), risk of developing type 2 diabetes later in life. Whether epigenetic mecha- the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study cohort nisms underlie this association remain unknown. Using an epigenome wide identifi ed a novel and highly signifi cant (p < 10-20) association between the approach in a subcohort of the Danish National Birth Cohort (DNBC), we previously uncharacterized hexokinase, HKDC1, and 2-hr glucose levels fol- aimed to explore whether DNA methylation in blood differ between 9-14 lowing an oral glucose tolerance test (OGTT) at ~28 weeks of pregnancy. year old offspring of GDM women versus matched controls. Since this report, we have observed that HKDC1 is expressed widely in- We recruited 623 GDM and 617 control offspring. DNA from 95 GDM off- cluding in kidney, colon, small intestine, and pancreatic beta cells, and that spring and 95 controls were analyzed for genome wide DNA methylation HKDC1 is a previously unknown functional hexokinase (Guo et al., 2014). profi les using Infi nium HM450 arrays. Here, we expanded on these data using purifi ed human HKDC1 and demon- BMI, weight, waist and hip-circumference, plasma insulin and c-peptide strate HKDC1 is a low affi nity hexokinase that has preference for glucose levels were higher among GDM offspring compared to controls (p≤0.04). and ATP as substrates. To explore its in vivo role, we established a mouse 1,828 sites were differentially methylated between the groups (p≤0.01) be- model that results in a truncated nonfunctional HKDC1 allele. It has been fore correction for multiple testing. Multiple sites were represented within observed that homozygous (HKDC1tg/tg) mice are embryonic lethal. Analysis same gene and several located in genes previously published with changes of heterozygous mice (HKDC1tg/wt) shows no differences in weight gain, fast- of DNA methylation in GDM cord blood/placenta samples including PYGO1, ing blood glucose, and insulin levels from 4 to 28 weeks of age. At 28 weeks CLN8, MSX1 and EPS8L1. Others including MEST, GNAS, LPL, IGF and H19 were of age, however, male and female HKDC1tg/wt mice exhibit impaired glucose not changed in this cohort. None of the previously unidentifi ed differential tolerance as compared to wild-type (WT) controls in both intraperitoneal DNA methylation marks among GDM offspring compared to controls re- and oral glucose tolerance tests. Investigating the role of HKDC1 during POSTERS Therapeutics mained statistical signifi cant after FDR correction. pregnancy, pregnant HKDC1tg/wt mice demonstrate impaired glucose toler-

Clinical Diabetes/ Offspring of GDM women exhibit pre-diabetes traits at preadolescent age. ance following an oral glucose challenge at gestational day 15 as compared Several DNA methylation changes previously identifi ed in GDM cord blood to WT female mice. Taken together, these data show that HKDC1 functions or placenta samples were detectable in the current GDM offspring subgroup in vitro as a low affi nity hexokinase, and suggest a role in vivo with glycemic at age 9-14 years, while others could not be validated. A substantial propor- control in both the normal and gravid state. tion of methylation differences observed in earlier GDM cord blood/placenta Supported By: American Diabetes Association (7-13-IN-20-BR to B.T.L.); U.S. studies are likely to resolve during childhood and thus, those marks may not Department of Veterans Affairs be causally related to the increased T2D risk later in life. Validation studies of the identifi ed 1,828 sites as well as of previously identifi ed GDM offspring & 1427-P methylation marks are in progress in the entire DNBC subcohort of 1,240 PQQ, a Novel Antioxidant Given during Obese Pregnancy, May Im- children. prove Metabolic Health in Male Mice KAREN R. JONSCHER, MATTHEW JACKMAN, ELLEN WIITALA, GARRETT FLO- & 1425-P REY, JACOB E. (JED) FRIEDMAN, Aurora, CO, Denver, CO Gestational Diabetes and Adipose Tissue Expansion The fetal programming Developmental Origins of Health and Disease (Do- RAZIEL ROJAS-RODRIGUEZ, OLGA GALEKMAN, SO YUN MIN, LAWRENCE LIF- HAD) hypothesis suggests an important developmental pathway to obesity SHITZ, KATHERINE LEUNG, SILVIA CORVERA, TIFFANNY A. MOORE-SIMAS, and its co-morbidities fl ows from mother to infants, refl ecting detrimental Worcester, MA effects of hypernutrition during early life. There is growing awareness that Gestational diabetes (GDM), a common pregnancy complication, increas- dietary intervention may be the primary line of defense against the rising es type 2 diabetes (T2DM) risk development. This effect has been attrib- tide of maternal overweight/obesity, now approaching 60% of adult women uted to placental hormone production inducing insulin resistance. However, of reproductive age. why some women develop GDM while others do not is unclear. The role of Here we investigated the effects of pyrroloquinoline quinone (PQQ), a adipose tissue (AT) in T2DM has been studied, revealing that impaired AT food-derived antioxidant and nutritional supplement, on short and long-term expansion can lead to ectopic lipid deposition, infl ammation, insulin resis- metabolic parameters in the offspring of lean and obese mothers fed PQQ. tance and T2DM. However, little is known of AT function during pregnancy. Mice were fed control (CTL) or Western diet (WD) (42% fat) with or without As a weight gain state, pregnancy provides a clinical setting for studying AT ~7.5 ug/day PQQ in water prior to mating and throughout weaning. Offspring growth and its relationship with GDM. were continued on the maternal program post-natally up to 4 (weanlings) or To asses AT characteristics and its potential relationship with GDM, bi- 20 (adults) wks or switched from CTL to WD after weaning. Body composi- opsies from visceral (VAT) and subcutaneous AT (SQAT) were obtained from tion of offspring was obtained by qMRI and mice were placed in metabolic patients undergoing cesarean delivery. Subjects with normal glycemia (con- chambers for 5 days to measure energy expenditure (EE), respiratory quo- trols), GDM and T2DM were compared. Adipocyte size was quantifi ed from tient (RQ) and metabolic rate (MR). H&E stained sections. VAT adipocytes from GDM were larger than controls WD resulted in signifi cantly altered metabolic parameters that were more (p<0.05), suggesting hypertrophy rather than hyperplasia during GDM preg- pronounced in males and further enhanced in adults, including increased nancies. Since the growth of AT requires expansion of its vasculature, AT body weight, fat mass, total EE and MR and reduced lean mass, RQ, and specimens were stained with lectin to visualize capillary density. A signifi - activity. Although signifi cant increases were observed in weanling males, cant reduction in capillary density was seen in GDM compared to controls, in WD plus PQQ treatment did not change weight gain or body composition in both SQAT (p=0.01) and VAT (p=0.009). To analyze if due to impaired angio- adult males despite increased EE, RQ and activity. However, maternal CTL genic capacity, AT biopsies embedded in matrigel and cultured under proan- diet partially protected adult WD males and females from weight gain and giogenic conditions were measured for capillary sprouting. VAT angiogenic increased fat mass, raised RQ and reduced MR in males. Post-natal PQQ potential was lower than SQAT, and a trend to decrease sprouting was seen enhanced the effect. in GDM when compared to controls. Taken together these results suggest Taken together, our data suggest maternal consumption of PQQ during impaired AT expandability underlying GDM development. pregnancy and weaning may improve metabolic health, particularly for Previous studies have indicated the important role of IGF1-IGFBP axis in males. We conclude that PQQ may be a new therapeutic for blunting meta- mouse AT angiogenesis. Here we fi nd that AT from GDM expressed signifi - bolic programming effects of maternal obesity in the offspring. cantly lower levels of insulin-like growth factor binding protein-5 (IGFBP5) Supported By: National Institutes of Health-National Institute of Diabetes and when compared to controls (p<0.05), further supporting an important role Digestive and Kidney Diseases (DK098615) for adipose tissue expandability in the etiology of GDM.

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Supported By: Department of Biotechnology, Government of India (BT/PR5915/ & 1428-P MED/31/172/2012, BT/PR7990/MED/32/282/2013); Department of Science and Antidiabetic Effects of Dwarf Lilyturf Tuber (Maidong) in Mice with Technology, Government of India; Science and Engineering Research Council, Gestational Diabetes Mellitus Government of India (SB/FT/LS-196/201) YAN TONG, CLARA BIK SAN LAU, RONALD CHI CHIU WANG, WING HUNG TAM, Hong Kong, China Dwarf Lilyturf Tuber (Maidong) is one of the most commonly used herbs PREGNANCY—CLINICAL for the treatment of diabetes mellitus and gestational diabetes in Chinese Medicine but its therapeutic effects in the glycaemic control is not fully understood. The study objective is to investigate any therapeutic effect of Guided Audio Tour: Novel and Ethnically Targeted Approaches to Identify Maidong water extract on maternal glucose intolerance in a pregnant mouse Mother and Infant Pairs at Risk for Adverse Outcomes (Posters: 1430-P to model. Maidong extract was prepared through water extraction and stored 1437-P), see page 15. in powder form. Pregnant C57BLKS/J-Leprdb/+ mice, which exhibit glucose in- tolerance at mid-gestation, were randomly allocated into 4 groups receiving & 1430-P 0 (0×), 0.75 (0.5×), 1.49 (1×) and 2.98 (2×) g/kg of Maidong extract (number in Pregnancy and Neonatal Diabetes Outcomes in Remote Australia: bracket represent the equivalent times of clinical dose). Wild-type C57BLKS/ +/+ +/+ The PANDORA Study J-Lepr (Lepr ) mice received only water served as non-diabetic control. LOUISE J. MAPLE-BROWN, ALEX BROWN, I-LYNN LEE, FEDERICA BARZI, CHRIS- Intraperitoneal glucose tolerance tests (IPGTT) were performed in all mice at TINE CONNORS, CHERIE WHITBREAD, MARIE KIRKWOOD, DANIELLE LONG- day 15.5 of gestation after overnight fasting. Blood sample was taken from MORE, KERIN O’DEA, JEREMY OATS, HAROLD D. MCINTYRE, PAUL ZIMMET, the tail veins at 0, 15, 30, 60, 90 and 120 min after intraperitoneal injection JONATHAN SHAW, ON BEHALF OF PANDORA STUDY RESEARCH TEAM, Darwin, of glucose. Glucose tolerance was analysed by repeated measures ANOVA. db/+ Australia, Adelaide, Australia, Brisbane, Australia, Melbourne, Australia Glucose levels at IPGTT were signifi cantly lower among Lepr mice treated The Northern Territory (NT) of Australia is a large geographical area, with all 3 doses of Maidong extract than those received no treatment (de- where 38% of babies are born to Indigenous mothers, among whom rates tails refer to Fig. 1). In conclusion, Maidong extract improves glucose toler- db/+ of type 2 diabetes in pregnancy are up to 10 times higher than in non-In- ance in pregnant Lepr mice and the effect appears to be dose related. digenous mothers. The PANDORA study is a longitudinal birth cohort study

recruited from a diabetes in pregnancy (DIP) register. Here we compare peri- POSTERS natal outcomes by ethnicity and diabetes type. Therapeutics Eligible participants are NT women with DIP aged ≥16 years. Information Clinical Diabetes/ collected includes antenatal and birth clinical information, cord blood, neo- natal anthropometry. Results of 486 women (39% Indigenous Australian, 30% Europid, 14% Indian subcontinent) and their babies born to July 2014 are reported. Data were analysed using t-tests, chi-squared tests; multivari- ate linear and logistic regression. Differences between Indigenous (n=191) and Europid (n=144) mothers were evident for: diabetes type (T2DM, 29% vs. 3%; GDM, 71% vs. 97%), smoking (45% vs. 19%), but not for body mass index (BMI, 30.4 vs. 29.3kg/m2, p=0.18). Birth outcomes were poorer for Indigenous than Europid women: caesarean section (54% vs. 38%, p=0.004), serious adverse event (21% vs. 8%, p=0.001; 2 stillbirths in Indigenous women with T2DM), 1 maternal death (end-stage kidney disease, 14 weeks gestation), large for gestational age (LGA, 23% vs. 14%, p=0.035). After adjustment for diabetes type, age, BMI and parity, the risk for Indigenous women remained higher for caesarean section only (OR 1.73, 1.01-2.95). T2DM remained a signifi cant independent predictor of all outcomes. Among women with GDM, there were no signifi cant differences between 135 Indigenous and 139 Europid women for: pre-eclampsia (2.2% vs. 2.2%, p=0.99), caesarean section (45% vs. 39%, p=0.29), serious adverse event (10% vs. 6%, p=0.25), LGA (19% vs. 12%, p=0.11). Supported By: O&G Trust Fund of Hong Kong (2012) The PANDORA study is ongoing, with initial data reporting higher rates of caesarean section and LGA for Indigenous women. Caesarean section rate & 1429-P remained signifi cantly higher after adjustment for diabetes type, age and Dysfunctional Placental Fetal Gestational Diabetic Vascular Pro- BMI. genitors Resemble Type 2 Diabetic Retinopathy Supported By: Australia National Health and Medical Research Council REKHA SAMUEL, CHITRA PREMKUMAR, SARANYA RAJENDRAN, KAVITHA (1032116) RAMANATHAN, SANTHOSH JOSEPH BENJAMIN, JIJI ELIZABETH MATHEWS, MANDALAM SUBRAMANIAN SESHADRI, Vellore, India, Ranipet, India & 1431-P In 2030, 100 million Indians will have diabetes. We report an interesting History of Gestational Diabetes Mellitus (GDM) and Long-Term Risk observation in a cohort of 10 cases each of healthy and Gestational Diabe- of Cardiovascular Disease (CVD) in a Large Prospective Cohort of tes Mellitus (GDM) placentas. Histology showed chorangiosis and increased U.S. Women capillary diameter of blood vessels in the GDM vasculature (p ≤ 0.001). Elec- DEIRDRE K. TOBIAS, JENNIFER STUART, WEI BAO, ERIC RIMM, JANET RICH- tron Microscopy showed that endothelial cells and pericytes shared base- EDWARDS, JOANN E. MANSON, FRANK B. HU, CUILIN ZHANG, Boston, MA, ment membranes in healthy placental vasculature. GDM vasculature dem- Rockville, MD onstrated pericyte ghost cells resembling adult type 2 diabetic retinopathy Recent fi ndings suggest GDM is associated with intermediate markers (p ≤ 0.001). GDM endothelial progenitor cells failed to form tubes on matrigel of CVD, including hypertension, atherosclerosis, infl ammation, and endothe- in vitro (Figure). Co-implantation of GDM endothelial progenitor cells/human lial dysfunction. Few studies, however, have prospectively evaluated the umbilical vein endothelial cells with GDM pericytes show functional abnor- scid relationship between GDM and clinical CVD events, and whether this rela- malities in vivo in CB17/Icr-Prkdc /IcrIcoCrl mice (p ≤ 0.001). Up regulation tionship is independent of intermediate T2D. Thus, we evaluated GDM and of angiogenic marker profi les reveal abnormalities of blood vessels of GDM subsequent CVD risk in a large U.S. cohort (1989-2013). Our analysis included vascular progenitor cells (p ≤ 0.001). 87,229 women in the Nurses’ Health Study II reporting a pregnancy and free of The resemblance of vascular changes in a 9-month organ, the GDM pla- CVD at baseline. Lifestyle and health outcomes were updated every 2 years. centa, and adult type 2 retinopathy point to the diabetic intrauterine environ- Multivariable Cox proportional hazards models estimated relative risks (HR) ment infl uencing the development of type 2 diabetes in adulthood. Dissect- and 95% confi dence intervals (CI). Validated self-report of GDM occurred in ing the pathophysiology and molecular signatures of vascular dysfunction 3608 women. There were 939 incident confi rmed CVD events (myocardial in GDM might lead to therapeutic targets to prevent or predict the develop- infarction [MI] or stroke). Compared to women without GDM, a history of ment of type 2 adult diabetic retinopathy. GDM was associated with a signifi cant 39% greater CVD risk (CI=1.04, 1.86),

