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Care Publish Ahead of Print, published online March 31, 2010

Adjunctive therapy of or sitagliptin to glargine + versus + metformin alone.

Further improvement in postprandial glucose control when adding exenatide (EXE) or sitagliptin (SITA) to combination therapy with insulin glargine (GLAR) and metformin (MET) – a proof-of-concept study

Sabine Arnolds, MD1, Sibylle Dellweg, MD1, Janina Clair, MD1, Marie-Paule Dain, MD², Michael A Nauck, MD3, Klaus Rave, MD1, Christoph Kapitza, MD1,

1. Profil Institut für Stoffwechselforschung GmbH, Neuss, Germany 2. Sanofi-Aventis, Paris, France 3. Diabeteszentrum Bad Lauterberg, Bad Lauterberg, Germany

Corresponding Author: Dr. S. Arnolds, Email: [email protected]

Clinical trial registration no.: NCT00971659; clinicaltrials.gov

This is an uncopyedited electronic version of an article accepted for publication in Diabetes Care. The American Diabetes Association, publisher of Diabetes Care, is not responsible for any errors or omissions in this version of the manuscript or any version derived from it by third parties. The definitive publisher- authenticated version will be available in a future issue of Diabetes Care in print and online at http://care.diabetesjournals.org.

Copyright American Diabetes Association, Inc., 2010 Adjunctive therapy of exenatide or sitagliptin to insulin glargine + metformin versus insulin glargine + metformin alone.

Objectives: To assess the effect of a 4-week adjunctive therapy of exenatide (EXE, 5 to 10 µg bid) or sitagliptin (SITA, 100 mg od) in response to a standardized breakfast meal challenge in 48 men or women with receiving insulin glargine (GLAR) + metformin (MET).

Research Design and Methods: This was a single-center, randomized, open-label, active comparator-controlled study with a 3-arm parallel group design, consisting of: screening, 4-8-week run-in period, 4-week treatment period, follow-up. In all 3 groups GLAR dose was titrated according to an algorithm (fasting blood glucose (BG) ≤100 mg/dL).

Results: The unadjusted 6-h postprandial BG excursion (AUCBG 0-6h) of both GLAR+MET+EXE and GLAR+MET+SITA was statistically significantly smaller than that of GLAR+MET (606±104 versus (vs) 612±133 vs 728±132 mg.dL-1.h-1; p=0.0036 and 0.0008). HbA1c significantly decreased in all 3 groups (p<0.0001), with the greatest reduction under GLAR+MET+EXE (-1.9±0.7; GLAR+MET+SITA -1.5±0.7; GLAR+MET - 1.2±0.5%-points); GLAR +MET+EXE vs GLAR+MET (p=0.0154). ADA HbA1c target of < 7.0% was reached by 80.0, 87.5 and 62.5% of subjects, respectively. GLAR+MET+EXE had the highest number (47) of adverse events (AEs), mostly gastrointestinal (56%) with 1 drop-out. GLAR+MET or GLAR+MET+SITA only had 10 and 12 AEs, respectively, and no drop-outs. (BG<50 mg/dL) rates were low and comparable between groups. Weight decreased with GLAR+MET+EXE (-0.9±1.7 kg, p=0.0396), and increased slightly with GLAR+MET (0.4±1.5 kg; p=ns); GLAR+MET+EXE vs GLAR+MET (p=0.0377).

Conclusions: EXE or SITA added to GLAR+MET further substantially reduced ppBG excursions. Longer term studies in a larger population are warranted to confirm these findings.

Trial registration: This trial was registered at clinicaltrials.gov, registration number NCT00971659.

