Enrolled subjects were men or women aged 35–70 years, with type 2 diabetes for >6 months and <10 years, treated either with a stable dose of metformin with or without sulfonylureas or treated solely with a long- or intermediate-acting insulin formulation (insulin glargine, insulin detemir, or NPH insulin) with or without a stable dose of metformin for at least 3 months. Inclusion criteria included BMI between 21.0 and 39.9 kg/m2 inclusive, A1C ≥7.0 and ≤10.0%, and stable antihypertensive or lipid-lowering therapy for at least 3 months, if applicable. Subjects were excluded, if they had a history or evidence of any other clinically relevant medical conditions or had used a rapid-acting insulin or a mixed insulin formulation or any other oral antidiabetic agent except for metformin or metformin plus sulfonylurea during the previous 3 months. Exclusion criteria further included abnormal laboratory test results, in particular, alanine aminotransferase and/or aspartate aminotransferase ≥3 times the laboratory's upper limit of reference range or serum creatinine ≥1.6 mg/dl for men and ≥1.4 mg/dl for women, uncontrolled hypertension, anemia, recurrent hypoglycemia, or any systemic or topical treatment with drugs known to influence glucose metabolism.
This single-center, randomized, open-label, active comparator–controlled study with a three-arm parallel group design was performed between 9 January and 29 September 2008. It was conducted in accordance with the principles of the Declaration of Helsinki (22
) and approved by the local ethics committee and regulatory authorities. All subjects provided written informed consent.
Study protocol and treatment
After a screening visit (visit 0) to assess a subject's eligibility for study participation, a 4- or 8-week run-in period, depending on the subject's preexisting antidiabetic therapy, with insulin glargine at bedtime followed, starting at visit 1:4 weeks run-in for a subject who already had an insulin pretreatment or 8 weeks for a subject who had oral antidiabetes treatment only (OHA). Preexisting treatment with metformin was continued for the entire study, whereas sulfonylurea treatment was stopped at the beginning of the run-in period. All subjects received insulin glargine at bedtime, at a starting dose of 10 units for those subjects new to insulin. During the whole course of the study each subject's insulin glargine dose was titrated to a FBG target of ≤5.6 mmol/l (≤100 mg/dl) using a predefined treatment algorithm which, with slight modifications, corresponds to that used by Riddle et al. (8
) in the treat-to-target trial for the introduction of insulin glargine to oral antidiabetes drug–treated patients with type 2 diabetes. During the run-in period telephone contacts (two per week) and weekly outpatient visits (visits 2–4 or 2–4 d for the 8-week run-in) at the study site were performed. At the end of the run-in period, 2 days before allocation to one of the three treatment arms, the insulin glargine dose was reduced by 20% to avoid hypoglycemia. At visit 5 (baseline), subjects in an open-label fashion were randomly assigned to either the addition of exenatide or sitagliptin to insulin glargine plus metformin (GLAR + MET + EXE or GLAR + MET + SITA, respectively) or to the continuation of insulin glargine plus metformin alone (GLAR + MET) for 4 weeks. Exenatide was to be administered subcutaneously at a dose of 5 μg in the morning and evening (b.i.d.) for 2 weeks followed by 10 μg b.i.d. for the second 2 weeks. Sitagliptin was taken orally at a dose of 100 mg once daily in the morning. During the 4-week-treatment period, weekly visits (visits 6–8) at the study site plus twice weekly telephone contacts were continued to further titrate blood glucose to the FBG target of ≤5.6 mmol/l (≤100 mg/dl). The 4-week treatment period ended with a 24-h in-house visit, during which efficacy assessments were performed (visit 9). The study was completed with a final visit (visit 10) 2–10 days after the in-house stay.