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adjusting for age, BMI, lifestyle, and other CVD risk factors. CVD risk was At baseline, groups were comparable regarding all the clinical variables highest among women with GDM and subsequent T2D (HR=4.13, CI=1.92, tested. During the follow-up period (36 days (1-141)), no correction of the 8.89), and attenuated among women reporting GDM without T2D (HR=1.29, automated-proposed treatment was done by doctors. Mean number of BG CI=0.93, 1.79), compared with no diabetes. Associations were stable regard- downloads by patient was 10.2±8 (1-29) and the mean number of changes in less of time since pregnancy and were similar for MI and stroke. Subgroup diet automatically proposed was 0.46. Mean number of BG values/day, mean analyses indicated a stronger CVD risk among currently obese participants BG and the % of BG values above 140 mg/dl, pre-partum HbA1c, and all the (BMI≥30) (HR=1.81, CI=1.18, 2.76) than non-obese patients (RR=1.05; 95% perinatal outcomes tested were similar between the groups. Mean number CI=0.67, 1.65). Additionally, among women with a family history of MI, of face-to-face visits performed including fi rst visit and training was 4.8±2.8 GDM was associated with a 78% greater MI risk (CI=1.01, 3.12), and among for the control group and 1.4±0.6 for the active group (p<0.001). those with a family history of stroke, with a nearly 4-fold greater stroke risk In conclusion, this computer-based smart telemedicine system success- (HR=3.98, CI=1.21, 13.13). Overall, GDM was associated with CVD later in fully replaced face-to-face follow-up visits in women diagnosed of GD while life, particularly among women with intermediate T2D or a family history of insulin therapy was not required. CVD. Studies are needed to confi rm these fi ndings and to identify lifestyle Supported By: F. Hoffmann-La Roche Ltd. factors to mitigate CVD risk among these high risk women. Supported By: 1K01DK103720-01 & 1434-P Excess Gestational Weight Gain Associated with Greater Accrual & 1432-P of Fat, but Not Lean, Mass Targeted and Nontargeted Metabolomics Profi ling Identifi es Meta- ERICA K. BERGGREN, SHARON L. GROH-WARGO, LARRAINE PRESLEY, SYLVIE bolic Signatures Unique to Maternal BMI and Glycemia HAUGUEL-DE MOUZON, PATRICK M. CATALANO, Cleveland, OH DENISE SCHOLTENS, JAMES BAIN, MICHAEL MUEHLBAUER, ROBERT STEVENS, Gestational weight gain (GWG) alters maternal body composition, but the OLGA ILKAYEVA, LYNN P. LOWE, CHRISTOPHER NEWGARD, BOYD E. METZGER, impact of excess GWG specifi c to fat and lean body mass accrual is unclear. WILLIAM L. LOWE, Chicago, IL, Durham, NC We conducted a secondary analysis of 49 overweight/obese women to mea- Maternal hyperglycemia and obesity during pregnancy contribute to new- sure maternal body composition changes with GWG. In early (13-16 weeks) born adiposity as demonstrated by the Hyperglycemia and Adverse Preg- and late (34-36 weeks) pregnancy, maternal height and weight, and body nancy Outcome (HAPO) Study and other studies. Mechanisms underlying composition (using BOD POD) were assessed. We measured correlations be-

POSTERS these associations are unclear, but these maternal phenotypes likely affect tween GWG and change in maternal lean body mass (ΔLBM) and fat mass Therapeutics the intrauterine metabolic milieu, with metabolic signatures that affect fetal (ΔFM), and compared ΔLBM and ΔFM by adherence to 2009 IOM GWG guide- Clinical Diabetes/ growth. To characterize the intrauterine environment and investigate asso- lines. We then used linear regression to explore associations between ΔFM ciations with newborn anthropometrics, we sampled 400 mothers and new- and: maternal lipids, insulin sensitivity (ISogtt), scored activity and nutri- borns of Northern European ancestry from the HAPO Study to span the range tion questionnaires. Mean BMI was 32.4+6.1 kg/m2; women gained 9.3+5.8 of maternal BMI and glucose as well as newborn birth weight (BW) and sum kg. Overweight, vs. obese, women were equally likely to have excess GWG of skinfold (SSF) measurements observed in HAPO. We applied biochemical (48% vs. 35%, p=0.6). ΔLBM was correlated with GWG (r2=0.52, p=0.001). analyses of conventional clinical metabolites, targeted metabolomics as- ΔLBM was similar whether excess or adequate GWG. ΔFM was correlated says of amino acids and acylcarnitines, and non-targeted gas-chromatogra- with GWG (r2=0.87, p<0.001). Women with excess, vs. adequate, GWG had phy/mass-spectrometry assays to analyze fasting and 1-hr serum in mothers greater ΔFM (8.4+1.7 vs. 6.0+3.4 kg, p<0.001). ΔFM was not associated with from an oral glucose tolerance test at 28 weeks’ gestation and stored cord change in fasting lipid profi le, ISogtt, physical activity, or dietary quantity or blood samples from the newborns. After Benjamini-Hochberg adjustment, composition. Excess GWG is associated primarily with maternal FM but not 35 metabolites demonstrated a signifi cant positive or negative association LBM accrual. Future research must evaluate maternal factors, other than with maternal BMI in the fasting and/or 1 hr samples. In contrast, only 8 those assessed here, to explain our fi ndings and explore implications. metabolites were positively or negatively associated with maternal fasting and/or 1 hr glucose. Palmitoleate, a common mono-unsaturated fatty acid, was the only metabolite associated with both phenotypes. Maternal BMI was associated with ketones, triglycerides, and carnitine esters of ketones and medium- and long-chain fatty acids, while maternal glucose was as- sociated with the gluconeogenic precursors lactate and alanine and laurate, a medium-chain fatty acid. Of the maternal metabolites, only the carnitine ester of ketones was associated with newborn SSF and BW. In summary, maternal BMI and glucose are associated with unique metabolic signatures with one metabolite also associated with newborn adiposity. Supported By: National Institutes of Health (5R01DK095963)

& 1433-P Successful Replacement of Weekly Face-to-Face Visits by Unsu- pervised Smart Home Telecare in Diet-Treated Gestational Diabetes Supported By: National Institute of Child Health and Human Development (GD) (NCT00957476) MERCEDES RIGLA, GEMA GARCÍA-SÁEZ, MARIA VILLAPLANA, ESTEFANÍA CABALLERO-RUIZ, BELÉN PONS, ANNA MÉNDEZ, MONTSERRAT AGUILAR, EN- & 1435-P RIQUE J. GÓMEZ, MARIA ELENA HERNANDO, Sabadell, Spain, Madrid, Spain New Screening Criteria for Glucokinase Monogenic Diabetes in We have developed a computer-based smart telemedicine system to give Pregnancy: Performance in a Multiethnic Cohort automated support to GD patients while insulin is not required. The system VICTORIA L. RUDLAND, GLYNIS P. ROSS, MARCUS HINCHCLIFFE, JASON PIN- combines a platform for remote monitoring of diabetes-related parameters NER, STUART COLE, BELINDA MERCORELLA, LYNDA MOLYNEAUX, MARIA I. with a decision-support system based on expert knowledge that generates CONSTANTINO, DENNIS K. YUE, JENCIA WONG, Sydney, Australia automatic feedback to patients. Blood glucose (BG) data downloaded to Despite the importance of identifying glucokinase monogenic diabetes the system from the patient’s glucose meter is automatically classifi ed into (GCK-MODY) in pregnancy, universal genetic testing is not yet practicable. mealtime intervals and timing of measurement (preprandial, postprandial) by Standard pre-genetic screening criteria (SSC) are well established. New a classifi er based on a decision tree. pregnancy-specifi c screening criteria (NSC) were recently proposed to iden- After downloading BG data and informing on ketonuria fasting status, the tify gestational diabetes (GDM) cases that should be tested for GCK-MODY. patient immediately receives an evaluation of the data including complete- The NSC (fasting glucose ≥5.5mmol/L and pre-pregnancy BMI <25kg/m2) ness and, if needed, a proposal of diet adjustment. In case insulin therapy is were derived from a predominantly Anglo-Celtic population. Its applicability advised, the system also contacts the responsible doctor who schedules a to other ethnicities has not been examined. face-to-face appointment. To test this, we used an enrichment strategy to identify cases of GCK- Sixty-nine patients diagnosed of GD following the NDDG criteria were MODY, previously diagnosed as GDM. A multiethnic GDM database with randomized (2:1) to use the system (active group) and to download BG data post-partum data from 776 women was used to identify 63 women whose every three days or to attend the usual weekly visits (control group). post-par tum OGTT was highly suggestive of GCK-MODY by SSC. 31/63 agreed

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A372 PREGNANCY—CLINICAL to undergo genetic testing. DNA sequencing of the promoter, all exons and children, 6.8% in GDM exposed and 7.7% in unexposed, were diagnosed splice sites of GCK, as well as MLPA to detect multi-exonic GCK deletions, with DD during a median of 5.1 years (range 1.0-18.0 years) of follow-up. Risk was performed. 4 women were diagnosed with GCK-MODY (prevalence in of DD among GDM exposed children was similar to that among unexposed GDM of ~0.5-1 in 100). The NSC were then applied to prior antepartum re- children (HR, 95% CI=1.00, 0.95-1.05). Risk of DD among children exposed to sults. The fasting glucose criteria of ≥5.5mmol/L identifi ed all GCK-MODY. GDM ≤26 wks was not signifi cantly different from children unexposed (HR, However, 1/4 had a higher BMI and would have been missed. NSC identifi ed 95% CI= 1.03, 0.95-1.13). Use of anti-diabetic medication was not signifi - all Anglo-Celtic women with GCK-MODY but missed an Indian woman. Using cant associated with risk of DD (HR, 95% CI=1.09, 0.99-1.19, compared with NSC, 33/776 women would have proceeded to genetic testing to identify GDM unexposed). Analyses for risk association before and after age 6 gave ~3-6 cases. Applying the NSC to a larger GDM database of 4415 women, similar conclusions. Thus, unlike our prior fi ndings with ASD, data from our 6.1% cases were eligible for GCK-MODY testing, reduced from 14.2% using large multi-ethnic and population-based clinical care system did not support the SSC. 3.2% of Anglo-Celtic women would be tested. However, a dispro- a signifi cant association between GDM exposure in utero and risk of DD in portionate number of SE Asian (8.0%) and Indian (7.5%) women would be offspring. tested. In summary, the prevalence of GCK-MODY in our multiethnic GDM Supported By: Kaiser Permanente cohort is consistent with other studies. The NSC for GCK-MODY halve the need for genetic testing and appear to be applicable to Anglo-Celtic women. 1438-P However, the NSC may perform less well in other ethnicities. Ethnic-specifi c Maternal Saturated Fat Intake during Pregnancy and Neonatal Adi- criteria should be explored. posity: The Healthy Start Study Supported By: Australia National Health and Medical Research Council TESSA L. CRUME, ALLISON B. SHAPIRO, JILL L. KAAR, JACOB E. (JED) FRIEDMAN, DANA DABELEA, Aurora, CO & 1436-P The fetal programming hypothesis suggests that maternal nutrition during Ethnic Differences in Fetal Growth Patterns in Gestational Diabetes pregnancy infl uences neonatal body composition. We tested the hypothesis (GDM) that maternal dietary saturated fat (SF) intake is associated with neonatal HEMA VENKATARAMAN, SAM CRAIK, UMA RAM, SURESH SESHADRI, PON- adiposity, and that this association is mediated by maternal insulin resis- NUSAMY SARAVANAN, Nuneaton, United Kingdom, Coventry, United Kingdom, tance and fuels (glucose and lipids). A multiple mediator path analysis was Chennai, India used to assess the total effect of SF intake on neonatal % FM, as well as

