Use of Twice-Daily Exenatide in Basal Insulin–Treated Patients With Type 2 Diabetes: A Randomized, Controlled Trial

Background: Insulin replacement in diabetes often requires prandial intervention to reach hemoglobin A 1c (HbA 1c ) targets. Objective: To test whether twice-daily exenatide injections reduce HbA 1c levels more than placebo in people receiving insulin glargine. Design: Parallel, randomized, placebo-controlled trial, blocked and stratified by HbA 1c level at site, performed from October 2008 to January 2010. Participants, investigators, and personnel conducting the study were masked to treatment assignments. (ClinicalTrials.gov registration number: NCT00765817) Setting: 59 centers in 5 countries. Patients: Adults with type 2 diabetes and an HbA 1c level of 7.1 % to 10.5% who were receiving insulin glargine alone or in combination with metformin or pioglitazone (or both agents). Intervention: Assignment by a centralized, computer-generated, random-sequence interactive voice-response system to exenatide, 10 μg twice daily, or placebo for 30 weeks. Measurements: The primary outcome was change in HbA 1c level. Secondary outcomes included the percentage of participants with HbA 1c values of 7.0% or less and 6.5% or less, 7-point self-monitored glucose profiles, body weight, waist circumference, insulin dose, hypoglycemia, and adverse events. Results: 112 of 138 exenatide recipients and 101 of 123 placebo recipients completed the study. The HbA 1c level decreased by 1.74% with exenatide and 1.04% with placebo (between-group difference, -0.69% [95% CI, -0.93% to -0.46%]; P < 0.001). Weight decreased by 1.8 kg with exenatide and increased by 1.0 kg with placebo (between-group difference, -2.7 kg [CI, -3.7 to -1.7]). Average increases in insulin dosage with exenatide and placebo were 13 U/d and 20 U/d. The estimated rate of minor hypoglycemia was similar between groups. Thirteen exenatide recipients and 1 placebo recipient discontinued the study because of adverse events (P < 0.010); rates of nausea (41 % vs. 8%), diarrhea (18% vs. 8%), vomiting (18% vs. 4%), headache (14% vs. 4%), and constipation (10% vs. 2%) were higher with exenatide than with placebo. Limitations: The study was of short duration. There were slight imbalances between groups at baseline in terms of sex, use of concomitant glucose-lowering medications, and HbA 1c levels, and more exenatide recipients than placebo recipients withdrew because of adverse events. Conclusion: Adding twice-daily exenatide injections improved glycemic control without increased hypoglycemia or weight gain in participants with uncontrolled type 2 diabetes who were receiving insulin glargine treatment. Adverse events of exenatide included nausea, diarrhea, vomiting, headache, and constipation. Primary Funding Source: Alliance of Eli Lilly and Company and Amylin Pharmaceuticals.