2 Adjunctive therapy of exenatide or sitagliptin to insulin glargine + metformin versus insulin glargine + metformin alone.

he UK prospective diabetes study (11,12,13,14). However, postprandial (UKPDS) has demonstrated that glycemia as well as weight was further T good glycemic control in type 2 reduced with exenatide compared to diabetes is associated with a reduced risk insulin glargine or biphasic insulin, with a of diabetes complications (1). Following similar risk of hypoglycemia (12,13). lifestyle modifications (diet and exercise) Sitagliptin is an approved once-daily, and oral hypoglycemic agents (OHAs) the potent and highly selective dipeptidyl addition of basal insulin to OHAs is peptidase-4 (DPP-4) inhibitor (15). When common practice (2), as this kind of added to metformin, sitagliptin – given at regimen requires only a single injection in a dose of 100 mg once-daily over 24 most cases and can improve glycemic weeks - led to significant reductions in control. Its use, however, may not HbA1c, fasting- and 2- hour postprandial adequately control postprandial plasma glucose and was weight-neutral hyperglycemia or may be associated with (16). hypoglycemia (hypo) and/or weight gain With this background, a therapy (3,4). As obesity is frequently present in controlling both fasting blood glucose and subjects with type 2 diabetes (5) and postprandial glucose excursions appears represents a contributing factor to insulin to be a promising approach for subjects resistance (5) and cardiovascular risk (5), with type 2 diabetes (17,18,19,20,21). weight gain may be particularly Therefore, the present study investigated undesirable. the influence of a 4-week adjunctive A significant advance in basal insulin therapy of either a GLP-1 receptor therapy was the introduction of insulin agonist (exenatide) or a DPP-4 inhibitor glargine, a long-acting with (sitagliptin) to titrated basal insulin (insulin extended duration of action of about 24 glargine) plus metformin versus the hours without exhibiting a pronounced continuation with titrated insulin glargine peak (6,7). In subjects with type 2 plus metformin alone as active diabetes, insulin glargine was shown to comparator in subjects with type 2 confer at least equivalent glycemic control diabetes. with a lower incidence of hypoglycemia, compared with NPH insulin (3,8,9). RESEARCH DESIGN AND METHODS However, insulin glargine still maintains Enrolled subjects were men or women drawbacks of insulin treatment like weight aged 35 – 70 years, with type 2 diabetes gain (3,8,9) and a lower effect on for >6 months and <10 years, treated postprandial glucose excursions (8) as either with a stable dose of metformin compared to fasting glucose values. with or without or treated Exenatide is the first-in-class - solely with a long or intermediate-acting like peptide-1 (GLP-1) receptor agonist insulin formulation (insulin glargine, (or mimetic) approved in the US or NPH insulin) with or and Europe (10). Compared with placebo without a stable dose of metformin for at exenatide statistically reduced HbA1c, least 3 months. Inclusion criteria included while there was no difference in HbA1c BMI between 21.0 and 39.9 kg/m², improvement between exenatide and inclusive, HbA1c ≥7.0 and ≤10.0%, as well insulin glargine or biphasic as a stable antihypertensive or lipid

3 Adjunctive therapy of exenatide or sitagliptin to insulin glargine + metformin versus insulin glargine + metformin alone.

lowering therapy for at least three 10 units (U) for those subjects new to months, if applicable. Subjects were insulin. During the whole course of the excluded, if they had a history or study each subject’s insulin glargine dose evidence of any other clinically relevant was titrated to a fasting blood glucose medical conditions or had used a rapid- (FBG) target of ≤5.6 mmol/L (≤100 acting insulin or a mixed insulin mg/dL) using a pre-defined treatment formulation or any other oral antidiabetic algorithm which, with slight modifications, agent except for metformin or metformin corresponds to that used by Riddle et al plus during the previous 3 in the treat-to-target trial for the months. Exclusion criteria further included introduction of insulin glargine to OAD- abnormal laboratory test results, in treated patients with type 2 diabetes (8). particular ALAT and/or ASAT ≥3 times During the run-in period telephone the laboratory´s upper limit of reference contacts (2 per week) and weekly range or serum creatinine ≥1.6 mg/dL for outpatient visits (visits 2-4 or 2-4d in case males and ≥1.4 mg/dL for females, of 8-weeks run-in) at the study site were uncontrolled hypertension, anemia, performed. At the end of the run-in recurrent hypoglycemia, or any systemic period, two days prior to allocation to one or topical treatment with drugs known to of the three treatment arms, the insulin influence glucose metabolism. glargine dose was reduced by 20% in Study design. This single-center, order to avoid hypoglycemia. At visit 5 randomized, open-label, active (baseline), subjects in an open-label comparator-controlled study with a three- fashion were randomized to either the arm parallel group design was performed addition of exenatide or sitagliptin to between January 9th and September 29th insulin glargine plus metformin or to the 2008. It was conducted in accordance continuation of insulin glargine plus with the Declaration of Helsinki (22) and metformin alone for four weeks. approved by the local ethics committee Exenatide was to be administered and regulatory authorities. All subjects subcutaneously (s.c.) at a dose of 5 µg in provided written informed consent. the morning and evening (BID) for two Study protocol and treatment. After a weeks followed by 10 µg BID for the screening visit (visit 0) in order to assess second two weeks. Sitagliptin was taken a subject´s eligibility for study orally at a dose of 100 mg once daily in participation, a four- or eight-week run-in the morning. During the 4 week-treatment period – depending on the subject´s period weekly visits (visits 6-8) at the preexisting anti-diabetic therapy - with study site plus twice weekly telephone insulin glargine at bedtime followed, contacts were continued in order to starting at visit 1: four weeks run-in in further titrate blood glucose (BG) to the case a subject already had an insulin pre- FBG target of ≤5.6 mmol/L (≤100 mg/dL). treatment, eight weeks in case of oral The 4-week treatment period ended with antidiabetic treatment only (OHA). a 24-hour in-house visit, during which Preexisting metformin was continued for efficacy assessments were performed the entire study, whereas sulfonylureas (visit 9). The study was completed with a were stopped at the beginning of the run- final visit (visit 10) 2 to 10 days after the in period. All subjects received insulin in-house stay. glargine at bedtime, at a starting dose of

