John B. Buse, MD, PhD; Richard M. Bergenstal, MD; Leonard C. Glass, MD; Cory R. Heilmann, PhD; Michelle S. Lewis, PhD; Anita Y.M. Kwan, MS; Byron J. Hoogwerf, MD; Julio Rosenstock, MD
Insulin replacement in diabetes often requires prandial intervention to reach hemoglobin A1c (HbA1c) targets.
To test whether twice-daily exenatide injections reduce HbA1c levels more than placebo in people receiving insulin glargine.
Parallel, randomized, placebo-controlled trial, blocked and stratified by HbA1c 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)
59 centers in 5 countries.
Adults with type 2 diabetes and an HbA1c level of 7.1% to 10.5% who were receiving insulin glargine alone or in combination with metformin or pioglitazone (or both agents).
Assignment by a centralized, computer-generated, random-sequence interactive voice-response system to exenatide, 10 µg twice daily, or placebo for 30 weeks.
The primary outcome was change in HbA1c level. Secondary outcomes included the percentage of participants with HbA1c 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.
112 of 138 exenatide recipients and 101 of 123 placebo recipients completed the study. The HbA1c 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.
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 HbA1c levels, and more exenatide recipients than placebo recipients withdrew because of adverse events.
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.
Alliance of Eli Lilly and Company and Amylin Pharmaceuticals.
Does exenatide improve glycemic control in patients with type 2 diabetes that is already being treated with insulin?
Adults receiving insulin glargine alone or in combination with metformin or pioglitazone (or both agents) were randomly assigned to twice-daily injections of exenatide or placebo for 30 weeks. Exenatide reduced hemoglobin A1c levels and body weight more than placebo, but it caused nausea, diarrhea, vomiting, and headache. Rates of hypoglycemia seemed to be similar for both groups.
More exenatide recipients than placebo recipients withdrew from the study.
Adding exenatide improved glycemic control without increased hypoglycemia or weight gain in diabetic patients already treated with insulin, but it caused nausea, diarrhea, and vomiting.
Data are least-squares means estimated from a mixed model, in which the postbaseline response variable = treatment + pooled investigator + visit + baseline + (treatment × visit), and the participant is treated as a random effect with an unstructured covariance matrix. Error bars are 95% CIs. HbA1c = hemoglobin A1c.
* P < 0.001 for between-group comparisons.
Change from baseline in hemoglobin A1c level. Data are least-squares means estimated from a mixed model, in which the postbaseline response variable = treatment + pooled investigator + visit + baseline + (treatment × visit), and the participant is treated as a random effect with an unstructured covariance matrix. Error bars are 95% CIs.
Data are least-squares means estimated from a mixed model, in which the postbaseline response variable = treatment + pooled investigator + visit + baseline + baseline hemoglobin A1c stratum (≤8.0% or >8.0%) +(treatment × visit), and the participant is treated as a random effect with an unstructured covariance matrix. Error bars are 95% CIs. Top. Change in body weight from baseline. From week 2 to week 30, P < 0.001 for between-group comparisons. Bottom. Results of self-monitoring of blood glucose. PP = postprandial.
* P < 0.001 for between-group difference.
† P < 0.010 for between-group difference.
Appendix Table 1.
Appendix Table 2.
Appendix Table 3.
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John B. Buse, Richard M. Bergenstal, Leonard C. Glass, Cory R. Heilmann, Michelle S. Lewis, Anita Y.M. Kwan, et al. Use of Twice-Daily Exenatide in Basal Insulin–Treated Patients With Type 2 Diabetes: A Randomized, Controlled Trial. Ann Intern Med. 2011;154:103–112. doi: 10.7326/0003-4819-154-2-201101180-00300
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Published: Ann Intern Med. 2011;154(2):103-112.
Cardiology, Coronary Risk Factors, Diabetes, Endocrine and Metabolism.
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