Aim: To study differences in fetal growth patterns in South Asians (SA) the mediated effect through maternal insulin resistance (HOMA-IR) and fu- POSTERS and White Caucasians (WC) with GDM. els (glucose, cholesterol [TC], triglycerides [TG], free fatty acid [FFA], high Therapeutics Methods: Multicentre retrospective data collection was undertaken for density lipoprotein [HDL-c]) among 899 mother-infant pairs enrolled in the Clinical Diabetes/ all women with GDM from 2 centres in the UK (2008-2012) and in India (2012- prospective Healthy Start study. Percent neonatal fat mass (% FM) was 2013). Fetal biometric data was obtained at 28, 32, 36 weeks gestation for measured by air displacement plethysmography and fuels/insulin resistance 125 SA (UK), 142 WC and 53 Indians. T-tests and linear regression were used were measured in fasting state at a median gestational age of 27 weeks. to compare growth patterns between ethnic groups. The total effect of maternal SF intake on % FM was signifi cant (β=0.09, p= Results: Compared to WC, SA had had lower BMI (28.5±6.1 vs. 32.2±7.4 0.01), independent of pre-pregnancy BMI, infant sex, maternal age, gravid- kg/m2), height (159, IQR: 155-163 vs. 165, IQR: 160-169 cm), less likely to ity, smoking, and total calorie intake. However, signifi cant meditation was smoke (1.3 vs. 17.5%), had lighter babies (3226.5 ± 588 vs. 3419.4±630 g) de- not detected through the pathways tested (Figure 1) and maternal SF intake spite higher FPG (5.3±0.7 vs. 5.1±0.76) and 2hPG (8.1±2.1 vs. 7.6±1.9) mmol/l was not signifi cantly associated with HOMA-IR. Our data implicate maternal (p<0.01 for all). Compared to SA (UK), Indians had lower BMI (25.6±10.2 kg/m2), dietary SF intake is a potential fetal programming exposure for neonatal height (156, IQR: 152-162cm), and birth-weight (3080 ± 545g) (p<0.001 for all) adiposity, however the responsible mechanisms are still unclear. despite similar FPG (5.15 ± 0.8) and 2hPG (7.7± 2.0) mmol/l. At 28 weeks, abdominal-circumference (AC) for SA, Indians and WC were similar (243.4±18 vs. 247±16 vs. 248.3±23, p=0.19). At 32 and 36 weeks, AC of SA was lower than WC despite adjustment for maternal BMI, height, glu- cose values at OGTT and offspring sex (p=0.03; p=0.007). Head circumfer- ence (HC) was similar in SA and WC at all gestations. Both HC/AC ratio and femur-length/AC ratio was higher in SA compared to WC at 28 and 36 weeks after full adjustment (p<0.02). Conclusions: Despite smaller overall size, SA showed evidence of abdomi- nal sparing in early fetal life. With progressing gestation there was a pat- tern of growth restriction with sparing of HC and lower AC compared to WC, signifying a possible adverse intra-uterine environment or differential response to treatment.

& 1437-P Gestational Diabetes Mellitus and Risk for Developmental Delays in Offspring ANNY H. XIANG, XINHUI WANG, MAYRA P. MARTINEZ, JOHANNA C. WALTHALL, Supported By: National Institute of Diabetes and Digestive and Kidney Diseases KATHLEEN PAGE, THOMAS A. BUCHANAN, DARIOS GETAHUN, Pasadena, CA, Los Angeles, CA 1439-P Our previous study suggested that offspring in utero exposed to gesta- TCF7L2 Genotype with Gestational and Postpartum Weight Change tional diabetes (GDM) before 26-wks gestation is at increased risk for au- in Women with Gestational Diabetes Mellitus tism spectrum disorders (ASD). Extending that work, we investigated if this YAN ZHENG, HUIKUN LIU, HAN-LING CHENG, LEISHEN WANG, TAO HUANG, association could occur with cognitive/learning, speech/language or motor SHUANG ZHANG, JUNHONG LENG, GANG HU, LU QI, Boston, MA, Tianjin, China, developmental delays (DD). Included were 305,521 singleton children with- Baton Rouge, LA out congenital anomalies born to women without a history of overt diabetes TCF7L2 is the strongest known genetic susceptibility locus for type 2 in KPSC hospitals (1995-2009). Children who were GDM exposed (n=24,213, diabetes; and variants in this gene have been also related to body weight. 8%) form the “exposed” group while the rest constitutes the “unexposed” Compelling evidence has shown that gestational and postpartum weight group. Children were followed through electronic health records from birth changes are closely related to glucose metabolism and diabetes risk after until the fi rst occurrence of one of the following four events: clinical diag- delivery in women. We aimed to test whether TCF7L2 rs7901695 genotype nosis of DD; inactive health plan membership > 4months; death due to any has an effect on gestational weight gain and postpartum weight change cause; or December 31, 2012. Children with a diagnosis of ASD or attention- in a retrospective cohort study of 1,194 Chinese women with a history of defi cit/hyperactivity disorders (ADHD) were excluded from analysis. Survival gestational diabetes mellitus (GDM). After adjustment for age, pregnant analysis was used to estimate hazard ratios (HR) of DD associated with GDM age, pre-pregnancy BMI, family history of diabetes, physical activity, daily exposure, timing of GDM exposure and anti-diabetic medication treatment energy intake, and dietary intake of fi ber and fat, the genotype of rs7901695 of GDM with adjustment for maternal and child covariates. A total of 19,810 was signifi cantly associated with gestational weight gain (p=0.016), but not

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A373 PREGNANCY—CLINICAL

with postpartum weight changes (p>0.05) (Figure 1). Each risk allele (T) was Sixty three of the women (62%) were diagnosed with prediabetes (age: 2 related with 1.31 kg greater gestational weight gain in average. No signifi - 38±1 years (mean±SEM); BMI: 32±1 kg/m ; glycated hemoglobin (HbA1c): cant association of rs7901695 with measures of gestational or postpartum 34±1 mmol/mol; insulin resistance according to homeostatic model as- glucose metabolism was found. In conclusion, our data suggest that TCF7L2 sessment 2 (HOMA2IR): 1.8±0.1), and 39 (38%) had NGT (age: 39±1 years; 2 genotype may affect gestational weight gain in women with GDM. BMI: 31±1 kg/m ; HbA1c: 33±1 mmol/mol; HOMA2IR: 1.9±0.2). Women with Figure 1. The association of TCF7L2 rs7901695 genotype with gestational prediabetes had higher FPG (5.5±0.1 vs. 5.2±0.1 mmol/L, P=0.002) and weight gain and postpartum weight change. Covariates include age, preg- 2-hour plasma glucose during OGTT (9.2±0.1 vs. 6.9±0.1 mmol/l, P<0.0001), nant age, pre-pregnancy BMI, family history of diabetes, sitting hours/ as well as lower insulin sensitivity measured by Matsuda Index (2.5±0.3 day, active hours/day, daily energy intake, dietary intake of fi ber, intakes of vs. 3.3±0.2, P<0.005) compared to women with NGT. The incretin effect

monounsaturated fat, polyunsaturated fat, and saturated fat. [100% × (AUCinsulin,OGTT – AUCinsulin,IIGI)/ AUCinsulin,OGTT] amounted to 45±3% and 54±2% in women prediabetes and NGT, respectively (P=0.042). The groups were similar with respect to age, BMI, HbA1c, HOMA2IR, fasting insulin (108±7 vs. 90±8 pmol/L, P=0.078), number of previous GDM-preg- nancies (1.2±0.1 vs. 1.1±0.1, P=0.448) and duration since index pregnancy (5.2±0.3 vs. 4.9±0.4 years, P=0.658). Our results show that prediabetes is prevalent in women with previous GDM, and alterations in the incretin ef- fect can be detected in high-risk individuals even before the development of type 2 diabetes. 1441-P Carriers of the TCF7L2 rs7903146 Variant with Gestational Diabetes Mellitus Have an Increased Risk of Developing Impaired Glucose Regulation after Pregnancy CLAUDIA IPPOLITO, ROMINA FICARELLA, ANGELO CIGNARELLI, LUIGI LAVIOLA, GIOVANNA STEFANELLI, FRANCESCO GIORGINO, Bari, Italy Epidemiological studies suggest an association between the transcription POSTERS Therapeutics factor 7-like 2 (TCF7L2) rs7903146 (C/T) allele and an increased risk of devel- Clinical Diabetes/ oping both type 2 (T2D) and gestational diabetes (GDM). We aimed to com- pare the CC, CT and TT genotype frequencies of TCF7L2 rs7903146 in women with history of GDM who remained normotolerant (NGT) or developed im- paired glucose tolerance (IGT) or T2D after pregnancy. 126 women with pre- vious GDM were challenged with an oral glucose tolerance test (OGTT) after a mean of 13.7 months following pregnancy. The OGTT identifi ed 80 women with NGT (63%), 21 with IGT (32%) and 6 with T2D (5%). When compared to CC carriers, CT/TT carriers displayed higher levels of fasting insulin (14.4 vs. 11.4 mUI/l, P<0.05) and insulin during OGTT (at 30 min: 54.6 vs. 44.2 mUI/l, P<0.05; at 120 min: 70.1 vs. 57.1 mUI/l, P<0.05), higher AUC of glycemia (8161 mg/h/dl vs. 7607 mg/h/dl, P<0.05) and insulinemia (3514 mcUI/h/ml vs. 2974 mcUI/h/ml, P<0.05) during OGTT, higher HOMA-IR (3.16 vs. 2.47, P<0.05), and lower Matsuda index (4.2 vs. 5.2, P<0.05), QUICKI (0.32 vs. 0.34, P<0.05) and Disposition Index (2.8 vs. 3.8, P<0.05). The CT/TT variant was also associated with higher BMI gain during follow up (+ 0.9 kg/m2; P<0.05). The prevalence of the CT/TT genotype differed between women with NGT and those who developed IGT or T2D (53%, 81%, and 66%, respectively; χ2 p=0.012). Carri- ers of the CT/TT genotype displayed higher hazard ratio to lose NGT (HR 5.5, 95% CI 1.9-16.3), independently of BMI, BMI variation, time of follow-up, his- tory of diabetes, HOMA-IR, and parity. In conclusion, the TCF7L2 rs7903146 variant is associated with an increased risk of developing IGT or T2D after pregnancy in women with GDM, which may be explained by the impairment in adapting insulin secretion to reduced insulin sensitivity. The identifi ca- tion of this risk genotype can potentially be of value in tailored follow-up programs for women with history of GDM. Supported By: European Foundation for the Study of Diabetes; Chinese Diabetes Society; Lilly Programme for Collaborative Research between China and Europe; 1442-P Tianjin Public Health Bureau of China Accuracy of the Estimation of Fetal Weight Near Delivery by Ultra- sound in Diabetic and Nondiabetic Pregnancies 1440-P AMY VALENT, TONDRA NEWMAN, CARRI R. WARSHAK, Cincinnati, OH A Reduced Incretin Effect Can Be detected in Nondiabetic Women Objective: Evaluate the accuracy of the sonographic estimation of fetal with Previous Gestational Diabetes Even Before the Development weight with increasing birth weight in diabetic (DM) and non-diabetic (non- of Diabetes DM) pregnancies. We conducted a retrospective cohort study of all singleton, SIGNE FOGHSGAARD, LOUISE VEDTOFTE, CAMILLA ANDREASEN, EMILIE S. non-anomalous live births who received an estimation of fetal weight within ANDERSEN, ELISABETH R. MATHIESEN, JENS A. SVARE, JENS J. HOLST, TINE two weeks of delivery. Our primary outcome compared the delta fetal weight, D. CLAUSEN, PETER DAMM, FILIP K. KNOP, TINA VILSBØLL, Hellerup, Denmark, calculated as birth weight - estimated fetal weight). Secondary outcomes in- Copenhagen, Denmark, Herlev, Denmark, Hilleroed, Denmark cluded percentage error and rate of substantial error. Sensitivity and specifi c- The incretin effect is decreased in patients with type 2 diabetes, which ity were calculated for the prediction of fetal weight over 4000 gm. prompted us to study whether reduced incretin effect can be detected in Results: A total of 1,678 patients were included in our analysis, 1,362 non- high-risk individuals such as women with previous gestational diabetes DM (81.1%) and 316 (18.8%) DM. The mean delta EFW was 62 and 103 gm mellitus (GDM). One hundred and two non-diabetic women with previous for non-DM and DM respectively, p=0.037. However, the percentage error GDM were examined on two separate occasions: 1) 4-hour 75g oral glu- (7.8 vs. 8.0%, p=0.62) and the rate of substantial error were similar between cose tolerance test (OGTT) and 2) isoglycemic intravenous glucose infusion study groups, (30.9 vs. 30.7%, p=0.94). Overall sensitivity was poor, 0.41 and (IIGI). Based on the fasting plasma glucose (FPG) and the 2-hour plasma 0.62 in non-diabetics and diabetics respectively, however the specifi city was glucose concentrations of the OGTT, the women were classifi ed as having high, 0.97 and 0.99. normal glucose tolerance (NGT) or prediabetes (impaired fasting glucose Conclusions: Although diabetes alters the biometry of the fetus these and/or impaired glucose tolerance) (World Health Organization 2006). changes lead to only minor alterations of the accuracy of fetal weight pre- diction by ultrasound when performed near delivery. Ultrasound has a high