2 Adjunctive therapy of exenatide or sitagliptin to insulin glargine + metformin versus insulin glargine + metformin alone.

During both the run-in and the treatment and at final visit), test for period subjects self-measured and women of childbearing potential (at recorded their FBG (and any potential, screening, visits 5, 9 and final visit), ECG voluntary pre- and/ or postprandial BG (at screening and final visit), FBG (at values) on a daily basis using a screening, visits 5, 7, 9 (on both days of commercial glucose meter (Accu-Chek® the 24-hour in-house stay)), fasting lipid Aviva, Roche Diagnostics, Mannheim, profile (at visits 5 and 9). At visit 9, during Germany). Once per week they the 24-hour in-house stay in addition the performed 7-point BG profiles at the following was assessed: Day 1: dosing of following times: before and 2 hours after either exenatide or sitagliptin 60 min prior breakfast, lunch and dinner, and before to a standardized 618.2 kilocalorie (kcal) bedtime (11:00 pm). All results and times breakfast consisting of 99.4 g of self-measurements of blood glucose carbohydrates, 11.9 g lipids and 26.2 g (SMBG) as well as insulin doses were protein, 7-point 24-hour BG profile, entered by the subjects into a study diary. postprandial BG excursions following the If at any time during the study (except at standardized breakfast (16 BG samples screening and the final visit) self- from -30 to 360 min). On day 2 of the in- measured FBG values on two house stay, after completion of all consecutive days of >13.3 mmol/L (>240 assessments including HbA1c, the mg/dL) were confirmed at the site by subjects were instructed on how to means of a validated glucose oxidase continue with their pre-study antidiabetic method (Super-GL, Glucose Analyzer, medication and were asked to measure at Hitado Diagnostic Systems GmbH, least FBG and document these as well as Möhnesee, Germany), the subject had to any additional BG values in the diary be withdrawn from the study. The same provided. procedure applied for hypoglycemic BG Study end points. The primary outcome values occurring at two consecutive days. measure was the unadjusted 6-hour Hypoglycemia was classified as major, if postprandial (pp) BG excursion (AUCBG 0- a subject was not able to treat the 6h) following ingestion of the standardized episode him/herself, and as minor in case breakfast, assessed at the end of the 4 the subject was able to treat the episode week treatment period. Secondary him/herself and BG was <2.8 mmol/L endpoints included: mean daily blood (<50 mg/dL), or if there was no BG glucose as assessed by means of the 7- available, or if BG was ≥2.8 mmol/L (≥50 point 24-hour blood glucose profile at the mg/dL) with symptoms only. end of the 4-week treatment period, the Apart from a thorough review of the subjects´ self-measurements of fasting subject´s BG values in the study diary blood glucose as well as 7-point blood and adjustments of the insulin glargine glucose profiles throughout the run-in and dose, the following assessments were the treatment period, percentage of performed at the weekly visits at the subjects achieving ADA treatment goals, study site: vital signs, i.e. blood pressure i.e. HbA1c <7.0%, at the end of the and heart rate, adverse events and treatment period, fasting lipid profile, body hypoglycemic episodes (at each visit), weight, each as assessed at the end of physical examination and safety lab (at the treatment period, number and severity screening, prior to randomization at visit 5 of hypoglycemic episodes, and general

