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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 7 3082-3089
Copyright © 2003 by The Endocrine Society

Synthetic Exendin-4 (Exenatide) Significantly Reduces Postprandial and Fasting Plasma Glucose in Subjects with Type 2 Diabetes

Orville G. Kolterman, John B. Buse, Mark S. Fineman, Eling Gaines, Sonja Heintz, Thomas A. Bicsak, Kristin Taylor, Dennis Kim, Maria Aisporna, Yan Wang and Alain D. Baron

Amylin Pharmaceuticals, Inc. (O.G.K., M.S.F., E.G., S.H., T.A.B., K.T., D.K., M.A., Y.W., A.D.B.), San Diego, California 92121; and University of North Carolina School of Medicine (J.B.B.), Chapel Hill, North Carolina 27599

Address all correspondence and requests for reprints to: Alain D. Baron, M.D., Amylin Pharmaceuticals, Inc., 9373 Towne Centre Drive, San Diego, California 92121. E-mail: abaron{at}amylin.com.

Despite the advent of new treatments, glucose control in the type 2 diabetes population is unsatisfactory. AC2993 (synthetic exendin-4; exenatide), a novel glucose-dependent insulinotropic agent, exhibited notable antidiabetic potential in two clinical studies in patients with type 2 diabetes. In study A, 24 subjects received sc injections of study medication (0.1 µg/kg AC2993 or placebo) twice daily with meals for 5 d. Statistically significant reductions in mean postprandial circulating concentrations of glucose, insulin, and glucagon occurred following treatment with AC2993. In study B, 13 subjects receiving a single dose of study medication (0.05, 0.1, or 0.2 µg/kg AC2993 or placebo) following an overnight fast had reduced fasting plasma glucose concentrations during the subsequent 8-h period. The relative glucose and insulin concentration profiles were consistent with glucose-dependent insulinotropism. AC2993 was well tolerated. Mild transient headache, nausea, and vomiting were the main adverse events. In conclusion, AC2993 acutely and markedly reduces fasting and postprandial glucose concentrations in patients with type 2 diabetes. During fasting, glucose-dependent enhancement of insulin secretion and suppression of glucagon secretion are the predominant mechanisms, and postprandially, slowing of gastric emptying is additionally operative. This robust antidiabetic effect warrants further evaluation of AC2993.

This work was supported by Amylin Pharmaceuticals, Inc. (San Diego, CA).

Abbreviations: AUC, Area under the curve; BID, administered twice daily; GLP-1, glucagon-like peptide-1; HbA1c, hemoglobin A1c; OAA, oral antidiabetic agent.




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