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A374 PREGNANCY—CLINICAL specifi city for birth weight over 4000 gm, which can be helpful for delivery 1444-P planning. A Randomized Trial of the Effects of Prenatal Education of Overweight or Obese Pregnant Women to Prevent Childhood Overweight: The ETOIG Study SOPHIE PARAT, VÉRONIQUE NÈGRE, AMANDINE BAPTISTE, MARIE-THÉRÈSE TAUBER, PAUL VALENSI, ANNE-MARIE BERTRAND, MYRIAM DABBAS, CARO- LINE ELIE, FRANÇOISE LORENZINI, EMMANUEL COSSON, Paris, France, Besan- çon, France, Toulouse, France, Bondy, France We aimed to evaluate whether prenatal education of overweight or obese pregnant women would reduce childhood overweight. Four French centers included before 20 weeks of gestation 268 pregnant women who were overweighed or obese before pregnancy (BMI 32.5±5.4 kg/m2, obesity 62%, age 30.4±5.0 years). They were randomized in a control group (n=136: routine care including at least one dietary visit) and an inter- ventional group (n=132). This intervention which included 2 individual and 4 collective dietary counseling at 18, 26, 33 weeks of gestation and 2 months after delivery aimed to educate the future mother for infant and maternal nutritional aspects, without weight objectives. The primary objective was postnatal catch-up growth from birth to two years (>0.67 DS), which is as- sociated with obesity in childhood. Events during pregnancy were similar in both groups, including incident gestational diabetes mellitus, maternal gestational weight gain and birth weight. The rate of postnatal catch-up growth was similar in interventional and control groups: in intention to treat (59.1 vs. 60.3% respectively, p=0.84), in available data (AD n=206) and in per-protocol population (PP n=177). Over- weight two years after delivery were less likely to occur in the interventional POSTERS group for the mothers (AD, n=149: 87.1 vs. 96.2%, p=0.04; PP, n=128: 95.8 vs. Therapeutics 89.3%, p=0.18) and the children (AD, n=204: 0 vs. 6.8%, p=0.014 ; PP, n=176: Clinical Diabetes/ 0 vs. 6.4%, p=0.03). 1443-P To conclude, intervention based on education and nutritional counseling Effect of Postpartum Weight Change on Risk Factors for Type 2 Dia- in women with overweight/obesity, starting at more than three months of betes among Women with Recent Gestational Diabetes gestation, has no effect on postnatal catch-up growth but seems to prevent JACINDA M. NICKLAS, CHLOE A. ZERA, SUE E. LEVKOFF, ELLEN W. SEELY, Aurora, overweight in mothers and children two years after delivery. CO, Boston, MA, Columbia, SC Supported By: PHRC, France Women with gestational diabetes (GDM) have a 30-70% risk for devel- oping type 2 diabetes (T2DM). Evidence from a post-hoc analysis of the 1445-P Diabetes Prevention Program suggests that weight loss can delay/prevent The Association of Elevated First Trimester ALT with Gestational development of type 2 diabetes in women with remote GDM, but little is Diabetes Mellitus known about how weight changes in the postpartum period modify risk fac- CHRISTINA D. YARRINGTON, DAVID CANTONWINE, ELLEN SEELY, THOMAS F. tors for T2DM. In the Balance after Baby (BAB) trial, women with recent MCELRATH, CHLOE ZERA, Boston, MA GDM randomly allocated to a year-long lifestyle intervention program lost There is a well-established association of elevated alanine aminotrans- signifi cantly more weight than the control group. The impact of the interven- ferase, attributed to non-alcoholic fatty liver disease, with later develop- tion on risk factors for T2DM was not signifi cant, however, there was a large ment of type 2 diabetes mellitus among non-pregnant adults. We therefore range of weight change in the entire population. Therefore, we sought to sought to determine whether ALT values in early pregnancy were associated determine if weight changes in the postpartum year were associated with with development of gestational diabetes (GDM). changes in risk factors for diabetes, regardless of group assignment. We performed a nested case-control study utilizing prospectively banked In the BAB trial, we measured weight, height, fasting insulin, adiponectin, serum samples collected between 8-18 weeks gestation. We excluded wom- and conducted 75g 2-hour oral glucose tolerance tests at 6 weeks, 6 and en with known diabetes, liver disease, or moderate self-reported alcohol use 12 months postpartum. The current study includes 59 women completing during pregnancy and documented by medical record review. We included the 12-month study visit (mean 33 ±5 years; 6 week postpartum BMI 31 ±6 83 cases who were later diagnosed with GDM and 247 controls matched kg/m2; 58% White, 31% African-American, 12% Asian, with 20% Hispanic). for pre-pregnancy BMI and with a 3rd trimester 50-g GLT result ≤120mg/dL. Median weight change from 6 weeks to 12 months postpartum was +0.4 We compared early ALT values in cases with controls. We then performed a kg (IQR -4.8, +2.7). Increases in weight from 6 weeks to 12 months postpar- conditional logistic regression to model the adjusted odds of GDM in women tum signifi cantly correlated with worsening risk factors, including changes with elevated ALT, stratifi ed by fi rst trimester BMI. in fasting glucose (Spearman’s r = 0.41, p=0.002), fasting insulin (r = 0.49, Cases, women who were later diagnosed with GDM, were older (mean p=0.0001), homeostasis model assessment of insulin sensitivity (HOMA) (r = age±SD 34±5 vs. 32±6 years, p=0.001) and more likely to be of Asian ethnic- 0.5, p<.0001), adiponectin (r = -0.38, p=0.004) and HbA1c (r = 0.45, p=0.001). ity (16.9% vs. 2.8%, p=0.03) than controls, but otherwise were similar. The The 2-hour glucose and Matsuda index were not signifi cantly correlated. median (IQR) ALT in cases was 15 (12, 19) IU/L compared to 13 (11, 18) IU/L in Weight changes in the postpartum year were signifi cantly correlated with women with normal glucose tolerance (p=0.07). Among non-obese women changes in risk factors for type 2 diabetes among women with recent GDM. (fi rst trimester BMI <30kg/m2), ALT above the 75% ile (19 IU/L) was associ- A longer study is needed to determine how postpartum weight changes af- ated with a four-fold increased risk of GDM (adjusted OR 4.56 [1.45, 14.27]), fect the rate of development of T2DM and repeat GDM. while there was no association (aOR 0.36 [0.11, 1.20]) among obese women. Supported By: Centers for Disease Control and Prevention (DCMM-1094–09/09); Similarly, each unit increase in log-transformed ALT was associated with a National Institutes of Health (5K12HD057022-08, T32AT000051 to J.M.N.); National threefold increased risk of GDM in non-obese (aOR 3.15 [1.04, 9.54]) but not Institutes of Health-National Heart, Lung, and Blood Institute (K24HL096141 to in obese (aOR 0.97 [0.30, 3.15]) women. E.W.S.) Elevated ALT early in pregnancy was associated with increased risk for GDM in non-obese women. Elevated ALT may be a useful indicator of GDM risk in a population currently considered low-risk for GDM.

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1446-P 1448-P Effect of Multiparity on the Risk of Development of Diabetes Perinatal Oxidative Stress Affects Fetal Ghrelin Concentrations BUTHAINA ALMAHMEED, BAIJU R. SHAH, GEETHA MUKERJI, GILLIAN L. BOOTH, ZHONG-CHENG LUO, JEAN-FRANÇOIS BILODEAU, ANNE MONIQUE NUYT, WIL- DENICE S. FEIG, Toronto, ON, Canada LIAM FRASER, PIERRE JULIEN, FRANCOIS AUDIBERT, LIN XIAO, CAROLE GARO- The relationship between parity and the development of type 2 diabetes FALO, EMILE LEVY, Shanghai, China, Quebec, QC, Canada, Montreal, QC, Canada, remains unclear and controversial. Our aim was to investigate the relation- Sherbrooke, QC, Canada ship between increasing parity and diabetes in a large, population-based Objective: The perinatal period is a critical developmental window in “pro- cohort, and examine if this relationship is different among high risk ethnic gramming” the vulnerability to the metabolic syndrome and related disorders. groups. The mechanisms remain unclear. Experimental studies (animals or cell models) A population-based, retrospective cohort study was performed for all suggest that oxidative stress may be involved in metabolic programming, but 823,023 women aged 18-50 years who had a delivery in Ontario between the evidence remains scarce in humans. This study tested the hypothesis that April 1, 2002 and March 31, 2011. Women were categorized according to perinatal oxidative stress may affect fetal metabolic health in humans. their parity and ethnic group (Chinese, South Asian or general population). Methods: In a singleton prospective pregnancy cohort (n=248 mother-newborn Diabetes incidence postpartum was calculated for each parity and ethnic pairs), we evaluated maternal (24-28 weeks gestation) and cord plasma biomarkers group. A multivariable analysis of the effect of parity and ethnicity on the in- of oxidative stress [malondialdehyde (MDA), F2-isoprostanes] in relation to fetal cidence of diabetes was performed using a Cox proportional hazards model, metabolic health biomarkers (cord plasma glucose-to-insulin ratio, proinsulin-to- adjusting for age, income, rural residency, recency of immigration, gesta- insulin ratio, IGF-I, IGF-II, leptin, adiponectin and ghrelin concentrations). tional diabetes, pre-existing hypertension, gestational hypertension, other Results: Positive correlations were observed between maternal and cord comorbidities and health care utilization. plasma biomarkers of oxidative stress (r=0.33 for MDA, r=0.74 for total F2- The incidence rate per 1,000 person-years was 3.22 in women with 1-2 isoprostanes, all p<0.001). Adjusting for gestational age at blood sampling, deliveries, 5.52 in women with 3-4 deliveries and 8.20 in women with ≥5 cord plasma ghrelin concentrations were negatively correlated to oxidative deliveries, compared with 3.34 in nulliparous women. Women with 3-4 deliv- stress biomarkers in maternal (r=-0.32, p<0.001 for MDA; r=-0.29, p<0.001 eries and ≥ 5 deliveries had a higher risk of developing diabetes compared to for F2-isoprostanes) or cord plasma (r=-0.13, p=0.04 for MDA; r=-0.30, nulliparous women (adjusted HR 1.34 (95% CI; 1.26-1.43) and 1.75 (1.55-1.98) p<0.001 for F2-isoprostanes). Other fetal metabolic health biomarkers were respectively). A similar rise in risk with increasing parity could be seen in Chi- not correlated with oxidative stress (all p>0.05). Similar associations were nese and South Asian women, with the greatest infl uence in Chinese women observed after adjusting for maternal and pregnancy characteristics. POSTERS Therapeutics (HR 5.41 (2.23-13.11) for ≥ 5 deliveries compared to nulliparous women. Conclusions: Oxidative stress may be transferrable from mothers to fe- Clinical Diabetes/ There was a positive and graded relationship between increasing parity tuses. Perinatal oxidative stress does not affect most fetal metabolic health and the risk of development of type 2 diabetes. The infl uence of parity was biomarkers, but may repress fetal ghrelin levels. It is unclear but possible greatest in women of Chinese ethnicity. This association may be related to that this inhibitory effect on ghrelin during fetal development may be in- increasing weight gain and retention with increasing parity, or may be re- volved in oxidative stress programming the vulnerability to the metabolic lated to deterioration in beta cell function. syndrome-related disorders. Supported By: Canadian Diabetes Association Supported By: Canadian Institutes of Health Research (79896, 78879); National Natural Science Foundation of China (81370742) 1447-P Maternal and Neonatal Outcomes in Women with a 1-Hour Glucose 1449-P Challenge Test Greater than 200 mg/dL Perinatal Outcomes Associated with Diabetes Screening Prior to ANNA BINSTOCK, MAISA FEGHALI, STEVE CARITIS, JANET CATOV, CHRISTINA 24 Weeks Gestation SCIFRES, Pittsburgh, PA, Oklahoma City, OK CAROL D. MOFFETT, GUDETA D. FUFAA, SAYUKO KOBES, KIM COUCH, DIANA L. Pregnant women with 50 gram glucose challenge test (GCT) values DUNNIGAN, SUZAN H. MURPHY, ROBERT G. NELSON, WILLIAM C. KNOWLER, greater than 200 mg/dL are often considered to have gestational diabetes JEREMY POMEROY, Phoenix, AZ (GDM) without additional testing, but there is limited data regarding preg- Testing for gestational diabetes (GDM) is widely recommended after 24 nancy outcomes in this population. To address this question we conducted weeks of gestation, but not before. We examined the impact of early screening a retrospective cohort study of 1258 women with GDM delivered between for GDM on perinatal outcomes in Native American women at the Phoenix Indian 2009 and 2012. Women with GDM diagnosed by a 50g GCT ≥200 mg/dL Medical Center (PIMC) in Arizona. Hospital records identifi ed pregnant women were compared to those diagnosed with GDM and a 1 hour diabetes screen who had a 50 g oral glucose challenge test (OGCT) prior to 24 weeks gestation. <200 mg/dL. Bivariate (chi square, t-test) and multivariate logistic regres- The women were followed to completion of pregnancy. Associations between sion analyses were used to assess the impact of GCT results ≥200 mg/dL on the 1-hour plasma glucose concentration (1hPG) from the OGCT and presence maternal and neonatal outcomes. We identifi ed 191/1258 (15.2%) of women of pre-eclampsia, cesarean section, large for gestational age infants, and birth with GDM who were diagnosed based on a 50g GCT ≥200 mg/dL. Women weight were examined by logistic and linear regression. Of 8611 women who with a 50g GCT ≥200 mg/dL had higher pre-pregnancy BMIs (32.0 ±8 vs. gave birth at PIMC between 2000 and 2012, 2929 (34%) had an OGCT prior to 24 29.5 ±7.5 kg/m2, p<0.001) and earlier diagnosis of GDM (25.4 ±6.3 vs. 27.8 weeks gestation (mean±SD=13±5 weeks). 1hPG concentration was 117±32 mg/ ±4.5 weeks, p<0.001). They more frequently required medical therapy (79 vs. dL, maternal age was 25.5±5.6 years, and BMI was 30.5±7.2 kg/m². Associations 60.9%, p=0.01), and had higher fasting (95.2 ±15.9 vs. 87.6 ±9.4, p<0.001) of 1hPG with each clinical outcome are shown (Table). Odds ratios are shown for and postprandial (132.9 ±19.5 vs. 122.0 ±13.2, p<0.001) blood sugars after the logistic models and increase in birth weight is shown for the linear model diagnosis despite more medication use. A 50g GCT ≥200 mg/dL was associ- for each 1 SD increase in 1hPG. Glucose screening in early pregnancy identifi es ated with an increased risk of preterm birth (aOR 1.79, 95% CI 1.10-2.93), women and their offspring who are at risk for pre-eclampsia and other adverse and particularly indicated preterm birth (OR 3.1, 95% CI 1.9-5.0, p<0.001). health outcomes. Lifestyle interventions initiated early in pregnancy in response Neonatal morbidity composite (neonatal hypoglycemia, respiratory distress to such testing may offer the best opportunity to mitigate adverse outcomes in syndrome, and hyperbilirubinemia) was higher in women with a 1 hr GCT mothers and babies, especially in high risk populations. ≥200 mg/dL (27 vs. 18%, p=0.002), although this risk was attenuated (aOR Table. 1.2, 95% CI 0.8-1.9, p=0.46) after adjustment for covariates including glyce- mic control. Women with a 1 hour GCT greater than or equal to 200 mg/dL Outcome Model 1* Model 2* Model 3* Model 4* are at increased risk for indicated preterm birth, which may occur secondary Logistic regression to persistent hyperglycemia. Interventions to optimize glycemic control may Pre-eclampsia 2.49 (2.23-2.79) 2.48 (2.21-2.77) 2.47 (2.18-2.80) 2.27 (2.00-2.59) reduce the risk for preterm birth and the associated neonatal morbidity in p<0.0001 p<0.0001 p<0.0001 p<0.0001 this patient population. (434 events/ (434 events/ (388 events/ 388 events/ 2929 observations) 2929 observations) 2537 observations) 2537 observations) Cesarean 1.16 (1.07-1.26) 1.15 (1.06-1.25) 1.04 (0.95-1.14) 1.04 (0.94-1.14) delivery p=0.0004 p=0.0011 p=0.3799 p=0.4665 (737 events/ (737 events/ (654 events/ (654 events/ 2929 observations) 2929 observations) 2537 observations) 2537 observations)