3 Adjunctive therapy of exenatide or sitagliptin to insulin glargine + metformin versus insulin glargine + metformin alone.

safety parameters (adverse events (AEs), calculated using the trapezoid rule. ∆ physical examination, vital signs, safety HbA1c was determined as difference of laboratory parameters, ECG). visit 9 HbA1c minus screening HbA1c. ∆ Statistical analysis. A sample size of 16 body weight as well as ∆ lipid were subjects per treatment arm (in total 48 calculated as visit 9 values minus visit 5 subjects) was estimated to detect values. Statistical significance level was significant differences between set p<0.05, data is given as mean±SD if treatments (23). SAS (version 9.1; SAS not otherwise stated. Institute, Cary, NC) was used to conduct all statistical analyses. ANCOVA models, RESULTS allowing the estimation of least square Subject disposition and clinical (LS) means with corresponding 95% characteristics (Figure 1). A total of 48 confidence limits were used on subjects with type 2 diabetes (60.4% untransformed ∆ bodyweight, ∆ lipids, ∆ male, mean±SD age 57±7 years, BMI HbA1c and on natural logarithm- 31.7±3.4 kg/m², diabetes duration 6±1 transformed AUC-BG(0-6h), 7-point blood years, HbA1C 8.1±0.7%) were glucose profile, with baseline randomized to 3 arms: GLAR+MET+EXE assessments as confounders. ANCOVA (up to 10µg bid; n=16), models with repeated measures on the GLAR+MET+SITA (100 mg qd; n=16) or factor day were applied to test for continuation with GLAR+MET (control; difference in logarithm-transformed n=16) for 4 weeks. 47 subjects completed fasting blood glucose and self-measured the study according to the protocol. One 7-point blood glucose. For log- subject in the GLAR+MET+ transformed data, the calculated 95% EXE group was withdrawn after the first 2 confidence intervals were back- weeks of the 4-week treatment period transformed to derive the appropriate (due to a loss of appetite deemed confidence limits for the geometric mean possibly related to the study treatment). ratios of the pair wise treatments Baseline HbA1c was 7.9% both in the comparisons. Paired t-tests were used to GLAR+MET+SITA and GLAR+MET test of within-group change and for group, whereas it was slightly higher between group comparisons unpaired t- (8.4%) in the GLAR+MET+EXE group. tests were applied. χ2 -tests were used to This difference, however, was not of compare the frequency of subjects statistical significance. All subjects were achieving ADA treatment goals receiving MET at study start, 7 subjects in (HbA1c<7.0%) as well as subjects addition had a pre-existing therapy with achieving IDF treatment goals SU, 9 subjects with insulin. (HbA1c<6.5%) at the end of the treatment Primary and secondary endpoints period. Descriptive statistics on (Table 2, Figure 2). After 4 weeks of demographics, safety and glycemic treatment the AUCBG 0-6h of both endpoints were provided for all GLAR+MET+EXE and GLAR+MET+SITA randomized subjects who received at was significantly smaller (EXE 17% least one dose of investigational reduction, p=0.0036, SITA 20% reduction, medication. The areas under the blood p=0.0008) than that of GLAR+MET, while glucose curve, extending from the meal the two combination treatments were not intake to 6 hours after ingestion, were

4 Adjunctive therapy of exenatide or sitagliptin to insulin glargine + metformin versus insulin glargine + metformin alone.

