Diabetes Care Volume 39, July 2016 1127 RIIILPANCREAS ARTIFICIAL

Jennifer L. Sherr, Neha S. Patel, Mitigating Meal-Related Glycemic Camille I. Michaud, Miladys M. Palau-Collazo, Excursions in an Insulin-Sparing Michelle A. Van Name, William V. Tamborlane, Eda Cengiz, Manner During Closed-Loop Lori R. Carria, Eileen M. Tichy, and Insulin Delivery: The Beneficial Stuart A. Weinzimer Effects of Adjunctive Pramlintide and Liraglutide Diabetes Care 2016;39:1127–1134 | DOI: 10.2337/dc16-0089

OBJECTIVE Closed-loop (CL) insulin delivery effectively maintains glucose overnight but struggles when challenged with meals. Use of single-day, 30-mg/meal pramlintide lowers meal excursions during CL. We sought to further elucidate the potential benefits of adjunctive agents after 3–4 weeks of outpatient dose titration.

RESEARCH DESIGN AND METHODS Two CL studies were conducted: one evaluating adjunctive pramlintide and the other liraglutide. Ten subjects (age 16–23 years; A1C 7.2 6 0.6% [55 6 6.6 mmol/mol]) completed two 24-h sessions: one on CL alone and one on CL plus 60-mgpramlintide (CL + P), after a 3–4-week outpatient dose escalation. Eleven subjects (age 18–27 years; A1C 7.5 6 0.9% [58 6 9.8 mmol/mol]) were studied before and after treat- ment with 1.8 mg liraglutide (CL + L) after a similar 3–4-week dose escalation period. Timing and content of meals during CL were identical within experiments; meals were not announced.

RESULTS Pramlintide delayed the time to peak plasma glucose (PG) excursion (CL 1.6 6 0.5 h Yale School of Medicine, New Haven, CT vs. CL + P 2.6 6 0.9 h, P < 0.001) with concomitant blunting of peak postprandial Corresponding author: Jennifer L. Sherr, jennifer. increments in PG (P < 0.0001) and reductions in postmeal incremental PG area [email protected]. under the curve (AUC) (P = 0.0002). CL + L also led to reductions in PG excursions Received 13 January 2016 and accepted 11 April 2016. (P = 0.05) and incremental PG AUC (P = 0.004), with a 28% reduction in prandial 6 Clinical trial reg. no. NCT01856790, clinicaltrials insulin delivery. Outpatient liraglutide therapy led to a weight loss of 3.2 1.8 kg, .gov. with a 26% reduction in total daily insulin dose. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is CONCLUSIONS properly cited, the use is educational and not for Adjunctive pramlintide and liraglutide treatment mitigated postprandial hyper- profit, and the work is not altered. glycemia during CL control; liraglutide demonstrated the additional benefitof See accompanying articles, pp. 1123, weight loss in an insulin-sparing manner. Further investigations of these and other 1135, 1143, 1151, 1161, 1168, 1175, adjunctive agents in long-term outpatient CL studies are needed. and 1180. 1128 Adjunctive Therapy During Closed-Loop Control Diabetes Care Volume 39, July 2016

Although the idea of closed-loop (CL) plasma glucagon levels. In eight partici- and participant assent were also obtained insulin delivery has been around for at pants, the use of adjunctive treatment for those between age 15 and 18 years. least half a century (1,2), the introduction with pramlintide 30 mg/meal was associ- Participants were recruited from the Yale of transcutaneous real-time continuous ated with a consistent 60-min delay in Children’s Diabetes Program and through glucose monitoring devices in combina- time to peak postprandial blood glu- local advertising. tion with computerized control algo- cose levels (19). Despite these delays in rithms and insulin pumps has turned carbohydrate absorption, peak postpran- Eligibility Criteria this dream into a reality. The past decade dial glucose concentrations were re- Participants for both studies met the fol- has seen a large number of closely super- duced by only 25 mg/dL, and 37% lowing eligibility criteria: clinical diagno- vised inpatient clinical research center of daytime glucose concentrations sis of type 1 diabetes of at least 1 year’s studies demonstrating the feasibility of remained .180 mg/dL (19). duration and use of insulin pump ther- automated insulin delivery systems that The modest benefit of pramlintide in apy for at least 3 months; A1C #9% allow for more targeted glycemic control our first study may have been due to the (#75 mmol/mol); normal hematocrit while reducing patient burden (3–13). low dose used in these drug-naive sub- and serum creatinine level; no history Moreover, as described in a number of jects as well as the single-day exposure of eating disorders, celiac disease, gas- articles in this special issue of Diabetes