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rd Large for 1.20 (1.08-1.34) 1.27 (1.13-1.42) 1.18 (1.04-1.34) 1.10 (0.96-1.26) Offspring born to mothers with good glycaemic control in the 3 trimester gestational p=0.0012 p<0.0001 p=0.0102 p=0.1679 obtained higher average school grades compared to their matched controls. age (270 events/ (270 events/ (238 events/ (238 events/ The opposite applied to offspring born to mothers with inadequate glycae- 2929 observations) 2929 observations) 2537 observations) 2537 observations) mic control who obtained signifi cantly lower average school grades com- Linear regression pared to their matched controls. Birth weight, g 35.7 (17.1-54.4) 48.8 (31.9-65.8) 25.5 (7.1-43.9) 10.31 (-8.52-29.14) These results show that offspring of mothers with pregestational T1DM (mean = p=0.0002 p<0.0001 p=0.0066 P=0.2829 obtained similar average grades when fi nishing primary school compared 3495.0) (2929 observations) (2929 observations) (2537 observations) (2537 observations) to matched controls. Among offspring of women with T1DM we found a consistent negative association between HbA before and during pregnancy *Model 1 is unadjusted, Model 2 is adjusted for gestational age at delivery, 1c Model 3 is also adjusted for early pregnancy BMI, Model 4 additionally and primary school grades. adjusted for maternal age at delivery. 1452-P 1450-P Predictors of Self-Effi cacy for Diet and Physical Activity at 6 Weeks Early Diabetes Screening in Women with Previous Gestational Dia- Postpartum in Women with Recent Gestational Diabetes betes: A New Insight GERALDINE SKURNIK, ELLEN W. SEELY, SUE E. LEVKOFF, CHLOE ZERA, JACINDA ALINE NABUCO, LENITA ZAJDENVERG, SAMARA PIMENTEL, MARCUS MIRAN- M. NICKLAS, Boston, MA, Columbia, SC, Aurora, CO DA, CAROLINA CABZUCA, MELANIE RODACKI, Rio de Janeiro, Brazil Women with prior gestational diabetes (GDM) have increased risk for type Gestational Diabetes Mellitus (GDM) is a risk factor for the development 2 diabetes, and this risk can by modifi ed by weight loss and physical activity of type 2 diabetes. However, many women do not return to the postpartum (PA). Self-effi cacy (SE), confi dence in one’s ability to perform activities, is an screening at 6 to 12 weeks. The rate of adherence could be higher by con- important determinant for making lifestyle changes. We analyzed baseline ducting the screening before hospital discharge. characteristics of participants in the Balance after Baby randomized trial to Our aim is to determine the accuracy of 75 gram 2 hour oral glucose toler- determine SE predictors for diet and PA. ance test (OGTT) performed between 48 and 72 hours after delivery for the Women with recent GDM completed 6 week (w) postpartum (pp) study diagnosis of diabetes using the same test after six weeks as the gold stan- visits. We measured weight and height, and women completed demograph- dard criteria, and to identify the optimal OGTT cutoff points between 48 and ic, sleep, and Edinburgh Postnatal Depression (EPDS) questionnaires. Partici-

72 hours for diabetes screening after pregnancy complicated by GDM. pants completed an adapted Sallis SE questionnaire for eating (E) and PA, POSTERS Therapeutics 257 women were identifi ed with GDM, but only 82 women met all the inclu- and we derived summary 5-point Likert scores for E and PA. We conducted Clinical Diabetes/ sion criteria. The mean age was 32.2 years (± 5.8), 54.4% were non-white, univariate analyses and chose potential predictors with a p value <.2 to build mean gestational age at GDM diagnosis was 23.1 weeks (± 7.4), 69.4% had linear regression models using backward elimination. cesarean delivery, and 64.6% needed insulin treatment. The prevalence of At mean 7.2 w (SD±2.1) pp, 75 women (age 33±5; BMI 31.4 (±5.6); 57% diabetes and prediabetes based on OGTT performed 48-72h after birth, was White, 29% African-American, 15% Asian; 20% Hispanic) completed base- 3.7% and 32.9%, respectively, and at the second OGTT was 8.5% and 20 7%, line visits. Participants had a mean of 2±1 children at home, 40% under- respectively. The area under the curve (AUC) for the group with diabetes based went cesarean delivery, 31% had depressive symptoms (EPDS score ≥9), on fasting plasma glucose (FPG) in the early period was 0.77 (95% CI 0.61-0.92), 29% were exclusively breastfeeding, and 33% slept ≥6 hours (h) daily. SE and based on 2h OGTT was 0.82 (95% CI 0.66 -0.97). The AUC for patients with score for E (4.5 ±.5) was signifi cantly higher than for PA (3.5 ±.9) (p<.0001), prediabetes based on early period FPG was 0.73 (95% CI 0.59-0.86), and based (Spearman’s r=0.6, p<.0001). In univariate analyses for SE for E, exclusive on the following 2h OGTT was 0.74 (95% CI 0.61 - 0.87). Using FPG cutoff value breastfeeding and number of children at home met criteria for inclusion of 4.3mmol/l (78mg/dl) and 2-h OGTT cutoff value of 7.2mmol/l (130mg/dl) for in the multivariate model, but no predictors were signifi cant. For PA, uni- diabetes, the specifi city was 58.7% and 60%, sensitivity 71.4% and 85.7%, the variate analyses showed younger age, no depressive symptoms, and ≥6h positive predictive value was 13.9% and 16.7% and the negative predictive sleep as signifi cantly associated with increasing SE. In multivariate analysis value was 95.7% and 97.9%, respectively. controlling for mode of delivery, only getting ≥6h sleep remained signifi cant The OGTT performed during the early postpartum on women with prior (Β=0.22, p=0.04). GDM is a useful tool for identify those who needs to perform OGTT 6 weeks In the early pp period, women with recent GDM demonstrated higher SE after delivery because of its high negative predictive value. Furthermore, for E than for PA, and these scores were modestly correlated. Adequate identifying women that should return at six weeks make easier to health- sleep may be an important predictor for SE for PA. care practitioners to do an effort to contact the patient. Supported By: Centers for Disease Control and Prevention (MM-1094–09/09); National Institutes of Health (T32HL007609 to G.S.); (5K12HD057022-08, 1451-P T32AT000051 to J.M.N.); National Institutes of Health-National Heart, Lung, and Academic Achievement in Primary School in Offspring Born to Blood Institute (K24HL096141 to E.W.S.) Mothers with Type 1 Diabetes—The Epicom Study: A Prospective Combined Clinical and Register-based Cohort Study 1453-P SINE KNORR, TINE D. CLAUSEN, ZUZANA VLACHOVÂ, BIRGITTE BYTOFT, PETER The Utility of Digital Blood Glucose Monitoring Metrics to Predict DAMM, HENNING BECK-NIELSEN, DORTE M. JENSEN, SVEND JUUL, CLAUS H. High Birth Weight in Women with Gestational Diabetes GRAVHOLT, Aarhus, Denmark, Hillerød, Denmark, Odense, Denmark, Copenhagen, JANE E. HIRST, ANDREW FARMER, LISE LOERUP, LUCY MACKILLOP, JONATHAN Denmark LEVY, KATY BARTLETT, YVONNE KENWORTHY, DEV A. KEVAT, CARMELO VE- The effect of intrauterine hyperglycemia on the developing fetal central LARDO, LIONEL TARASSENKO, Oxford, United Kingdom nervous system is unclear and other conditions during fetal life, birth compli- Quantifying blood glucose (BG) control in gestational diabetes mellitus cations, neonatal complications and socioeconomic factors also contribute (GDM) is diffi cult. Digital systems provide new metrics, yet clinical and re- to later neuro-cognitive function. This study aimed to evaluate the effect of search utility is not established. We aimed to determine utility of digital BG maternal pregestational type 1 diabetes (T1DM) on offspring primary school metrics as predictors for large for gestational age (LGA). GDM screening performance. The study was a prospective combined clinical and register- was per 2008 NICE guidance. If positive, fasting, pre- and 2-hour post-pran- based cohort study where the participants were offspring of women with dial self-monitoring of BG was advised using a smartphone-based digital pregestational T1DM (n=707) and random controls from the background BG management system with regular clinician review. Mean total, fasting, population matched according to maternal age, date of birth and gender post-prandial BG and proportion of BGs over target were calculated (me- (n=60,341). dian duration of monitoring 9 weeks). Birth weight was classifi ed as LGA (> Offspring of mothers with pregestational T1DM obtained similar school 90th centile for gestation and gender) per INTERGROWTH-21st standards. grades as controls when fi nishing primary school (β= -0.13, 95% CI= -0.30, Continuous variables were converted to z scores. Logistic regression was 0.03, P=0.12). Adjusting for parental educational status also resulted in an adjusted for parity, height, BMI. Of 41 women, 12 had LGA babies (29%). insignifi cant difference between the two groups (β= -0.07, 95% CI= -0.23, The odds of LGA increased with every SD increase (0.62 mmol/L) in mean 0.09, P=0.37). BG (aOR 3.2, 95% CI 1.1-9.6) and SD increase (0.84) in post-prandial BG (aOR Among offspring of women with T1DM increasing maternal HbA1c, both 3.7,1.2-11.2), but not fasting BG (aOR 1.9, 0.8-4.7), SD (0.66). 33% of readings pregestationally and throughout the pregnancy was associated with lower were above target (SD 16%). For every 16% increase in high readings, risk average school grades, even after excluding children born before 37 weeks of LGA increased (aOR 4.2, 95% CI 1.20-14.5). BG weekly moving averages of gestation.

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were higher for LGA babies for the duration of monitoring. These associa- PlGF. We also constructed log-binomial regression models to evaluate the tions justify further studies to validate potential uses for digital BG metrics. association between log-transformed PlGF and macrosomia. Models were adjusted for potential confounders including maternal age. Approximately 75% of women had type 1 diabetes. There was a statistical- ly signifi cant positive association between PlGF and birth weight (p=0.008). Late third trimester PlGF levels showed the strongest association (r=0.26, p<0.009). After full adjustment, there was a 6.7% increase in birth weight for gestational age percentile for each unit increase in log-transformed PlGF averaged across pregnancy (95% CI: 1.4%, 12.0%). We found a suggestion of an increased risk of macrosomia among women with higher log-transformed PlGF levels (RR: 1.43; 95% CI: 0.99, 2.06). These associations were not medi- ated by hemoglobin A1c. PlGF was independently associated with increased birth weight in women with preexisting diabetes. This angiogenic factor may provide an additional marker of fetal overgrowth in this high-risk group of women.