significantly different from each other (-0.9±1.7 kg), which was statistically (p=0.5734). significant versus GLAR+MET HbA1c significantly declined in all 3 (p=0.0377). groups (LS-means GLAR+MET+EXE Hypoglycemic episodes and general -1.8; GLAR+MET+SITA -1.5; safety. Over the 4-week treatment period GLAR+MET -1.2; p<0.0001 each) with no major hypoglycemic episode occurred GLAR+MET+EXE leading to a in any of the three groups, 13 subjects significantly higher HbA1c decrease than experienced in total 22 hypoglycemic GLAR+MET (LS-mean -0.6, p=0.0154). episodes: five subjects in the Metabolic control on average was GLAR+MET+EXE group experienced 12 excellent: ADA HbA1c target of <7% was hypos (10.1 events/subject year), 2 of achieved by 80% of subjects in the these were minor (1.7 events/subject GLAR+MET+EXE group (88% year), and 10 were symptoms only GLAR+MET+SITA group, and 63% (GLAR+MET+SITA 2 subjects 4 hypos, GLAR+MET group, respectively). 3.3 events/subject year, 3=minor=2.5 Under GLAR+MET+EXE and events/subject year; GLAR+MET 6 GLAR+MET+SITA the 7-point 24-hour subjects 6 hypos, 2=minor=1.6 BG profiles after 4 weeks of treatment events/subject year). Two subjects in the were significantly lower than those under GLAR+MET+EXE group had 4 hypos GLAR+MET, as were also the weekly each. There was no nocturnal hypo self-measured 7-point BG profiles during (between 11 pm and 6 am) in any of the 3 the treatment period. groups. Eight of the 12 hypos in the Self-measured daily fasting BG values GLAR+MET+EXE group occurred (mean of all measurements in treatment between 6 and 7 pm, whereas all hypos period) were comparable between the in the GLAR+MET group took place three treatments after significant between 10 am and 2:30 pm. decreases in FBG had been reached The insulin glargine dose did not already during the run-in period. decrease with EXE or SITA, whereas it However, when comparing FBG at increased in the control group. Mean randomization (visit 5) with that at the end insulin doses at randomization and at end of the 4-week treatment (visit 9), a of treatment were 40.3 IU (0.60±0.25 significant reduction was observed for IU/kg, mean±SD) and 41.1 IU (0.42±0.18 each of the combination treatments IU/kg) in the GLAR+MET+EXE group (p=0.0018 for GLAR+MET+EXE and (GLAR+MET+SITA 33.4 IU [0.50±0.20 p=0.0016 for GLAR+MET+SITA), while IU/kg] and 35.0 IU [0.36±0.17 IU/kg]; this was not the case for GLAR+MET GLAR+MET 32.3 IU [0.50±0.21 IU/kg] (p=0.2084). and 37.9 IU [0.42±0.20 IU/kg]), with a Both adjunctive therapies showed a mean increase of 5.6 IU in the GLAR comparable lowering effect on serum group. cholesterol (total and LDL) which was not Ten of the 16 subjects (62.5%) in the seen in the control group. GLAR+MET+EXE group experienced in Body weight was stable with GLAR+MET total 47 adverse events, 56% being due and GLAR+MET+SITA (mean±SD to gastrointestinal disorders causing one 0.4±1.5 and 0.1±1.6 kg, respectively) and drop-out after 2 weeks slightly decreased with GLAR+MET+EXE (GLAR+MET+SITA 7 subjects 12 AE,

5 Adjunctive therapy of exenatide or sitagliptin to insulin glargine + metformin versus insulin glargine + metformin alone.