to the drug. We hypothesized that a troparesis, or other disorder of intesti- Care (14–18), these systems have now longer outpatient treatment period of nal absorption or motility; no history moved out of clinical research centers 3–4 weeks during which pramlintide is of hypoglycemic seizures in the past to experimental, unsupervised use at titrated up to the full therapeutic dose 3 months; no other chronic medical home in patients with type 1 diabetes. of 60 mg before each meal would result condition (except treated hypothyroid- Despite the remarkable progress that in an even greater mitigation of prandial ism); no current use of medications has been made in developing artificial glycemic excursions compared with CL (other than insulin) known to affect blood pancreas systems, issues with post- alone. Because GLP-1 agonists have glucose level or GI motility, and no prior prandial hyperglycemia remain. These been shown to suppress glucagon secre- adverse reactions to the adjunctive agent problems are primarily due to delays in tion and to reduce appetite through cen- under study. Female participants could not absorption of insulin from the subcutane- tral action (20), we concurrently explored be pregnant or lactating. ous site of insulin infusion and because whether liraglutide might provide an- For the pramlintide trial, participants the algorithm drags out the meal bolus other approach to lowering postmeal needed to be between 15–30 years old, over a period of 2–3 h during fully auto- glucose excursions during CL insulin have a BMI ,95% for age and sex, and mated glucose control. We demonstrated delivery when titrated to its full thera- weight $40 kg. Eligible participants in the effectiveness of hybrid CL control (4) peutic dose (i.e., 1.8 mg given once daily) the liraglutide study were aged 18–40 in which part of the insulin required to over a 3–4-week period. In view of the years with a body weight .50 kg; no cover the carbohydrate content of a meal similarities in the two study designs, in- history of pancreatitis, gallstones, alcohol- is provided through a manual bolus cluding the use of the same fully auto- ism, or high triglyceride levels; and no dose, but this approach adds to the bur- mated CL system, the results of these personal or family history of thyroid cancer den on patients and is subject to human two experiments are presented here. on multiple endocrine neoplasia type 2. error. Accelerating the rate of absorption of insulin might help to lessen the degree Study Design RESEARCH DESIGN AND METHODS This article describes two separate studies of postprandial hyperglycemia but may Both studies were reviewed and ap- of similar design that used two separate require an alternate site of insulin de- proved by the Yale University Human In- groups of subjects that received two sep- livery, such as the peritoneum. Use of vestigation Committee. After a complete arate adjunctive drug treatments. In both noninsulin adjunctive agents, including explanation of study procedures, written studies, CL system performance was ini- new drugs that have been approved for informed consent was obtained for par- tially assessed before adjunctive drug use in type 2 diabetes, provides another ticipants $18 years of age. For the pram- treatment. Results of the baseline pre- approach to improve postprandial glucose lintide study, written parental permission treatment studies were compared with control during open-loop and CL insulin delivery in type 1 diabetes. We first explored the use of pramlintide Table 1—Macronutrient content of meals during CL experiments as a potential adjunctive therapy to re- Macronutrient content of meals (g) duce postprandial hyperglycemia during 24 h of CL insulin delivery without man- Carbohydrate Protein Fat ual premeal priming doses of insulin Pramlintide (19). Pramlintide is an analog of the nat- Breakfast 67.4 6 23.2 21.8 6 7.7 16.4 6 7.9 urally occurring peptide amylin, which Lunch 78.2 6 20.8 26.5 6 13.3 33.4 6 8.3 6 6 6 has beneficial effects on diabetes control Dinner 84.0 28.8 32.5 13.4 27.6 16.0 believed to occur in two ways: 1)byslow- Liraglutide Breakfast 75.2 6 49.1 24.0 6 16.3 16.9 6 13.6 ing carbohydrate appearance by delaying Lunch 78.4 6 26.9 26.4 6 15.8 32.3 6 13.5 gastric emptying and enabling a better Dinner 87.8 6 31.1 35.0 6 15.6 35.3 6 15.4 match with insulin absorption and 2)by Data are mean 6 SD. lowering meal-stimulated increases in care.diabetesjournals.org Sherr and Associates 1129