1456-P Free-Living Glucose in Late Pregnancy Is Positively Associated Supported By: UK National Institute for Health Research; Oxford Biomedical with Neonatal Fat-Free Mass, but Not Fat Mass, in African Ameri- Research Centre can Infants PAULA C. CHANDLER-LANEY, DESTI SHEPARD, BARBARA A. GOWER, MELISSA 1454-P S. MANCUSO, JOSEPH R. BIGGIO, Birmingham, AL, Akron, OH A Phase-Three, Open-Label Randomized Controlled Trial to Com- Consistent with the Developmental Origins of Health and Disease hy- pare the Effi cacy of Oral Hypoglycemic Agents with Insulin in the pothesis, obesity and glucose concentrations during pregnancy have been Treatment of Gestational Diabetes Mellitus associated with offspring birth weight, adiposity, and long-term risk for

POSTERS AISHA WALI, AISHA SHEIKH, LUMAAN SHEIKH, NEELOFUR BABAR, SIDRAH obesity. Despite the high prevalence of obesity among African American Therapeutics NAUSHEEN, JAWEED AKHTER, Karachi, Pakistan (AA) women, few studies have examined associations among BMI and Clinical Diabetes/ Till date no clinical trial has compared the use of metformin and glibencl- glucose of AA women during pregnancy with neonatal body composition. amide in combination with the gold standard insulin in the treatment of Ges- The purpose of this study was to test the hypothesis that, irrespective of tational Diabetes Mellitus (GDM). Our study was a multicenter trial. We ran- BMI in early pregnancy, third trimester 24-hour glucose concentrations in domly assigned 154 women with International Association for the Diabetes AA women would be positively associated with offspring birth weight, and in Pregnancy Study Group suggested criteria for GDM (FBS before 24 weeks: neonatal fat mass (FM) and fat free mass (FFM). Non-diabetic AA women 92-125 mg/dl or OGTT at 24-28 weeks: FBS 92-125 or 1hr ≥ 180 or 2hr ≥ 153 wore continuous glucose monitors for 72-hours during late pregnancy under mg/dl) at less than 33 weeks of gestation to open treatment with OHA or Hu- free-living conditions, from which 24-hour glucose area under the curve was man Insulin, who remained uncontrolled after one week trial of medical nu- calculated. Weight and length of infants (N=35) was measured at birth and trition therapy. The primary outcome was comparison of effi cacy in glycemic converted to z-scores using World Health Organization reference data. Neo- control between the two groups. Insulin arm included 71 women. Of the 74 natal body composition was measured by air displacement plethysmography women assigned to OHA group, 41 (55.5%) continued metformin till delivery, at 2-weeks of age. Free-living 24-hour glucose concentration was positively 5 (6.6%) did not tolerate metformin and were switched to glibenclamide and associated with birth weight and birth length z-scores (P<0.05), but not in 24 (32.5%) glibenclamide was added. Excellent glycemic control (fasting < weight-for-length z-score. In linear regression models, maternal BMI and 24- 95 mg/dl and 2-h <120 mg/dl) was achieved in 33.9% women in OHA group hour glucose were not associated with infant FM, after adjusting for infant vs. 21.4% in insulin group; satisfactory glycemic control (fasting 95-110 mg/ FFM, sex, and weight change since birth (P>0.30). However, 24-hour glucose dl and 2-h 120-140 mg/dl) was achieved in 57.6% in OHA vs. 62.9 in insulin was positively associated with infant FFM, after adjusting for maternal BMI group; while poor glycemic control (fasting >110 mg/dl and 2-h >140 mg/dl) and infant length, sex, and weight gain since birth (partial r=0.37, P<0.05). due to non-compliance was shown in 8.5% in OHA vs. 15.7% in insulin group Results from this cohort suggest that free-living third trimester glucose is (P=NS). There was no signifi cant difference in neonatal birth-weight and an- associated with overall body size, but not adiposity, of AA neonates. It will thropometric measurements in both the groups. Secondary outcome was be of interest in the future to compare these associations among African acceptability to treatment and survey showed preferred treatment in sub- American and Caucasian infants within the same study. sequent pregnancy being OHA in 90.5% women vs. insulin in 23.9% women Supported By: P30DK079626 (P-value=0.002). No serious adverse event was reported in either group. We conclude that in women with GDM, metformin alone or in combination with 1457-P glibenclamide is non-inferior to insulin in achieving glycemic control. More- Diagnosis of Gestational Diabetes: Falling Through the Net over; OHA is safe, more feasible and user friendly therapy for GDM. CLAIRE L. MEEK, HANNAH B. LEWIS, CHARLOTTE PATIENT, HELEN R. MURPHY, Supported By: Aga Khan University Hospital DAVID SIMMONS, Cambridge, United Kingdom Gestational diabetes (GDM) is associated with risks to mother and child 1455-P but globally agreed diagnostic criteria remain elusive. The aim of this study Placental-like Growth Factor (PlGF) and Infant Birth Weight in was to compare outcome data for women with antenatal 75g oral glucose Women with Preexisting Diabetes tolerance test (OGTT) results consistent with a diagnosis of GDM using the TAMARRA JAMES-TODD, ALLISON COHEN, JULIA WENGER, FLORENCE M. International Association of Diabetes in Pregnancy Study Group (IADPSG; BROWN, Boston, MA 0hr>5.1, 1hr>10.0, 2hr>8.5mmol/l)) or proposed National Institute for Clinical Women with preexisting type 1 or 2 diabetes have an increased risk of Excellence (NICE) 2015 criteria (0hr>5.6, 2hr>7.8mmol/l). delivering an infant with macrosomia or who is large-for-gestational age. Data from 25543 singleton births from 2004-2008 were obtained retro- While maternal hyperglycemia is involved, elevated glucose levels do not spectively from hospital obstetric records. Women were offered screening completely explain fetal overgrowth. Recent studies suggest placental-like with a random blood glucose (RBG) before 20 weeks’ gestation and a 50g growth factor (PlGF) may also be involved in fetal growth; however, few glucose challenge test at 26 weeks. If RBG was >7.0 mmol/l (126mg/dl) or studies have evaluated maternal PlGF levels and infant birth weight among GCT glucose >7.7 mmol/l (139mg/dl) or symptoms were present, an OGTT women with preexisting diabetes. was offered. Groups were compared to pregnancies where no OGTT was A total of 150 women were recruited from the Joslin Diabetes Center’s/ performed using logistic regression. Beth Israel Deaconess Medical Center’s Diabetes in Pregnancy Program. Women who fell through the net, testing negative for NICE but positive PlGF was measured up to 4 times across pregnancy from blood samples us- for IADPSG criteria (n=387) had a high risk of macrosomia (birth weight>90th ing a one-step immunoenzymatic “sandwich’ assay. Infant birth weight and percentile for gestational age; unadjusted OR (95% CI) 3.64 (2.91-4.56); covariate data were collected from medical records. Hemoglobin A1c was p<0.001), caesarean delivery (1.85 (1.51-2.28); p<0.001), pre-eclampsia (2.01 assessed from drawn blood samples. We used generalized linear models to (1.43-2.81); p<0.001) and polyhydramnios (7.13 (4.13-12.31); p<0.001) com- calculate the change in birth weight for every unit change in log-transformed pared to women who were negative for screening tests and had no OGTT

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(n=21695). Adjusting for maternal age, obesity, parity, ethnicity and smoking 0.01) and insulin use (2.92 [1.51, 5.64]; p= 0.001) also predicted an increased caused the risk of pre-eclampsia to become non-signifi cant but did not signif- risk of any placental vasculopathy in women with diabetes. icantly change other fi ndings. The highest risk of macrosomia was observed Maternal diabetes and placental vasculopathy are associated with CVD for women with a fasting blood glucose of 5.1-5.5mmol/l (92-99mg/dl; risk factors, specifi cally weight gain and insulin use. Further research on the n=167): 37.7% of these pregnancies were affected by macrosomia and a implications of the intersection of maternal diabetes, placental vasculopa- mean birth weight 350g higher than that of the reference population. thy, and CVD risk is warranted. This study demonstrates that women who ‘fall through the net’, testing Supported By: National Institutes of Health (1R03DK096152); Massachusetts positive for IADPSG criteria but not NICE-2015 criteria are at substantial risk General Hospital (to R.B-L.) of operative delivery and excess macrosomia. 1460-P 1458-P Association between History of Gestational Diabetes and Exclusive Gestational Diabetes: Should Two Abnormal Values Be Required for Breastfeeding at Hospital Discharge Diagnosis? ZELALEM HAILE, REENA OZA-FRANK, ILANA CHERTOK, Dublin, OH, Columbus, CLAIRE L. MEEK, HANNAH B. LEWIS, HELEN R. MURPHY, DAVID SIMMONS, Cam- OH, Morgantown, WV bridge, United Kingdom Exclusive breastfeeding is recommended in the fi rst 6 months of life, es- Gestational diabetes diagnosis is controversial. American College of Ob- pecially for infants born to women with a history of gestational diabetes stetrics and Gynaecology (ACOG) criteria require 2 abnormal values on 100g mellitus (GDM) because breastfeeding is associated with decreased risk of oral glucose tolerance test (OGTT) but International Association of Diabetes developing type 2 diabetes in both the mother and the infant. Yet, women with in Pregnancy Study Group (IADPSG) criteria require 1 abnormality on 75g a history of GDM face challenges with exclusive breastfeeding in the early OGTT. The study aim was to assess if women with only 1 IADPSG abnormal- postpartum period, a critical period for setting up longer-term breastfeeding ity are at excess risk of adverse pregnancy outcomes. success. Minimal research has been published on associated risk factors for Data from 25543 singleton births from 2004-2008 were obtained ret- not exclusively breastfeeding. The purpose of this study was to examine the rospectively from hospital obstetric records. Women were screened with association between GDM and exclusive breastfeeding at hospital discharge. random blood glucose (16 weeks), a 50g glucose challenge (26 weeks) fol- We conducted a cross-sectional analysis including 2,044 women who par- lowed by a 75g OGTT if abnormalities were present (n=3848). Women with ticipated in the population-based Infant Feeding Practices Study II between

an abnormal OGTT (IADPSG criteria; 0hr>5.1; 1hr>10.0; 2hr>8.5mmol/l) were May 2005 and June 2007. GDM prevalence was 5.8%. The crude prevalence POSTERS classifi ed according to the abnormal value(s) and timepoint at which they of exclusive breastfeeding at hospital discharge was 62.2% among women Therapeutics occurred (0hr; 1hr; 2hr; 0 & 1hr; 1 & 2hr; 0 & 2hr; 0,1 & 2hr). Groups were with GDM compared to 75.3% of women without GDM (p<0.01). After adjust- Clinical Diabetes/ compared to pregnancies with no OGTT using logistic regression. ing for sociodemographic, behavioral, and anthropometric factors, the odds Macrosomia (birth weight >90th percentile for gestational age) was high- of exclusive breastfeeding were lower among women with GDM compared est in women with an abnormal 0hr result alone (unadjusted odds ratio 5.32; to women without diabetes (odds ratio: 0.59; 95% confi dence interval 0.39, 95% confi dence interval 3.83-7.37; n=157) and an abnormal 0 and 1hr result 0.89). Furthermore, women who had inadequate gestational weight gain (5.16; 3.64-7.31; n=139). The risk of pre-eclampsia was highest with an abnor- (GWG; based on the 2009 Institute of Medicine guidelines) during pregnancy mal 0 and 1hr (3.55; 2.26-5.58) and abnormal 0 and 2hr (3.58; 1.37-9.38; n=30) had lower odds of exclusive breastfeeding compared to women who had ex- but was also signifi cantly elevated in women with an abnormal 0hr value cessive GWG (0.67; 0.51, 0.88). There was no signifi cant interaction between only (2.03; 1.21-3.42). Polyhydramnios risk was highest in women with abnor- GDM and GWG. Both GDM history and GWG appear to be independent risk mal 0 and 2hr values (12.63; 2.98-53.6) and an abnormal 1hr value only (10.33; factors for lack of exclusive breastfeeding at hospital discharge. Women with 6.22-17.17; n=326). Adjusting for maternal age, obesity, parity & smoking did GDM history and inadequate GWG may need additional education to promote not signifi cantly alter macrosomia or polyhydramnios risks. Criteria requir- exclusive breastfeeding. It is important for healthcare providers to assess ing 2 abnormal values failed to identify 5.2% (156/3010) macrosomia, 3.6% both factors in relation to education on exclusive breastfeeding and to support (53/1454) pre-eclampsia and 8.8% (25/283) polyhydramnios identifi ed with these women’s breastfeeding efforts in the early postpartum period. 1 abnormal result. Requiring 2 abnormal OGTT values fails to identify women at signifi cantly 1461-P elevated risk of avoidable adverse pregnancy outcomes. Ten-Year Postpartum Follow-up of Women with Diabetes Neph- ropathy 1459-P RAMAZ B. KURASHVILI, NATALIA G. ASATIANI, MZIA G. DUNDUA, ELENA L. Cardiovascular Disease Risk Factors in Maternal Diabetes Are As- SHELESTOVA, LIANA R. TSUTSKIRIDZE, Tbilisi, Georgia sociated with Placental Vasculopathy The aim of the present work was to assess results of ten-year post- JENNIFER HUYNH, CATHERINE C. BEAUHARNAIS, JULIA WENGER, RAVI THAD- partum follow-up of women with type 1 diabetes (T1DM) with micro- and HANI, DEBORAH J. WEXLER, DRUCILLA J. ROBERTS, RHONDA BENTLEY-LEWIS, macroalbuminuria. Boston, MA Materials and Methods: In total, 268 patients with T1DM were enrolled Women with maternal diabetes, including type 1 (T1DM), type 2 (T2DM), in the study. Based on albuminuria (NormA, MicrA, MacrA) levels in the 1st and gestational diabetes mellitus (GDM), have a greater prevalence of car- trimester women were separated into 3 groups (Gr.). Gr.1 - 191 women with diovascular disease (CVD) risk factors than women with normoglycemic NormA, Gr.2 - 65 women with MicrA, Gr.3 - 12 women with MacrA. Patients pregnancies. Additionally, a higher prevalence of placental vasculopathy has were supervised during their pregnancies, and repeated examinations were been reported among women with compared to women without diabetes in performed 10 years post-partum. pregnancy. However, the relationship between placental vasculopathy and Results: At entry HbA1c (%) levels for Gr.1, 2, 3 were: 6.6±1.04, 7.7±1.7, CVD risk factors in women with diabetes has not been elucidated. 6.74±1.6, respectively; by the end of the pregnancies they statistically de- We retrospectively analyzed the CVD risk profi les of pregnant women creased in all the groups (P=0.024, P=0.000, P=0.000, respectively). By term with (T1DM [n= 25], T2DM [n= 34], and biochemically-confi rmed GDM [n= 67]) MacrA was observed in 3.1% (Gr.1) and in 23.8% (Gr.2) of patients. In Gr.1 and without placental vasculopathy (T1DM [n= 11], T2DM [n= 3], and GDM patients percent of pre-eclampsia and preterm deliveries before 37 weeks [n= 62]) with self-reported race/ethnicity and live, full-term singleton births. of gestation was lower, than in Gr.2 and 3 (pre-eclampsia - P1-2=0.0003; P1- Placental vasculopathy included decidual and fetal thrombotic vasculopa- 3=0.0001; preterm deliveries P1-2=0.0001; P1-3=0.0001). Perinatal mortality thy, chorangiosis, and placental infarct. Odds ratios [OR; 95% CI] measured was registered in women from Gr.2 (3.08%) and Gr.3 (25.0%). Repeated ex- the univariate associations between placental vasculopathy and CVD risk aminations 10 years post-partum showed that HbA1c levels were statistically related factors, including age, body mass index, blood pressure, gestational higher, than at term: 8.8±1.5, Gr.1; 8.4±1.12, Gr.2, and 7.1±0.68, Gr.3. Kidney weight gain, non-white race, smoking, and insulin use. function indices worsened 10 years post-partum: Gr.1 - 26.1% of patients had Women with compared to those without placental vasculopathy had MicrA; Gr.2 - 76.5% of patients had MicrA, and 23.5% of patients had MacrA. greater gestational weight gain (24.1 ± 12.9 vs. 18.9 ± 12.4 kg; p= 0.01) and in- Nine patients from Gr.2 and 3 are on regular hemodialysis; three died of acute sulin use (43.8 vs. 21.1%; p= 0.001). Gestational weight gain (1.03 [1.00, 1.05]; renal failure, and in two patient kidney transplantation was performed. p= 0.03) and insulin use (OR [95% CI]: 3.37[1.81, 6.27]; p <0.001) predicted Conclusion: If MicrA or MacrA is present in the 1st trimester, pregnancy an increased risk of chorangiosis; non-white race (0.49 [0.28, 0.86]; p= 0.01) in T1DM patients increases the risk of perinatal mortality. Ten years post- predicted a decreased risk of chorangiosis. Weight gain (1.04 [1.01, 1.06]; p= partum kidney function signifi cantly deteriorates, including end-stage condi- tions, if pregnancy proceeded with MicroA and MacrA.