GLAR+MET 4 subjects 10 AE; exenatide, which is consistent with the gastrointestinal disorders 19% and 16%, adverse event profile seen during phase respectively). All gastrointestinal AEs III (10). were of mild or moderate intensity. There Several factors should be considered was no serious AE in any of the groups when interpreting our results. and only one severe AE, not related to First, the number of patients (16 in each trial drug, in the GLAR+MET+SITA group. group) is relatively small, thus further No clinically relevant findings or changes studies both in a larger number of were seen in safety laboratory tests, patients and of longer duration are physical examination results, ECG warranted. Secondly, mean duration of recordings, and vital sign measurements. type 2 diabetes in this population was only 6±1 years, and mean baseline CONCLUSIONS HbA1c was 8.1±0.7 %. Patients with To our knowledge this is the first study longer disease duration and/or worse investigating a 4-week adjunctive therapy metabolic control might be less likely to of either a GLP-1 analog or a DPPIV- benefit to such an extent seen in the inhibitor added to titrated insulin glargine study population, especially when plus metformin, in comparison to insulin focussing on postprandial blood glucose glargine plus metformin alone acting as (25). For the present subject group one active control in subjects with type 2 could also conclude that it is more cost- diabetes. The addition of exenatide or effective to just continue metformin plus sitagliptin to insulin glargine plus basal insulin glargine, because overall metformin led to statistically significant glucose control at the end of the study improvements in nearly all parameters of has significantly improved in all three metabolic control: postprandial glucose groups, with a slightly further excursions as well as HbA1c, 7-point BG improvement only seen for the addition of profiles, fasting blood glucose, and lipids exenatide given to titrated insulin glargine were all lower with the combination plus metformin. Moreover, the present therapy compared with the control group, subjects might not be the ones requiring which is in line with previous data the combination of metformin with insulin (17,19,20). Overall glycemic control in all and sitagliptin/exenatide, since excellent groups was excellent, as shown by more glucose control is achieved with insulin than 60% of all patients reaching ADA and metformin alone and would most HbA1c target of below 7%. Body weight likely also be achieved with metformin decreased with exenatide and was stable plus an incretin. Nevertheless, this study in the other two groups, indicating that the provides a proof of concept. Besides, weight-lowering activity of GLP-1 receptor given the increasing incidence of type 2 stimulation (10,20) persists even with diabetes and obesity (5), there is a need concomitant insulin treatment. This is an for further effective, weight-focused, important novel finding. The incidence of convenient and safe therapies including hypoglycemic episodes (BG<50 mg/dL) incretins (21). Future research will be was comparable between groups, and in necessary to clarify whether there are the expected range for insulin-treated clinical benefits in choosing exenatide or patients (24). Gastrointestinal side sitagliptin versus another commonly used effects, however, were more frequent with agent to lower post-prandial BG. Another

6 Adjunctive therapy of exenatide or sitagliptin to insulin glargine + metformin versus insulin glargine + metformin alone.

limitation of the study was a statistically no relevant conflict of interest to disclose. non-significant, slight difference, Marie-Paule Dain is an employee of however, in baseline HbA1c values Sanofi-Aventis. Michael Nauck has between the three groups, which should received research grants from Bayer Vital be taken into account when interpreting Pharma, Leverkusen, Germany, Eli Lilly & the results. Furthermore, the duration of Co. Indianapolis, Indiana, USA , the study was too short to see the full Menarini/Berlin-Chemie, Berlin, Germany, effect on HbA1c. The open-label design Merck, Sharp Dohme, Munich, also represents a certain limitation. A Germany, Novartis Pharma, Basel, double-blind double-dummy design, Switzerland, and NovoNordisk, however, would have put a lot of effort Copenhagen, Denmark; he has accepted into the conduct of the trial and a major honoraria for membership in advisory additional restriction to the study subjects. boards and consulting, and has received In conclusion, this study demonstrates honoraria for speaking on incretin-based that insulin glargine/metformin provides antidiabetic medications from excellent fasting glycemic control and that Pharmaceuticals San Diego, California, additional exenatide, to a lesser degree USA, AstraZeneca, Mjölndal, Sweden, sitagliptin, provides additional post- Bayer Vital Pharma, Leverkusen, prandial glucose control, without the Germany, Berlin Chemie/Menarini, Berlin, necessity for a major change in insulin Germany, Biovitrum, Stockholm, dose because of hypoglycemia. In Schweden, Eli Lilly & Co., Indianapolis, addition, the weight-reducing ability of Indiana, USA,Glaxo, Smith, Kline, exenatide persists despite concomitant Munich, Germany, Hoffman La Roche, insulin administration. Longer-term Basel, Switzerland, Novartis Pharma, studies are warranted to further explore Basel, Switzerland/Nürnberg, Germany, the benefits of this novel treatment NovoNordisk, Copenhagen, Denmark, approach. Sanofi-Aventis Pharma, Bad Soden/Taunus, Germany, and Takeda, ACKNOWLEDGEMENTS Deerfield, IL, USA.. Christoph Kapitza is The authors would like to thank the shareholder of PROFIL Institut für clinical staff at PROFIL Institut für Stoffwechselforschung GmbH, which Stoffwechselforschung GmbH, Neuss, received research grants from several Germany, for their dedicated work. The pharmaceutical companies, including the study was funded by Sanofi-Aventis, insulin producing companies Eli Lilly, Paris, France. Sabine Arnolds, Sibylle Sanofi-Aventis (the manufacturer of Dellweg, Janina Clair, and Klaus Rave ) and Novo Nordisk (the are all employees of PROFIL Institut für manufacturer of insulin aspart). Stoffwechselforschung GmbH and have

