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

A Randomized Trial

  1. Bernard Zinman, MD;
  2. Byron J. Hoogwerf, MD;
  3. Santiago Durán García, MD;
  4. Denái R. Milton, MS;
  5. Joseph M. Giaconia, MS;
  6. Dennis D. Kim, MD;
  7. Michael E. Trautmann, MD; and
  8. Robert G. Brodows, MD
  1. 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.

    Abstract

    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 A1c 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 A1c level. Other outcomes were fasting serum glucose level, body weight, self-monitored blood glucose level, and any adverse events.

    Results: Exenatide treatment reduced hemoglobin A1c 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.

    Article and Author Information

    • 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.

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    1. Ann Intern Med April 3, 2007 vol. 146 no. 7 477-485
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