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1462-P 1464-P Principal Components Analysis of OGTT Data Refl ects Underlying Impact of Diabetes on Delivery Timing for Preeclampsia Pathophysiological Characteristics and the Risk for Developing AMY M. VALENT, CARRI WARSHAK, Cincinnati, OH Type 2 Diabetes in Females with Recent History of GDM Determine the frequency of preeclampsia (PEC) & the impact of delivery CHRISTIAN S. GÖBL, LATIFE BOZKURT, MARTINA MITTLBOECK, MICHAEL LEUT- timing in women with pre-gestational diabetes (PDM) & gestational diabe- NER, RAJASHRI YARRAGUDI, ANDREA TURA, GIOVANNI PACINI, ALEXANDRA tes (GDM) compared to women without diabetes (non-DM). Retrospective KAUTZKY-WILLER, Vienna, Austria, Padua, Italy cohort study of all singleton, non-anomalous live births at the U of Cincin- Introduction: Early re-examination of carbohydrate metabolism via an nati 2008-2011. Primary outcome compared PEC rates among GDM & PDM oral glucose tolerance test (OGTT) is recommended after pregnancy with compared non-DM pregnancies. Kaplan-Meier curves determined delivery gestational diabetes (GDM). In this report we aimed to assess the dominant estimates & hazard ratios of women with PEC & DM vs. non-DM. Logis- patterns of dynamic OGTT measurements and subsequently explained them tic regression estimated the OR of PEC, adjusting for signifi cant covariates. by meanings of the underlying pathophysiological processes. 6458 births were analyzed, 5886 (91.1%) non-DM, 416 (6.4%) GDM, & 156 Methods: Principal components analysis (PCA), was performed on 151 (2.4%) PDM. DM women were likely older, cHTN, CS delivery, & have higher women (including dynamics of glucose, insulin and C-peptide in addition to BMI, birth wt, & NICU admits. DM pregnancies had higher PEC rates than age and BMI of n=110 females after GDM and n=41 controls at 3-6 month non-DM (16.8 vs. 8.0%, p<0.001). GDM had signifi cantly higher rates even after delivery), aiming to reduce the dimensionality of this large number after adjusting for relevant confounders, aOR 1.26 [95% CI 1.08-1.47]. PDM of correlated variables to a fewer number of uncorrelated parameters (i.e. did not have signifi cantly ↑ PEC frequencies after estimate adjustment, aOR principal components), explaining most of the variation. These components 1.20 [95% CI 0.96-1.50]. Compared to non-DM women, DM pregnancies ↑ were explained by frequently-sampled-intravenous-glucose-tolerance-test the delivery risk for PEC at >32 wks by 45%, HR 1.45 [95% CI 1.09-1.93], but (FSIGT) parameters. Moreover, their relation with the later development of did not ↑ the risk of delivery for PEC at <32 wks, HR 1.08 [95% CI 0.54-2.16]. overt diabetes was studied. DM has been recognized to ↑ the risk of PEC, but our study does not show an Results: Three principal components (PC) were identifi ed, which explained ↑ risk of delivery <32 wks with the associated early preterm morbidity. DM 71.5% of the variation of the original 17 variables. PC1 (explained 47.1%) does ↑ the risk of delivery for PEC in the late preterm period, likely contribut- was closely related to postprandial OGTT levels and FSIGT derived insulin ing to ↑ NICU admissions. sensitivity (r=0.68), indicating that it mirrors insulin sensitivity in the skeletal muscle. PC2 (explained 17.3%) and PC3 (explained 7.1%) were shown to be POSTERS Therapeutics associated with β-cell failure and fasting (i.e. hepatic) insulin resistance, Clinical Diabetes/ respectively. All three components were independently related with diabe- tes progression in females after GDM and showed signifi cant changes in long-term trajectories. Conclusion: A high amount of the postpartum OGTT data is explained by principal components, representing pathophysiologic mechanisms on the pathway of impaired carbohydrate metabolism. Our results improve our understanding of the underlying biologic processes to provide an accurate postgestational risk stratifi cation. Supported By: Austrian Science Fund (P14515-MED to A.K-W.)

1463-P Relationship of Circulating Adiponectin and Resistin Levels with Excessive Gestational Weight Gain and Fetal Overgrowth in Nor- mal Pregnant Women XINHUA CHEN, THERESA O. SCHOLL, Stratford, NJ Adiponectin and resistin are adipokines that have opposing roles for the infl ammatory response. Excessive gestational weight gain (GWG) increases 1465-P risk of fetal overgrowth (large-for-gestational age, LGA). We examined the Placental Pathologic Changes in Women with Gestational Diabetes relationship between maternal serum adiponectin and resistin levels with Refl ect Those Observed in Type 2 Diabetes excessive GWG during early and late pregnancy. JENNIFER HUYNH, CATHERINE C. BEAUHARNAIS, JULIA WENGER, RAVI THAD- Pregnant women (n=2,028) were enrolled to a prospective cohort study HANI, DEBORAH J. WEXLER, DRUCILLA J. ROBERTS, RHONDA BENTLEY-LEWIS, (African-American 37%, Hispanic 48%, Caucasian 15%, age 22.0±5.2 (yr.), Boston, MA pregravid BMI (kg/m2) 25.7±6.3). Serum adiponectin and resistin were as- During a pregnancy complicated by diabetes, the human placenta under- sayed at entry (week 16) and the 3rd trimester (week 30) by multiplex on the goes a number of functional and structural pathologic changes. However, Magpix system using Luminex xMAP technology. Adequate, inadequate and pathologic fi ndings reported have differed among studies, potentially re- excessive GWG were assessed longitudinally during pregnancy by using the fl ecting pathophysiologic differences among types of diabetes. 2009 Institute of Medicine guidelines. We retrospectively analyzed women with pregestational (type 1 [T1DM]; Data were analyzed by multivariable analysis after controlling for age, n=36 and type 2 [T2DM]; n=37) and biochemically-confi rmed gestational dia- BMI, parity, cigarette smoking and ethnicity. betes mellitus (GDM; n=129) with self-reported race/ethnicity and live, full- Women with excessive GWG at delivery had signifi cantly decreased term, singleton births. Clinical data were abstracted from medical records. adiponectin (ug/ml) (14.17±0.27) as compared to those who had adequate Placental diagnoses were established by examination by one of 4 perinatal (15.4±0.37) and/or inadequate (15.9±0.42) GWG (p<0.05-p<0.001). The re- pathologists and confi rmed by DJR. Placental diagnoses included decidual sults were consistent for GWG assessed at weeks 24, 28 and 32 (p<0.01 to vasculopathy, villous immaturity, chorangiosis, and placental infarcts. Inde- p<0.001 for each). In contrast, resistin levels were signifi cantly increased in pendent samples t and chi-square tests were used for between group com- women with excessive GWG at delivery (ng/ml) (50.30±0.87) vs. adequate parisons; data are presented as mean ± SD or percentages. (45.92±1.17, p<0.001) and inadequate GWG (45.86±1.34, p<0.01). Excessive Women with T1DM compared to women with either T2DM or GDM had GWG is associated with risk of LGA (adjusted odds ratio (AOR) 2.23, 95% higher gestational weight gain (T2DM: 28.5 ± 12.4 vs. 20.5 ± 13.4 kg; p=0.03 or confi dence interval (CI) 1.34-3.69). Risk was moderately increased after ad- GDM: 21.3 ± 12.7 kg; p=0.008), 1st trimester systolic blood pressure (T2DM: ditionally including high resistin (AOR 2.93, 95% CI 1.60-5.39) or low adi- 123.9 ± 12.3 vs. 108.5 ± 13.4 mmHg; p= 0.008 or GDM: 111.6 ± 12.0 mmHg; ponectin (AOR 2.93, 95% CI 1.59-5.38) in the models. The observations of p <0.001), and insulin use (T2DM: 100.0 vs. 85.3%; p=0.02 or GDM: 3.9%; the opposing associations between adiponectin and resistin with excessive p<0.001); but lower frequency of non-white race (T2DM: 25.0 vs. 67.6%; GWG in normal pregnancies suggest that adipokines may have an important p <0.001 or GDM: 62.8 %; p<0.001). There was a similarly higher prevalence infl uence on GWG and an indirect impact on the fetal overgrowth. of placental infarcts among placentas from women with GDM (15.5 vs. 2.8%; Supported By: National Institutes of Health p=0.04) and T2DM (24.3; p= 0.04) compared with T1DM. However, placen- tas from women with T2DM compared to GDM had higher rates of decidual vasculopathy (8.3 vs. 1.6%; p=0.04) and chorangiosis (77.8 vs. 38%; p< 0.001) but a lower rate of villous immaturity (10.8 vs. 90.7%; p< 0.001).

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A380 PREGNANCY—CLINICAL

Placental pathology differs according to maternal diabetes type, poten- 3.7, 95% CI: 1.3-10.3) but less likely to continue to breastfeed (OR: 0.49; 95% tially refl ecting underlying disease mechanism. Further research on the rela- CI: 0.24-0.99). There were no other differences in breastfeeding initiation or tionship between placental and metabolic derangements is warranted. continuation by weight class and receipt of education. Supported By: National Institutes of Health (1R03DK096152); Massachusetts Reported receipt of prenatal breastfeeding education did not have an im- General Hospital (to R.B-L.) pact on breastfeeding initiation or continuation among women with recent GDM, except among class III obese women. Additional research is needed to 1466-P determine the optimal strategies to promote breastfeeding among women Can Women with Gestational Diabetes (GDM) Be Screened Immedi- with recent GDM. ately Postpartum for Diabetes Mellitus (DM)? THADDEUS P. WATERS, SHIN Y. KIM, ANDREA J. SHARMA, PAMALA SCHNEL- 1468-P LINGER, DENINE RYAN, JANET K. BOBO, ROBERT WOODRUFF, LISA CUBBINS, Undercarboxylated Osteocalcin Is Increased in Insulin-Resistant MARY HAGIAC, JUDY MINIUM, LARRAINE PRESLEY, HONOR WOLFE, SYLVIE Patients and Is Related to Enhanced Insulin Secretion during HAUGUEL-DE MOUZON, PATRICK M. CATALANO, Maywood, IL, Atlanta, GA, Cleve- Pregnancy land, OH, Seattle, WA KANAKO HORIE, YOSHIFUMI SUZUKI, YUKIE SAKUMA, SATOKO SAITO, NORIKO Less than half of women with GDM are screened for DM postpartum YOSHIDA, CHIHIRO YONEDA, SAYAKA FUKUSHIMA, TAKENORI HARUKI, JUN (PP). We assessed the performance of an oral glucose tolerance test (OGTT) OGINO, NAOTAKE HASHIMOTO, Chiba, Japan, Asahi, Japan, Yachiyo, Japan administered during delivery hospitalization (PP1) compared to the 6-week Insulin resistance, an important cause of gestational diabetes (GD), in- postpartum visit (PP2). creases during pregnancy and is associated with placental hormones, certain We conducted a prospective observational study of 61 women with GDM cytokines, and adipokines. GD results from an imbalance between increas- who delivered a singleton live birth >34 weeks, had no preexisting DM, and ing insulin resistance and enhanced insulin secretion. There is increasing had no PP infection or use of glucose control medication. Subjects under- evidence that undercarboxylated osteocalcin (unOC), an osteoblast-secreted went a 75g OGTT at 2-3 days and 6-12 weeks PP. Sensitivity, specifi city, protein, can enhance both insulin secretion and sensitivity in animal models. negative (NPV) and positive predictive (PPV) values of the PP1 test were es- The aim of our study was to investigate the relationships between unOC, timated for diagnosis of DM and any abnormality (impaired fasting glucose, adiponectin (AN) which is considered to be closely associated with insulin impaired glucose tolerance, or DM). Through logistic regression models, we sensitivity, and insulin secretion levels in pregnant women. This analysis