REFERENCES 1. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-853

7 Adjunctive therapy of exenatide or sitagliptin to insulin glargine + metformin versus insulin glargine + metformin alone.

2. Nathan DM, Buse JB, Davidson MB, Heine RJ, Holman RR, Sherwin R, Zinman B. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2006;29:1963-1972 3. Van Avendonk MJP, Rutten EHM. Insulin therapy in type 2 diabetes: what is the evidence? Diabetes Obes Metab 2009;11:415-432 4. Mäkimattila S, Nikkilä K, Yki-Järvinen H. Causes of weight gain during insulin therapy with and without metformin in patients with type II diabetes mellitus. Diabetologia 1999;42:406-412 5. Klein S, Sheard NF, Pi-Sunyer X, Daly A, Wylie-Rosett J, Kulkarni K, Clark NG. Weight management through lifestyle modification for the prevention and management of type 2 diabetes: rationale and strategies: a statement of the American Diabetes Association, the North American Association for the Study of Obesity, and the American Society for Clinical Nutrition. Diabetes Care 2004;27:2067-2073 6. Owens DR, Bolli GB. Beyond the era of NPH insulin – long-acting insulin analogs: chemistry comparative pharmacology, and clinical application. Diabetes Technol Ther 2008;10 (5):333-349 7. Sanofi-Aventis Deutschland GmbH: Lantus®. Summary of Product Characteristics (SPC), September 2008. Available from URL: http//www.fachinfo.de (Accessed June 2009) 8. Riddle M, Rosenstock J, Gerich J. The treat-to-target trial. Randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 2003;26:3080-3086 9. Bazzano LA, Lee LJ, Shi L, Jackson JA, Fonseca V. Safety and efficacy of gl’argine compared with NPH insulin for the treatment of type 2 diabetes: a meta- analysis of randomized controlled trias. Diabet Med 2008;25:924-932 10. Lilly Deutschland GmbH. Byetta®. Summary of product characteristics. March 2009. Available from URL: http//www.fachinfo.de (Accessed June 2009) 11. Kendall DM, Riddle MC, Rosenstock R, Zhuang D, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care 2005;28:1083-1091 12. Heine RJ, Van Gaal LF, Johns D, Mihm J, Widel MH, Brodows RG. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes. Ann Intern Med 2005;143:559-569 13. Nauck MA, Duran S, Kim D, Johns D, Northrup J, Festa A, Brodows R, Trautmann M. A comparison of twice-daily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study. Diabetologia 2007;50:259-267 14. Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes. Systematic review and meta-analysis. JAMA 2007;298(2):194-206 15. MSD Sharp & Dohme GmbH. Januvia®. Summary of product characteristics. February 2008. Available from URL: http//www.fachinfo.de (Accessed June 2009)

2 Adjunctive therapy of exenatide or sitagliptin to insulin glargine + metformin versus insulin glargine + metformin alone.