During both the run-in and the treatment period, subjects self-measured and recorded their FBG (and any potential voluntary preprandial and/or postprandial blood glucose values) on a daily basis using a commercial glucose meter (Accu-Chek® Aviva; Roche Diagnostics, Mannheim, Germany). Once per week they performed 7-point blood glucose profiles at the following times: before and 2 h after breakfast, lunch, and dinner and before bedtime (11:00 p.m.). All results and times of self-measurements of blood glucose as well as insulin doses were entered by the subjects into a study diary. If at any time during the study (except at screening and the final visit) self-measured FBG values on 2 consecutive days of >13.3 mmol/l (>240 mg/dl) were confirmed at the site by means of a validated glucose oxidase method (Super-GL glucose analyzer; Hitado Diagnostic Systems, Möhnesee, Germany), the subject had to be withdrawn from the study. The same procedure applied for hypoglycemic blood glucose values occurring at 2 consecutive days. Hypoglycemia was classified as major if a subject was not able to treat the episode himself or herself, and as minor if the subject was able to treat the episode himself or herself and blood glucose was <2.8 mmol/l (<50 mg/dl) or if no blood glucose value was available or if blood glucose was ≥2.8 mmol/l (≥50 mg/dl) with symptoms only.
In addition to a thorough review of the subject's blood glucose values in the study diary and adjustments of the insulin glargine dose, the following assessments were performed at the weekly visits at the study site: vital signs, i.e., blood pressure and heart rate; adverse events and hypoglycemic episodes (at each visit); physical examination and safety laboratory (at screening, before random assignment at visit 5 and at the final visit); pregnancy test for women of child-bearing potential (at screening, at visits 5 and 9, and at the final visit); electrocardiogram (ECG) (at screening and at the final visit), FBG (at screening and at visits 5, 7, and 9 [on both days of the 24-h in-house stay]); and fasting lipid profile (at visits 5 and 9). At visit 9, during the 24-h in-house stay the following was assessed on day 1: dosing of either exenatide or sitagliptin 60 min before a standardized 618.2 kcal breakfast consisting of 99.4 g carbohydrates, 11.9 g lipids, and 26.2 g protein, a 7-point 24-h blood glucose profile, postprandial blood glucose excursions after the standardized breakfast (16 blood glucose samples from −30 to 360 min). On day 2 of the in-house stay, after completion of all assessments including A1C, the subjects were instructed on how to continue with their prestudy antidiabetes medication and were asked to measure at least FBG and document these measurements as well as any additional blood glucose values in the diary provided.
Study end points
The primary outcome measure was the unadjusted 6-h postprandial blood glucose excursion (AUC BG0–6 h) after ingestion of the standardized breakfast, assessed at the end of the 4-week treatment period. Secondary end points included the following: mean daily blood glucose as assessed by means of the 7-point 24-h blood glucose profile at the end of the 4-week treatment period, the subjects' self-measurements of FBG and the 7-point blood glucose profiles throughout the run-in and the treatment period, the percentage of subjects achieving American Diabetes Association treatment goals, i.e., A1C <7.0%, at the end of the treatment period, fasting lipid profile, body weight, each as assessed at the end of the treatment period, number and severity of hypoglycemic episodes, and general safety parameters (adverse events, physical examination, vital signs, safety laboratory parameters, and ECG recordings).
A sample size of 16 subjects per treatment arm (in a total of 48 subjects) was estimated to detect significant differences between treatments (23
). SAS (version 9.1; SAS Institute, Cary, NC) was used to conduct all statistical analyses. ANCOVA models, allowing the estimation of least squares means with corresponding 95% confidence limits, were used on untransformed Δ body weight, Δ lipids, and Δ A1C and on natural logarithm–transformed AUC BG(0–6 h)
, and 7-point blood glucose profile, with baseline assessments as confounders. ANCOVA models with repeated measures on the factor day were applied to test for differences in logarithm-transformed FBG and self-measured 7-point blood glucose. For log-transformed data, the calculated 95% CIs were back-transformed to derive the appropriate confidence limits for the geometric mean ratios of the pairwise treatment comparisons. Paired t
tests were used to test within-group changes, and for between-group comparisons unpaired t
tests were applied. χ2
tests were used to compare the frequency of subjects achieving ADA treatment goals (A1C <7.0%) and of subjects achieving International Diabetes Federation treatment goals (A1C <6.5%) at the end of the treatment period. Descriptive statistics on demographics, safety, and glycemic end points were provided for all randomly assigned subjects who received at least one dose of investigational medication. The areas under the blood glucose curve, extending from the meal intake to 6 h after ingestion, were calculated using the trapezoid rule. Δ A1C was determined as the difference of visit 9 A1C minus screening A1C. Δ body weight as well as Δ lipid were calculated as visit 9 values minus visit 5 values. The statistical significance level was set at P
< 0.05. Data are means ± SD if not otherwise stated.