examined the ROC curve and effect modifi cation by glucose control medica- included 40 pregnant participants: 16 women with normal glucose toler- POSTERS tion use during pregnancy. ance (NG) and 24 women with GD, based on a standard 75g OGTT. Blood Therapeutics Among women who completed both OGTTs (n=61), 58% were obese and analyses, including unOC and AN, were performed in the last trimester. Clinical Diabetes/ 46% required glucose control medication during pregnancy. OGTTs were The women with GD had an increased family history of GD (p=0.0029), in- completed on average 2.1 days (1-5) for PP1 and 55.6 days (42-90) for PP2. creased pre-pregnancy BMI (GD=25.8±6.3; NG=21.0±2.7 kg/m²; p=0.0065), Table 1 presents performance of the OGTT at PP1. Effect modifi cation was elevated HbA1c (GD=5.6±0.3; NG=5.2±0.4%; p=0.0002), and lower AN levels not signifi cant (p=0.39) and the adjusted model C-statistic was 0.75. (GD=6.55±3.30; NG=10.83±4.92 µg/ml; p=0.0021). UnOC levels and the post- Whereas our sample size was small, the NPV of an OGTT during the deliv- prandial C-peptide index (p-CPI) did not differ in both groups. UnOC levels ery hospitalization indicates the potential to rule out DM in most women with were inversely correlated with AN levels in the whole study group (r=-0.366, GDM and signifi cantly reduce the number needing an OGTT at 6 weeks PP. p=0.0197), in the women with NG (r=-0.511, p=0.0421) and in the women Table 1. Performance of an OGTT at Delivery (PP1) Compared to 6 Weeks with GD (r=-0.576, p=0.0026). Furthermore unOC levels were positively re- Post Partum (PP2). lated to p-CPI in the whole study group (r=0.427, p=0.0055) and in the women with NG (r=0.566, p=0.0208), whereas no difference was observed in the Diabetes Any abnormal (DM, IFG or IGT) women with GD (r=0.100, p=0.6456). Our results suggest that unOC, which might be elevated by decreased AN levels through unknown mechanisms, Sample size % (95% CI)* Sample size % (95% CI)* can enhance insulin secretion in insulin-resistant patients during pregnancy. Sensitivity 0/0 N/A 20/28 71.4 (52.8, 84.9) The change in this balance of unOC, AN, and insulin molecules may be as- Specifi city 59/61 96.7 (88.2, 99.8) 19/33 57.6 (40.8, 72.8) sociated with an increased risk of developing GD. Positive Predictive Value 0/2 0 (0, 70.9) 20/34 58.8 (42.2, 73.7) Negative Predictive Value 59/59 100 (92.7, 100) 19/27 70.4 (51.3, 84.3) 1469-P Prevalent Gestational Diabetes Mellitus in HIV-Infected and -Unin- DM=Diabetes Mellitus; IFG=Impaired Fasting Glucose; IGT=Impaired Glu- fected Pregnant Women Living in Sub-Saharan Africa cose Tolerance; *Agresti-Coull interval approximation. NICOLA NAPOLI, FRANCESCA MAZZANTI, EGLE GIAMBRA, ROCKY STROLLO, Supported By: Centers for Disease Control and Prevention GIOVANNI MOTTINI, PAOLO POZZILLI, Rome, Italy Limited data are available for gestational diabetes (GD) in both pregnant 1467-P HIV-infected and -uninfected women. cART, a widely used combination of Effect of Prenatal Education on Breastfeeding Initiation and Con- antiretroviral medications, may cause glucose intolerance or diabetes. With tinuation among Women with Recent Gestational Diabetes more than 25 million HIV+ treated patients in Sub-Saharan Africa, diabetes, RASHMI KACHORIA, REENA OZA-FRANK, Columbus, OH often a neglected condition in this context, may become a new burden for Prior research indicates that prenatal breastfeeding education has a posi- health care in these countries. We evaluated GD in both HIV+ and non-HIV tive impact on breastfeeding initiation. However, if this is also true among pregnant women in Tanza nia, Congo and Uganda. women with recent gestational diabetes mellitus (GDM) remains unknown. We enrolled 289 consecutive adult HIV+ pregnant women (24-28 The objective of this study was to explore the relationship between prenatal weeks’gestational age) treated with cART and 1669 non-HIV+ pregnant breastfeeding education and breastfeeding initiation and continuation at 8 women, attending to rural hospitals in Tanzania (Dodoma area), Congo (Kin- weeks, among women with recent GDM. Data are from the Pregnancy Risk shasa district), Uganda (Gulu area). Gestational diabetes was diagnosed ac- Assessment Monitoring System (2009-2011) from 30 states and New York cording to ADA criteria. Eating habits were analysed through a validated City. Among women with recent GDM, multivariable logistic regression and questionnaire and anthropometric parameters were also collected. χ2 tests were used to test differences in breastfeeding initiation and con- Mean age of cART treated patients was 26.2±5.1 y.o vs. 27.5±3.6 in not tinuation at 8 weeks of women who did/did not report a healthcare worker treated ones (P, NS). Caloric intake in the cART patients (1,952 Kcal daily, talking about breastfeeding during a prenatal visit. Because breastfeeding 15.36% protein, 25.50% lipid and 59.15% carbohydrates) did not differ with initiation and continuation decrease as prepregnancy body mass index (BMI) non-cART ones. 4.89% of patients on cART had GD compared with 1.8% of increases, analyses were stratifi ed by BMI class. Among 7,891 women with subjects not on cART (p<0.001). Both systolic and diastolic blood pressure recent GDM, 35% were normal weight, 28% overweight, 18% obese class was higher in cART vs. non cART (121.3±3.4 vs. 116.4±3.1 mmHg, P=0.01 and I, 10% obese class II and 9% obese class III. Reported receipt of educa- 84.2±2.8 vs. 76.7±3.5 mmHg, P=0.03, respectively). tion ranged from 84%-86%, with no signifi cant difference by weight class. In conclusion our data support the increasing concern for GD in developing Among obese class III women, those who reported receiving education were countries. Higher risk of GD is observed mostly in those women treated with more likely to initiate breastfeeding than those who did not report receiv- cART. Considering the easier access to treatment and longer survival to disease ing education (77% vs. 52%, p=0.01). In adjusted analyses, obese class III in HIV+ patients, a multifaceted health intervention should be implemented. women who reported receiving education were more likely to initiate (OR: Supported By: Farmindustria for “Africa Together” Project

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A381 EPIDEMIOLOGY—AGINGCATEGORY

1470-P time is indeed benefi cial for metabolism of overweight and obese pregnant Correlation of Serum Folate Levels with Glucose Levels in Gesta- women needs to be assessed in further studies. tional Diabetes Mellitus (GDM) in Relation to Vitamin B12 Levels MAY O.O. KHIN, SIMON GATES, PONNUSAMY SARAVANAN, Coventry, United Kingdom EPIDEMIOLOGY—AGING In non-pregnant type 2 diabetes, high serum folate levels have adverse effects on metabolic markers in vitamin B12 defi cient setting, whereas folic acid supplementation can improve glycaemic control in some patients. Guided Audio Tour: Diabetes and Aging—It’s All the Rage! (Posters: 1472-P This study aims to examine the association between serum folate levels to 1479-P), see page 15. and plasma glucose levels in normal and insuffi cient B12 (<150pmol/l) GDM. This retrospective study included GDM identifi ed between 2009-2012 in a & 1472-P district general hospital, UK. All GDM received folic acid (40ug/day) as rou- Disability-Free Life-Years Lost due to Diabetes Mellitus among tine antenatal care. Serum folate, B12 and homocysteine were measured at Older U.S. Adults 24-28 weeks and compared with glucose levels at diagnostic and postpar- BARBARA BARDENHEIER, JI LIN, XIAOHUI ZHUO, MOHAMMED K. ALI, TED tum OGTT. THOMPSON, EDWARD W. GREGG, Atlanta, GA, North Wales, PA Total of 188 pregnancy included, 60 GDM (31.9%) were B12 defi cient and 31 Increases in diabetes incidence and life expectancy among the diabetes GDM (17%) had high folate levels (>16ug/l). In both normal and B12 defi cient population have led to an increase in the number of years spent with diabe- GDM, plasma homocysteine had signifi cant negative correlation with folate tes. However, the effect of diabetes on the quality of those extra years is (r=-0.38 vs. r=-0.44), and not B12 levels. There was a signifi cant inverse as- unknown. sociation between serum folate and fasting glucose levels at both diagnostic We analyzed longitudinal data from the Health and Retirement Study and postpartum OGTT. The association was signifi cant in normal B12 GDM and modeled disability-free life-years lost due to diabetes over a lifetime and not B12 defi ciency, and was independent of age, BMI and parity. in the United States. We estimated incidence of disability, remission from Our fi ndings suggest that the effects of serum folate levels on fasting disability, and mortality by self-reported diabetes status among 11,141 glucose levels may differ by vitamin B12 status and highlight the importance adults aged > 50 years with baseline years of 1998 and 2004, followed to of normal vitamin B12 levels for folate to act on glycaemic levels. 2010. Three measures of disability were examined: severe functional de- Table. Pearson’s Correlation-Plasma Glucose Correlates with Serum Folate cline (mobility), some diffi culty with >1 instrumental activities of daily liv- Levels. ing (IADL), and some diffi culty with >1 activities of daily living (ADL). Using All GDM Normal B12GDM B12 insuffi cient GDM these estimates, we developed a discrete-time fi ve state Markov model to estimate the numbers of years with and without disability by baseline age mid-pregnancy Postpartum mid-pregnancy Postpartum mid-pregnancy Postpartum and diabetes status. From ages 50 and 60 for all 3 disability defi nitions, (n=188) (n=67) (n=128) (n=45) (n=60) (n=22) diabetes was signifi cantly associated (p<0.05) with earlier average age of fasting -0.17(<0.05) -0.26(<0.05) -0.19(<0.05) -0.36(<0.01) -0.08 (NS) -0.02(NS) disability onset, reduced total years of life and reduced disability-free life 2hr postprandial -0.14(<0.05) -0.14(NS) -0.18(<0.05) -0.20 (NS) -0.02(NS) -0.08(NS) years. Compared to those without diabetics, from age 50 men have 1.5 to BMI -0.23(<0.01) -0.29(<0.01) -0.04(NS) 2.2 more disabled years for all 3 disability measures and women have 3.5 Genetics

POSTERS more mobility loss disabled years and 2.6 more ADL disabled years. From

Epidemiology/ Multiple regression for fasting glucose age 50, men with diabetes have 6-7 years earlier onset of disability (mobil- All GDM Normal B12GDM B12 insuffi cient GDM ity, IADL, ADL) than non-diabetic men, 2-4 fewer total years of remaining folate mid-pregnancy Postpartum mid-pregnancy Postpartum mid-pregnancy Postpartum life, and have 6-7 fewer disability-free total years of life. From age 50, (n=188) (n=67) (n=128) (n=45) (n=60) (n=22) women with diabetes have a 7-8 year earlier onset of disability (mobility, β -0.04(<0.05) -0.04(<0.05) -0.04(<0.05) -0.06(<0.05) -0.01(NS) -0.003(NS) IADL, ADL) than non-diabetic women, 2-4.5 fewer total years of remain- ing life, and have 6-7 fewer disability-free total years of life. This study Adjusted β -0.03(<0.05) -0.05(<0.05) -0.04(<0.05) -0.07(<0.01) -0.01(NS) -0.007(NS) (Age,BMI,Parity) suggests diabetes reduces the quality of life of adults by exposing them to disability at earlier ages and reducing disability-free years remaining NS=Not Signifi cant. compared to adults without diabetes.

1471-P & 1473-P Sedentary Behavior Is Associated with Improved Cytokine Pro- Incidence of Mobility Loss and Subsequent Recovery by Diabetes fi le but Not with Glucose or Lipid Metabolism in Obese Pregnant Status, 1998-2010 Women BARBARA BARDENHEIER, JI LIN, XIAOHUI ZHUO, MOHAMMED K. ALI, TED MIREILLE VAN POPPEL, MINAKSHI NAYAK, AKOS HEINEMANN, MIRIAM PEIN- THOMPSON, EDWARD W. GREGG, Atlanta, GA, North Wales, PA HAUPT, GERNOT DESOYE, Graz, Austria, Amsterdam, Netherlands Few studies have quantifi ed the incidence of mobility loss or subsequent Sedentary behavior is an independent risk factor for the metabolic syn- recovery associated with diabetes. We used generalized estimating equa- drome, but the role of sedentary behavior in the development of gestational tions to analyze prospective data from the Health and Retirement study, a diabetes is unclear. U.S. population-based sample of 11,141 adults aged > 50 years with biennial This longitudinal cohort study tested the hypothesis that less sedentary visits from 1998 through 2010. Compared to non-diabetic persons, incidence behavior is related to better insulin sensitivity, lipid and cytokine profi le in of mobility loss was 75% higher (p<0.05) for diabetic men (24.1 vs. 13.8 per obese pregnant women. 1000 PY) and 83% for diabetic women (34.6 vs. 18.9 per 1000 PY). [Figure Among 46 overweight and obese pregnant women, fasting blood was 1] Recovery from incident mobility loss was lower for those with diabetes taken at 15, 24 and 32 weeks of gestation, and a 100 g oral glucose tolerance than without, but was similar by sex (226.4 for non-diabetic women, 244.5 test was performed at 24 and 32 weeks. Fasting levels of glucose, insulin, to- for non-diabetic men, 220.0 for diabetic women, 210.8 for diabetic men per tal cholesterol, HDL, LDL, triglycerides were measured, as well as cytokines. 1,000 PY). [Figure 2] Incident mobility loss was higher among diabetic women Insulin sensitivity, fi rst and second phase insulin response were calculated. than men, with little difference in recovery. Sedentary behavior was measured objectively using accelerometers. The relationship between sedentary behavior and metabolic outcomes were as- sessed using linear regression analysis. Women spent about 60% of their time sitting throughout pregnancy. In cross sectional analyses, an association of sedentary time at 15 and 24 weeks with increased total cholesterol and HDL was found. Changes in sedentary time were not associated with glucose metabolic or other lipid outcomes, but increased sedentary time was associated with lower CRP and leptin levels, and with higher adiponectin levels at 32 weeks of pregnancy. In conclusion, no consistent longitudinal relationship between sedentary habits of obese and overweight pregnant women with glucose or lipid me- tabolism was found. Increases in time spent sedentary in pregnancy were associated with improved cytokine profi le. Whether increasing sedentary

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