16. Krentz AJ, Patel MB, Bailey CJ. New drugs for type 2 diabetes mellitus. What is their place in therapy? Drugs 2008;68(15):2131-2162 17. Barnett AH. New treatments in type 2 diabetes: a focus on the incretin-based therapies. Clin Endocrinol 2009;70:343-353 18. Nauck MA. Unraveling the science of incretin biology. Am J Med 2009;122:S3- S10 19. Gilbert MP, Pratley RE. Efficacy and safety of incretin-based therapies in patients with type 2 diabetes mellitus. Am J Med 2009;122:S11-S24 20. Mudaliar S, Henry RR. Incretin therapies: effects beyond glycemic control. Am J Med 2009;122:S25-S36 21. Kendall DM, Cuddihy RM, Bergenstal RM. Clinical application of incretin-based therapy: therapeutic potential, patient selection and clinical use. Am J Med 2009;122:S37-S50 22. World Medical Association. Declaration of Helsinki. Ethical principles for medical research involving human subjects. 52nd WMA general assembly, Edinburgh, Scotland, October 2000. Last amended with note of clarification on paragraph 29 by the WMA general assembly, Washington 2002, and the note of clarification on paragraph 30 by the WMA general assembly, Tokyo 2004 23. Linnebjerg H, Kothare PA, Skrivanek Z, de la Pena A, Atkins M, Ernest CS, Trautmann ME. Exenatide: effect of injection time on postprandial glucose in patients with type 2 diabetes. Diabet Med 2006;23:240-245 24. Amiel SA, Dixon T, Mann R, Jameson K. Hypoglycaemia in type 2 diabetes. Diabet Med 2008 ;25 :245-254 25. Monnier L, Colette C, Dunseath CJ, Owens DR. The loss of postprandial glycemic control precedes stepwise deterioration of fasting with worsening diabetes. Diabetes Care 2007;30:263-269

3 Adjunctive therapy of exenatide or sitagliptin to insulin glargine + metformin versus insulin glargine + metformin alone.

Table 1. Primary and secondary endpoints Parameter Time point GLAR+MET+EXE GLAR+MET+SITA GLAR+MET (n=15) (n=16) (n=16) AUC-BG 0-6h(mg/dL/h) EOT 606(104) + 612 (133) + 728 (132) BG 0-6h □(mg/dL) EOT 97 ’ 96 ‘ 116 Mean BG (mg/dL) EOT 97 (17)+ 100 (18)+ 121 (19) FBG (mg/dL) Baseline 94 96 94 EOT 82 * 84 * 89 Mean from self- Baseline – EOT 109 + 109 + 118 measured 7-point BG profiles (mg/dL) Self-measured FBG Baseline - EOT 93 93 96 (mg/dL) HbA1c (%) Screen 8.39 (0.98) 7.89 (0.48) 7.91 (0.57) EOT 6.53 (0.59) 6.41 (0.50) 6.73 (0.42) Change -1.80 *+ -1.49 * -1.23 *

HbA1c<7.0%(% patients) EOT 80 ° 88 ° 63 Changes in total Baseline - EOT -0.24 (0.48) ‘ -0.27 (0.61) ‘ 0.30 (0.52) * cholesterol (mmol/L) Changes in HDL- Baseline - EOT -0.04 (0.14) -0.04 (0.21) 0.08 (0.17) cholesterol (mmol/L) Changes in LDL- Baseline - EOT -0.30 (0.46) *+ -0.28 (0.42) *+ 0.09 (0.36) cholesterol (mmol/L) Changes in body weight Baseline - EOT -0.9 (1.7) *+ 0.1 (1.6) 0.4 (1.5) (kg) Hypoglycemic Major - - - episodes, n BG<50mg/dL 2 (1.68) 3 (2.45) 2 (1.62) (events/subj. year) Symptoms only 10 1 4 Adverse events, n (%) Total 47 (62.5) 12 (43.8) 10 (25.0) Gastro-intestinal 28 (56.3) 4 (18.8) 1 (6.3) disorders Means (SD)/ Geometric means (LS-means) in case of comparisons; Screen: before wash-out of oral agents except for metformin and run-in period, Baseline: prior to randomization, EOT: end of treatment, AUC-BG 0-6h: Area under the blood glucose curve 0-6h after a standard breakfast, *p<0.05 vs. Screen/Baseline, +p<0.05 vs. GLAR, °p<0.05 (X2-Test) vs. HbA1c<7.0%, ‘p<0.01 vs. GLAR, ~p<0.001 vs. GLAR, ^p<0.05 vs. GLAR+SITA, □ post-hoc analysis (repeated measure ANCOVA)

4 Adjunctive therapy of exenatide or sitagliptin to insulin glargine + metformin versus insulin glargine + metformin alone.

Fig 1

5 Adjunctive therapy of exenatide or sitagliptin to insulin glargine + metformin versus insulin glargine + metformin alone.

Fig 2

6