CL system performance after 3–4 weeks of Medtronic). The total daily insulin doses Paradigm 715 insulin pump, a Medtronic outpatient adjunctive drug treatment. that the participant had received over MiniLink REAL-Time transmitter (MMT- Thus, each study involved baseline versus the past 3, 7, and 14 days were recorded; 7703) adapted for 1-min transmission, a on-treatment paired comparisons for each these data along with the preprogrammed Medtronic continuous glucose sensor drug separately, with one group receiving open-loop basal rate were used to ad- (Sof-sensor in the pramlintide study and pramlintide and the other liraglutide. The just the algorithm. An intravenous cath- Enlite sensor in the liraglutide study), studies were not designed or powered to eterwasplacedintoanarmveinto and the Medtronic external physiological compare the effects of pramlintide and facilitate frequent blood sampling. insulin delivery algorithm. Algorithm cal- liraglutide with each other. After dinner on study day 1, a run-in culations were performed on a laptop In both studies, study staff maintained period of CL control was initiated at computer that received the glucose frequent telephone contact with the par- ;9:00 P.M. to achieve stable target glucose sensor signal each minute from a radio- ticipants during the outpatient open-loop levels at the start of the CL data collection frequency transmitter and delivered treatment phase to titrate doses of pram- the next morning (8:00 A.M.). During the insulin commands to the pump by radio- lintide to 60 mg/meal and liraglutide to 24-h CL control observation period, partic- frequency signaling. The external phy- 1.8 mg/day and to adjust insulin doses as ipants were free to move about their room siological insulin delivery controller needed. During these contacts, partici- and hallway. uses a proportional-integral-derivative pants were asked about potential adverse algorithm modified to include insulin effects from the adjunctive therapy. During System Considerations feedback, which has been extensively the second CL admission, pramlintide was TheCLsystemusedinthisstudycon- described (21,22). CL target glucose level administered 15 min before each meal, sisted of four components: a Medtronic was set to 120 mg/dL for the pramlintide whereas liraglutide 1.8 mg was adminis- tered once daily at 8:00 A.M. with the start of breakfast. After the second CL admis- sion, study staff aided participants with dis- continuation of adjunctive therapy and subsequent readjustment of insulin doses.

Study Outcomes The primary outcome in both studies was the change in meal-stimulated plasma glucose excursions during CL control as re- flected by changes in the peak increment in plasma glucose levels above premeal values as well as the area under the incre- mental glucose response curve for 5 h af- tereachmeal.OtheroutcomesduringCL control were changes in time to peak post- prandial glucose levels and the amount of insulin delivered for each meal. Safety outcomes were the number of hypogly- cemic events with plasma glucose ,60 mg/dL and other adverse events. Out- comes of interest during the open- loop treatment phase were changes in insulin doses and body weight. Safety issues included tolerability of higher drug doses and the occurrence of adverse events.

Participant Preparation for CL Studies In both studies and on both occasions within each study, participants were admitted to the clinical research center in the midafternoon on study day 1 to allow for initialization of the CL system. Two continuous glucose sensors (the study sensor and a backup sensor) were inserted and calibrated, a new insulin infusion set was placed, and the partic- Figure 1—Glucose profiles during control and adjunctive therapy conditions. A: Pramlintide 120 mg/dL. ipant’s usual insulin pump was replaced B: Liraglutide 100 mg/dL. The red line denotes 60 mg/dL, which is the threshold defining hypogly- by the study pump (Paradigm 715; cemia. The black line denotes the system target. Meals are indicated by triangles along the x-axis. 1130 Adjunctive Therapy During Closed-Loop Control Diabetes Care Volume 39, July 2016

