The Effect of Adding Exenatide to a Thiazolidinedione in Suboptimally Controlled Type 2 Diabetes

A Randomized Trial

3 April 2007 | Volume 146 Issue 7 | Pages 477-485

Background: Exenatide therapy is effective in combination with metformin or sulfonylureas for treating type 2 diabetes. Thiazolidinediones (TZDs) also are commonly used, but the efficacy of exenatide with a TZD has not been reported.

Objective: To compare the effects of exenatide versus placebo on glycemic control.

Design: Placebo run-in, randomized, double-blind, placebo-controlled trial conducted from May 2004 to August 2005.

Setting: 49 sites in Canada, Spain, and the United States.

Patients: 233 (exenatide group, n = 121; placebo group, n = 112) patients with type 2 diabetes that was suboptimally controlled with TZD treatment (with or without metformin). Mean (±SE) baseline glycated hemoglobin A_1c level was 7.9% ± 0.1%.

Interventions: Subcutaneous abdominal injections of 10 µg of exenatide or placebo twice daily, added to a TZD (with or without metformin) for 16 weeks.

Measurements: The primary outcome was change from baseline in hemoglobin A_1c level. Other outcomes were fasting serum glucose level, body weight, self-monitored blood glucose level, and any adverse events.

Results: Exenatide treatment reduced hemoglobin A_1c level (mean difference, –0.98% [95% CI, –1.21% to –0.74%]), serum fasting glucose level (mean difference, –1.69 mmol/L [–30.5 mg/dL] [CI, –2.22 to –1.17 mmol/L {–40.0 to –21.1 mg/dL}]), and body weight (mean difference, –1.51 kg [CI, –2.15 to –0.88 kg]). Sixteen percent of patients in the exenatide group and 2% of patients in the placebo group discontinued treatment because of adverse events. In the exenatide group, 40% (n = 48) of patients experienced nausea (mostly mild [n = 21] or moderate [n = 19]), 13% experienced vomiting, and 11% experienced hypoglycemia. In the placebo group, 15% of patients experienced nausea, 1% experienced vomiting, and 7% experienced hypoglycemia.

Limitations: Combinations with TZDs and sulfonylureas were not tested. Trial duration was relatively short. Only 71% and 86% of patients in the exenatide and placebo groups, respectively, completed the study.

Conclusions: Exenatide therapy improved glycemic control, reduced body weight, and caused gastrointestinal symptoms more than placebo in patients with type 2 diabetes that was suboptimally controlled with TZD therapy.

ClinicalTrials.gov registration number: NCT00099320.

For more information on exenatide click here.

Editors' Notes Context The effects of adding exenatide to thiazolidinediones (TZDs) for treating type 2 diabetes are not clear. Contribution The investigators of this double-blind trial randomly assigned 233 adults with type 2 diabetes that was suboptimallycontrolled with TZD (with or without metformin) to twice-daily injections of exenatide or placebo. At 16 weeks, exenatide reduced hemoglobin A1c levels (mean difference, –0.98%), fasting glucose levels (mean difference, –1.69 mmol/L [–30.5 mg/dL]), and body weight (mean difference, –1.51 kg) more than placebo. More patients in the exenatide group than in the placebo group had nausea (40% vs. 15%) and vomiting (13% vs. 1%). Implications Adding exenatide to TZD modestly improves glycemic control and reduces body weight but causes nausea and vomiting in some patients. —The Editors

 

Author and Article Information

From the Samuel Lunenfeld Research Institute, Mount Sinai Hospital, and University of Toronto, Toronto, Ontario, Canada; The Cleveland Clinic, Cleveland, Ohio; Hospital Universitario Nuestra Señora de Valme, Seville, Spain; Eli Lilly and Company, Indianapolis, Indiana; Amylin Pharmaceuticals, San Diego, California; and Eli Lilly and Company, Hamburg, Germany.

Acknowledgments: The authors thank David Kendall, Michael Mihm, Jill Beach, Margaret Perry, and William Gurdian for their contributions to the conduct of the study and the development of the manuscript.

Grant Support: By Eli Lilly and Company, Indianapolis, Indiana, and Amylin Pharmaceuticals, San Diego, California.

Potential Financial Conflicts of Interest: Employment: D.R. Milton (Eli Lilly and Company), J.M. Giaconia (Eli Lilly and Company), D.D. Kim (Amylin Pharmaceuticals Inc.), M.E. Trautmann (Eli Lilly and Company), R.G. Brodows (Eli Lilly and Company); Consultancies: B. Zinman (Amylin Pharmaceuticals Inc., Eli Lilly and Company), B.J. Hoogwerf (Amylin Pharmaceuticals Inc.); Honoraria: B. Zinman (Eli Lilly and Company), B.J. Hoogwerf (Amylin Pharmaceuticals Inc., Eli Lilly and Company), S. Durán García (Eli Lilly and Company); Stock ownership or options (other than mutual funds): D.R. Milton (Eli Lilly and Company), J.M. Giaconia (Eli Lilly and Company), D.D. Kim (Amylin Pharmaceuticals Inc.), M.E. Trautmann (Eli Lilly and Company), R.G. Brodows (Eli Lilly and Company); Grants received: B. Zinman (Eli Lilly and Company); Patents pending: M.E. Trautmann (Eli Lilly and Company).

Requests for Single Reprints: Bernard Zinman, MD, Mount Sinai Hospital, 60 Murray Street, Suite L 5-024, Mail Box 17, Toronto, M5T 3L9 Ontario, Canada; e-mail, zinman{at}mshri.on.ca.

Current Author Addresses: Dr. Zinman: Mount Sinai Hospital, 60 Murray Street, Suite L 5-024, Mail Box 17, Toronto, M5T 3L9 Ontario, Canada.

Dr. Hoogwerf: Desk A-53, Endocrinology, Diabetes and Metabolism, The Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195.

Dr. Durán García: Department of Endocrinology, Valme Hospital, 41018 Seville, Spain.

Ms. Milton, Mr. Giaconia, and Dr. Brodows: Eli Lilly and Company, Lilly Corporate Center, DC 6015, Indianapolis, IN 46285.

Dr. Kim: Amylin Pharmaceuticals, 9360 Towne Centre Drive, San Diego, CA 92121.

Dr. Trautmann: Lilly Research, Essener Bogen 7, Hamburg, D-22419, Germany.

Author Contributions: Conception and design: B. Zinman, D.D. Kim, M.E. Trautmann, R.G. Brodows.

Analysis and interpretation of the data: B. Zinman, B.J. Hoogwerf, S. Durán García, D.R. Milton, J.M. Giaconia, D.D. Kim, M.E. Trautmann, R.G. Brodows.

Drafting of the article: B. Zinman, B.J. Hoogwerf, S. Durán García, D.R. Milton, J.M. Giaconia, D.D. Kim, M.E. Trautmann, R.G. Brodows.

Critical revision of the article for important intellectual content: B. Zinman, B.J. Hoogwerf, S. Durán García, D.R. Milton, J.M. Giaconia, D.D. Kim, R.G. Brodows.

Final approval of the article: B. Zinman, B.J. Hoogwerf, S. Durán García, D.R. Milton, J.M. Giaconia, D.D. Kim, M.E. Trautmann, R.G. Brodows.

Provision of study materials or patients: B. Zinman, S. Durán García.

Statistical expertise: D.R. Milton.

Administrative, technical, or logistic support: B. Zinman, J.M. Giaconia, R.G. Brodows.