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Diabetes Care 26:2370-2377, 2003
© 2003 by the American Diabetes Association, Inc.

Emerging Treatments and Technologies
Original Article

Effect on Glycemic Control of Exenatide (Synthetic Exendin-4) Additive to Existing Metformin and/or Sulfonylurea Treatment in Patients With Type 2 Diabetes

Mark S. Fineman, BS, Thomas A. Bicsak, PHD, Larry Z. Shen, PHD, Kristin Taylor, PHD, Eling Gaines, BS, Amanda Varns, BA, Dennis Kim, MD and Alain D. Baron, MD

From Amylin Pharmaceuticals, Inc., San Diego, California

Address correspondence and reprint requests to Alain D. Baron, MD, Amylin Pharmaceuticals, Inc., 9373 Towne Centre Dr., San Diego, CA 92121. E-mail: abaron{at}amylin.com

OBJECTIVE—AC2993 (synthetic exendin-4; exenatide) is a peptide that enhances glucose-dependent insulin secretion, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying. AC2993 also promotes ß-cell proliferation and neogenesis in vitro and in animal models. This study examines the activity and safety of subcutaneously injected AC2993 in patients with type 2 diabetes currently treated with diet and/or oral antidiabetic agents (OAAs).

RESEARCH DESIGN AND METHODS—A total of 109 patients treated with diet and a sulfonylurea and/or metformin were enrolled in a blinded study. Patients were randomly assigned to one of three subcutaneously (SC) injected regimens of AC2993 (0.08 µg/kg) or placebo for 28 days.

RESULTS—All three AC2993 regimens led to significant reductions in serum fructosamine relative to placebo (P <= 0.004). Mean reductions ranged from 39 to 46 µmol/l. All AC2993 groups had reductions in HbA1c ranging from 0.7 to 1.1% (P <= 0.006). An end-of-study HbA1c <7% was achieved by 15% of AC2993 patients versus 4% of placebo patients, confirming AC2993 effects on fasting and postprandial glycemia. On days 14 and 28, the ß-cell index (homeostasis model assessment) for patients treated with AC2993 was 50–100% higher than baseline, contrasting with unchanged levels for placebo. The most common adverse event was transient mild-to-moderate nausea.

CONCLUSIONS—AC2993 is a promising therapeutic for patients with type 2 diabetes. In this study, it had significant effects on HbA1c levels in patients not currently achieving optimal glucose control with diet and/or OAAs.

Abbreviations: AUC, area under the concentration–time curve • BID, twice daily • DPP-IV, dipeptidyl peptidase-IV • GLP-1, glucagon-like peptide-1 • HOMA, homeostasis model assessment • HPLC, high-performance liquid chromatography • SC, subcutaneous • TID, thrice daily


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