protocol and to 100 mg/dL for the liraglu- Additional blood glucose measurements the curve (AUC), and the time to peak tide experiments. weresampledwhensensororplasma increment in plasma glucose were com- Sensors were calibrated at system glucose levels were ,60 mg/dL. Per pro- pared. Statistical comparisons between initiation and every 12 h thereafter by tocol, urine and blood ketones were groups in each protocol (CL alone vs. CL using a best-fit linear regression calibra- measured if plasma glucose was .250 with adjunctive therapy) were accom- tion scheme and fixed offset with a refer- mg/dL for 4 h or .300 mg/dL for 1 h. plished with paired t tests for normally dis- ence sensor pairing delay of 10 min. tributeddataandWilcoxonmatchedpair Additional calibrations were performed Biochemical Analysis signed rank tests for nonnormally distrib- if sensor errors exceeded 20%. Sensor Plasma glucose levels were sampled uted data. Effects of adjunctive therapy on accuracy was similar in both studies: every 30 min throughout the CL admis- weight and total daily insulin dose were mean absolute relative deviation was sions with the YSI 2300 STAT Plus glu- calculated for each adjunctive therapy. 11.5 6 3.8% in the pramlintide study cose analyzer (YSI Life Sciences, Yellow Additionally, a post hoc analysis using an and 11.1 6 2.8% in the liraglutide study. Springs, OH). These data were used to unpaired t test was performed to assess compare differences in glucose control differences in change in weight and insulin CL Study Procedure between the two treatment condi- dose between the two adjunctive thera- The same breakfast, lunch, and dinner tions of CL alone and CL with adjunctive pies. Calculations were performed with meals were provided at 8:00 A.M.,1:00P.M., therapy. GraphPad Prism 6 software (GraphPad and 6:00 P.M., respectively, during both CL Software, Inc., La Jolla, CA). admissions in both studies. Participants Statistical Considerations self-selected the meals and were not lim- Descriptive statistics were calculated RESULTS ited by calorie or carbohydrate content. for plasma glucose levels and doses of Participants Details regarding macronutrient content insulin administered. Data are expressed Pramlintide Adjunctive Therapy of meals are presented in Table 1. No as mean 6 SD or SEM as indicated. Thirteen participants who met the manual boluses were given for meals, Meal-stimulated glucose excursions inclusion/exclusion criteria were enrolled and the meals were not announced to were calculated as the increment in in the study; one participant in whom the controller. plasma glucose levels above premeal hyperglycemia and ketosis developed be- Hypoglycemia, defined as a plasma values for the 5 h following each meal. fore any CL study procedures was discon- glucose level ,60 mg/dL, was treated Peak postmeal plasma glucose levels, the tinued from the study and two other with 15 g fast-acting carbohydrate. incremental plasma glucose area under participants withdrew due to scheduling

Figure 2—Meal-related glycemic excursions are presented for the 5-h period after meals. A: Pramlintide. B: Liraglutide. Glucose levels are corrected for baseline glucose at the start of the meal. The control visit is represented in green and the adjunctive therapy in purple. care.diabetesjournals.org Sherr and Associates 1131

fl con icts. The 10 remaining participants Table 2—Data from inpatient CL admissions (4 males) who completed all study proce- CL + adjunctive dures and were included in the analysis CL alone therapy P value ranged in age from 16 to 23 years (mean Pramlintide 19.9 years) and had a diabetes duration of Time to peak plasma glucose (h) 3.9–15.4 years (mean 9.1 years) and A1C Average of all meals 1.6 6 0.5 2.9 6 0.9 ,0.0001 level of 6.7–8.0% (mean 7.2%) (50– Breakfast 1.5 6 0.4 3.2 6 0.6 ,0.0001 64 mmol/mol [mean 55 mmol/mol]). Lunch 1.8 6 0.8 2.7 6 1.3 0.01 Dinner 1.7 6 0.3 2.8 6 0.5 0.002 Liraglutide Adjunctive Therapy Plasma glucose excursion (mg/dL) Fifteen participants were enrolled in the Average all meals 96 6 30 59 6 46 ,0.0001 study; two withdrew before any inpa- Breakfast 116 6 30 91 6 44 0.03 tient CL admissions, and one withdrew Lunch 99 6 19 42 6 38 0.01 consent due to problems with intrave- Dinner 72 6 23 43 6 42 0.11 nous access during the first CL admission. Plasma glucose AUC meal excursion z Another withdrew after the first CL (mg/dL h) Total all meals 677 6 96 412 6 159 0.002 admission. The 11 remaining participants Breakfast 269 6 117 203 6 113 0.06 (4 males) who completed all study proce- Lunch 239 6 121 77 6 103 0.01 dures and were included in the analysis Dinner 168 6 87 110 6 117 0.25 ranged in age from 18 to 27 years (mean Prandial insulin delivery (units) 22 years) and had a diabetes duration of Total all meals 32.6 6 6.5 28.2 6 8.8 0.047 1–23 years (mean 10.5 years) and A1C Breakfast 10.7 6 4.4 9.8 6 4.4 0.37 6 6 level of 5.8–9% (mean 7.5%) (40– Lunch 10.9 2.0 8.4 3.5 0.04 Dinner 12.5 6 4.2 9.1 6 2.4 0.04 75 mmol/mol [mean 58 mmol/mol]). Liraglutide Time to peak plasma glucose (h) Effect of Adjunctive Therapy on Average all meals 1.8 6 0.5 1.8 6 0.6 0.97 Prandial Glucose Excursions During Breakfast 1.9 6 0.5 2.1 6 1.1 0.75 CL Control Lunch 1.4 6 0.6 1.5 6 0.9 0.99 6 6 Pramlintide Adjunctive Therapy Dinner 2.2 0.9 1.7 0.8 0.27 Mean plasma glucose levels during the 24 Plasma glucose excursion (mg/dL) Average all meals 98 6 24 76 6 17 0.05 h of CL control before and after treatment Breakfast 114 6 45 103 6 56 0.60 with pramlintide are shown in Fig. 1A, Lunch 77 6 53 57 6 21 0.17 whereas Fig. 2A illustrates the effect of Dinner 106 6 41 71 6 43 0.11 treatment in blunting and delaying Plasma glucose AUC meal excursion meal-stimulated increments in plasma (mg/dL z h) glucose levels. As shown in Table 2, the Total all meals 789 6 176 500 6 151 0.002 6 6 addition of pramlintide to CL control was Breakfast 289 151 226 192 0.27 Lunch 178 6 178 106 6 70 0.32 associated with a 39% reduction in the Dinner 304 6 143 175 6 153 0.05 peak increment in postprandial plasma Prandial insulin delivery (units) glucose levels and incremental plasma Total all meals 22.6 6 8.4 16.3 6 8.3 0.005 glucose AUC as well as with a significant Breakfast 8.8 6 4.1 6.5 6 4.1 0.006 delay in the time to peak plasma glucose Lunch 6.4 6 3.0 5.3 6 2.8 0.17 level when averaged for all meals and for Dinner 8.2 6 2.8 5.1 6 2.1 0.003 most individual meals. Meal-related glu- Data are mean 6 SD. System target glucose was 120 mg/dL for the pramlintide study and cose excursions were reduced with pram- 100 mg/dL for the liraglutide study. lintide even in the face of a 13% reduction in prandial insulin delivery (Table 2). Ad- ditionally, time in target (70–180 mg/dL) during daytime hours was greater with (Fig. 1B). Although the time to peak in- three meals was reduced by 28% during adjunctive pramlintide (P =0.004)ther- crement in postprandial glucose was not treatment with liraglutide. Eight episodes apy, as shown in Table 3. One hypoglyce- delayed, liraglutide treatment did cause of hypoglycemia occurred during the fi mic event occurred during two control modest, but statistically signi cant reduc- liraglutide admissions compared with admissions and one pramlintide admis- tions in the peak increment in postmeal seven during the control admissions. sion. No episodes of nocturnal hypoglyce- plasma glucose levels over all meals com- mia were noted during either study. bined and a 35% reduction in postmeal Effects of Outpatient Open-Loop plasma glucose AUC. Figure 2B depicts Treatment Liraglutide Adjunctive Therapy the incremental meal-related glycemic Pramlintide was well tolerated, and only At first glance, adjunctive treatment excursions by correcting for baseline glu- one participant was unable to increase with liraglutide appeared to have had cose values at the start of each meal. the pramlintide dose to .30 mgdueto minimal effects on the mean 24-h These differences were observed even loss of appetite and bloating at a higher plasma glucose levels during CL control though prandial insulin delivery over the dose level. During open-loop treatment 1132 Adjunctive Therapy During Closed-Loop Control Diabetes Care Volume 39, July 2016

Table 3—Mean glucose levels and time in target for inpatient CL admissions to effectively control glucose excursions CL alone CL + adjunctive therapy P value after breakfast. In our earlier study, low-dose pramlintide had little effect Pramlintide – on CL control of postbreakfast glucose Daytime (8:00 A.M. 11:00 P.M.) fi Mean blood glucose (mg/dL) 166 6 47 160 6 40 0.08 excursion. Thus, the signi cant lowering ,70 mg/dL 1.9 0.3 of postbreakfast glucose excursions in 70–180 mg/dL 59.7 71.1 0.004 the present study is a notable finding. .180 mg/dL 38.4 28.5 GLP-1 agonists, like liraglutide, have Nocturnal (11:00 P.M.–6:00 A.M.) been suggested as alternatives to Mean blood glucose (mg/dL) 121 6 20 122 6 28 0.87 pramlintide as an adjunctive treatment , 70 mg/dL 0 2.7 of type1 diabetes because their mecha- 70–180 mg/dL 98.7 93.3 0.12 .180 mg/dL 1.3 4 nisms of action (i.e., suppression of plasma Liraglutide glucagon levels and delays in gastric emp- Daytime (8:00 A.M.–11:00 P.M.) tying) appear to be similar to pramlintide Mean blood glucose (mg/dL) 143 6 55 146 6 47 0.13 and their longer duration of action allows ,70 mg/dL 5.9 3.3 once-daily to once-weekly injections. 70–180 mg/dL 71.6 74.4 0.50 Thus, that we were able to show only a .180 mg/dL 22.4 22.3 modest improvement in CL control of – Nocturnal (11:00 P.M. 6:00 A.M.) meal-stimulated glucose excursions in Mean blood glucose (mg/dL) 104 6 23 113 6 24 0.0001 ,70 mg/dL 5.5 2.4 the present study is disappointing. More- 70–180 mg/dL 94.5 96.4 0.13 over, unlike pramlintide, there was no .180 mg/dL 0 1.2 evidence of lasting effects of liraglutide Data are mean 6 SD for glucose levels and percent of time in various ranges (,70, 70–180, in delaying rates of gastric emptying. and .180 mg/dL). System target glucose was 120 mg/dL for the pramlintide study and Single-dose experiments have shown 100 mg/dL for the liraglutide study. that GLP-1 agonists suppress meal- stimulated increases in plasma gluca- gon levels (23). However, more-recent with liraglutide, 54% of participants ex- CONCLUSIONS studies have indicated that treatment perienced GI issues (nausea, decreased An important finding of this study is that with GLP-1 agonists over weeks and appetite, constipation, bloating, and/or treatment with the full recommended months may actually increase circulating diarrhea). However, these issues were dose of 60 mg/meal of pramlintide plasma glucagon levels; such increases in transient and did not prevent anyone over 3–4 weeks of outpatient open-loop glucagon may help to explain the limited from reaching the goal dose of 1.8 mg therapy improved prandial CL glucose benefit of liraglutide during CL control during their second CL admission. In view control by reducing both peak plasma in the present study (24). of the short 3–4-week duration of the out- glucose excursions and incremental Nevertheless, the present results patient phase of the study, liraglutide- plasma glucose AUC by 39%. In contrast, indicate that liraglutide may play an treated participants lost ;5.0% body the improvements in both these metrics adjunctive role in open-loop treatment weight and lowered total daily insulin were only 22% and 26%, respectively, in of type 1 diabetes. A surprising finding doses by ;26%, changes that were greater our prior single-day 30 mg/meal study of this study was the degree of weight than that observed with pramlintide treat- (19). Because there is no carryover effect loss (and the corresponding reduction in ment (Table 4). There were no episodes of of prior premeal doses of insulin before insulin requirements) observed over a severe hypoglycemia or diabetic ketoaci- breakfast in the morning, it has been a remarkably short period of treatment dosis during the open-loop outpatient difficult challenge for most CL systems with liraglutide. Although the central dose titration phases. that do not manually announce meals action of liraglutide to reduce appetite and promote weight loss in obese indi- viduals with or without type 2 diabetes is well recognized, these actions may Table 4—Comparison of outpatient weight and insulin dose changes also be beneficial for patients with Pramlintide Liraglutide P value type 1 diabetes. In the current intensive Weight (kg) treatment era, an increasingly large pro- Baseline 73.0 6 13.4 66.2 6 9.3 portion of pediatric and adult patients Posttreatment 72.3 6 13.4 62.9 6 8.1 with type 1 diabetes are overweight or Change in weight 0.7 6 1.4 3.2 6 1.88 0.003 obese, which in turn contributes to prob- % change in weight 1 6 256 2.4 0.002 lems in achieving optimal metabolic con- Insulin dose (units) trol and increases the risk of future 6 6 Baseline 58.7 17.4 51.5 14.1 cardiovascular disease (25). The recent Posttreatment 52.1 6 12.4 37.5 6 12.9 Change in dose 6.6 6 10.9 13.9 6 13.3 0.19 failure of metformin to improve meta- % change in dose 9 6 14 26 6 21 0.05 bolic control of obese adolescents with type 1 diabetes (26) illustrates a continu- Data are mean 6 SD. ing unmet need for an adjunctive therapy care.diabetesjournals.org Sherr and Associates 1133

like liraglutide that could promote weight overweight and obese patients with type 1 4. Weinzimer SA, Steil GM, Swan KL, Dziura J, loss and reduce insulin requirements in diabetes. Outpatient studies of CL insulin Kurtz N, Tamborlane WV. Fully automated type 1 diabetes. delivery with these adjunctive agents are closed-loop insulin delivery versus semiautomated hybrid control in pediatric patients with type 1 The CL system used in the present needed to determine their full efficacy and diabetes using an artificial pancreas. Diabetes experiments relied on total daily insulin safety profiles. Care 2008;31:934–939 dose as the primary variable to tune algo- 5. Hovorka R, Allen JM, Elleri D, et al. Manual rithm parameters; subjects requiring closed-loop insulin delivery in children and adoles- cents with type 1 diabetes: a phase 2 randomised lower doses have less aggressive insulin Acknowledgments. The authors thank the crossover trial. Lancet 2010;375:743–751 delivery during meal-related glucose ex- participants and their families, the health care professionals and staff of Yale Children’s Diabetes 6. Hovorka R, Kumareswaran K, Harris J, et al. cursions. Thus, the 26% reduction in total fi Clinic, the Yale Center for Clinical Investigation, Overnight closed loop insulin delivery (arti cial daily doses achieved during outpatient, and the dedicated nursing staff of the hospital pancreas) in adults with type 1 diabetes: cross- open-loop treatment with liraglutide research unit for the support and participation over randomised controlled studies. BMJ may have offset our ability to demon- that made this project possible. 2011;342:d1855 strate differences in prandial increments Funding. This study was made possible through 7. Kovatchev B, Cobelli C, Renard E, et al. Multinational study of subcutaneous model- in plasma glucose during the second CL the support of grants from JDRF (22-2009-799, 17-2013-5, and 5-ECR-2014-112-A-N), the Na- predictive closed-loop control in type 1 diabetes experiments. tional Institutes of Health (R01-DK-085618, K12- mellitus: summary of the results. J Diabetes Sci Of note, the present studies were not DK-094714, UL1-TR-000142, and P30-DK-45735), Technol 2010;4:1374–1381 designed or powered to provide a direct and the Michael D. Ryan and Rosemary McNicholas 8. Nimri R, Atlas E, Ajzensztejn M, Miller S, comparison of the effects of pramlintide RyanPediatricDiabetesResearchFund.Medtronic Oron T, Phillip M. Feasibility study of auto- Diabetes provided the pumps, sensors, infusion mated overnight closed-loop glucose control with liraglutide as adjunctive agents to sets, reservoirs, and laptop computers for the under MD-logic artificial pancreas in patients CL insulin delivery. As noted in Table 3, CL experiments. with type 1 diabetes: the DREAM Project. Diabetes both the control and the liraglutide exper- Duality of Interest. W.V.T. is a consultant for Technol Ther 2012;14:728–735 iments had lower mean glucose levels Novo Nordisk and Sanofi.E.C.isaspeakerforNovo 9. Nimri R, Danne T, Kordonouri O, et al. The “ ” than that achieved during the pramlintide Nordisk. S.A.W. is a consultant for Medtronic Dia- Glucositter overnight automated closed betes and Tandem and serves on a medical advisory loop system for type 1 diabetes: a random- experiments, which is likely due to the board for Insulet. No other potential conflicts of ized crossover trial. Pediatr Diabetes 2013; lower system set point (target 120 mg/dL interest relevant to this article were reported. 14:159–167 for the pramlintide study vs. 100 mg/dL No sponsor had any role in the study design, 10. Russell SJ, El-Khatib FH, Nathan DM, for the liraglutide study). The lower data collection, data analysis, data interpreta- Magyar KL, Jiang J, Damiano ER. Blood glucose set point used in the liraglutide studies tion, or writing of the manuscript. control in type 1 diabetes with a bihormonal Author Contributions. J.L.S. researched data bionic endocrine pancreas. Diabetes Care may also explain the higher frequency of and wrote the manuscript. N.S.P., C.I.M., M.M.P.-C., 2012;35:2148–2155 hypoglycemia with liraglutide than with M.A.V.N., E.C., L.R.C., and E.M.T. researched 11. Castle JR, Engle JM, El Youssef J, et al. Novel pramlintide. data and contributed to the discussion. W.V.T. use of glucagon in a closed-loop system for The first generations of ambulatory and S.A.W. researched data, contributed to the prevention of hypoglycemia in type 1 diabetes. – CL systems approaching commercial discussion, and reviewed and edited the manu- Diabetes Care 2010;33:1282 1287 script. J.L.S. is the guarantor of this work and, as 12. Haidar A, Legault L, Dallaire M, et al. Glucose- development must be shown to be such, had full access to all the data in the study responsive insulin and glucagon delivery (dual- safe before gaining regulatory approval, and takes responsibility for the integrity of the hormone artificial pancreas) in adults with trading some controller aggressive- data and the accuracy of the data analysis. type 1 diabetes: a randomized crossover controlled ness in insulin delivery for avoidance of Prior Presentation. Parts of this study were trial. CMAJ 2013;185:297–305 presented in abstract form at the 72nd Scientific 13. Van Bon AC, Jonker LD, Koebrugge R, Koops R, hypoglycemia. Consequently, all these Sessions of the American Diabetes Association, Hoekstra JB, DeVries JH. Feasibility of a bihormonal systems require manual boluses of pre- Philadelphia, PA, 8–12 June 2012; 12th Annual closed-loop system to control postexercise and meal insulin to handle meal-related chal- Diabetes Technology Meeting, Bethesda, MD, postprandial glucose excursions. J Diabetes Sci lenges. The use of adjunctive therapy may 8–10 November 2012; the 6th International Technol 2012;6:1114–1122 ease the burden placed on these CL sys- Conference on Advanced Technologies & Treat- 14. Pinsker JE, Lee JB, Dassau E, et al. Random- ments for Diabetes, Paris, France, 27 February–2 ized crossover comparison of personalized MPC tems to mitigate postprandial glycemic March 2013; 73rd Scientific Sessions of the and PID control algorithms for the artificial pan- excursions in an insulin-sparing manner, American Diabetes Association, Chicago, IL, creas. Diabetes Care 2016;39:1135–1142 thereby achieving lower glycemic excur- 21–25 June 2013; 8th International Conference 15. Anderson SM, Raghinaru D, Pinsker JE, et al. sions with a lower risk of hypoglycemia. on Advanced Technologies & Treatments for Multinational home use of closed-loop con- – Although pramlintide appears to provide Diabetes, Paris, France, 18 21 February 2015; trol is safe and effective. Diabetes Care 2016; and 15th Annual Diabetes Technology Meeting, 39:1143–1150 robust and durable reductions and delays Bethesda, MD, 22–24 October 2015. 16. Renard E, Farret A, Kropff J, et al.; AP@home in prandial glucose excursions, its attrac- Consortium. Day-and-night closed-loop glucose tiveness as an adjunctive treatment is re- control in patients with type I diabetes under duced by the need for premeal injections. References free-living conditions: results of a single-arm GLP-1 agonists require only once-daily or 1. Albisser AM, Leibel BS, Ewart TG, Davidovac Z, 1-month experience compared with a previously Botz CK, Zingg W. An artificial endocrine pancreas. reported feasibility study of evening and night at once-weekly injections, but their ability to Diabetes 1974;23:389–396 home. Diabetes Care 2016;39:1151–1160 mitigate postmeal excursions with long- 2. Albisser AM, Leibel BS, Ewart TG, et al. Clin- 17. Tauschmann M, Allen JM, Wilinska ME, term treatment remains to be established. ical control of diabetes by the artificial pancreas. et al. Day-and-night hybrid closed-loop insulin The present data suggest that the major Diabetes 1974;23:397–404 delivery in adolescents with type 1 diabetes: a fi 3. Steil GM, Rebrin K, Darwin C, Hariri F, Saad free-living, randomized clinical trial. Diabetes bene t of these agents as adjunctive treat- MF. Feasibility of automating insulin delivery for Care 2016;39:1168–1174 ment may be for weight loss and con- the treatment of type 1 diabetes. Diabetes 18. Del Favero S, Boscari F, Messori M, et al. comitant increases in insulin sensitivity in 2006;55:3344–3350 Randomized summer camp crossover trial in 1134 Adjunctive Therapy During Closed-Loop Control Diabetes Care Volume 39, July 2016

5- to 9-year-old children: outpatient wearable control. J Clin Endocrinol Metab 2011;96:1402– therapy on glucagon secretion in type 2 diabe- artificial pancreas is feasible and safe. Diabetes 1408 tes: insight from the LIBRA trial. J Clin Endocrinol Care 2016;39:1180–1185 22. Palerm CC. Physiologic insulin delivery with Metab 2015;100:3702–3709 19. Weinzimer SA, Sherr JL, Cengiz E, et al. Effect insulin feedback: a control systems perspec- 25. Chillaron´ JJ, Flores Le-Roux JA, Benaiges D, of pramlintide on prandial glycemic excursions tive. Comput Methods Programs Biomed Pedro-Botet J. Type 1 diabetes, metabolic syn- during closed-loop control in adolescents and 2011;102:130–137 drome and cardiovascular risk. Metabolism young adults with type 1 diabetes. Diabetes 23. Hare KJ, Knop FK, Asmar M, et al. Preserved 2014;63:181–187 Care 2012;35:1994–1999 inhibitory potency of GLP-1 on glucagon secre- 26. Libman IM, Miller KM, DiMeglio LA, et al. 20. Nauck MA. Is glucagon-like peptide 1 an incre- tion in type 2 diabetes mellitus. J Clin Endocrinol Effect of metformin added to insulin on glycemic tin hormone? Diabetologia 1999;42:373–379 Metab 2009;94:4679–4687 control among overweight/obese adolescents 21. Steil GM, Palerm CC, Kurtz N, et al. The 24. Kramer CK, Zinman B, Choi H, Connelly PW, with type 1 diabetes: a randomized clinical trial. effect of insulin feedback on closed loop glucose Retnakaran R. The impact of chronic liraglutide JAMA 2015;314:2241–2250