Discovery and development of exenatide: the first antidiabetic agent to leverage the multiple benefits of the incretin hormone, GLP-1

Abstract

Introduction: The GLP-1 receptor agonist exenatide is synthetic exendin-4, a peptide originally isolated from the salivary secretions of the Gila monster. Exenatide was developed as a first-in-class diabetes therapy, with immediate- and extended-release formulations. In preclinical diabetes models, exenatide enhanced glucose-dependent insulin secretion, suppressed inappropriately elevated glucagon secretion, slowed gastric emptying, reduced body weight, enhanced satiety, and preserved pancreatic β-cell function. In clinical trials, both exenatide formulations reduced hyperglycemia in patients with type 2 diabetes mellitus (T2DM) and were associated with weight loss.

Areas covered: This article reviews the development of exenatide from its discovery and preclinical investigations, to the elucidation of its pharmacological mechanisms of action in mammalian systems. The article also presents the pharmacokinetic profiling and toxicology studies of exenatide, as well as its validation in clinical trials.

Expert opinion: GLP-1 receptor agonists represent a new paradigm for the treatment of patients with T2DM. By leveraging incretin physiology, a natural regulatory system that coordinates oral nutrient intake with mechanisms of metabolic control, these agents address multiple core defects in the pathophysiology of T2DM. Studies have identified unique benefits including improvements in glycemic control and weight, and the potential for beneficial effects on the cardiometabolic system without the increased risk of hypoglycemia associated with insulin therapy. Peptide hormone therapeutics can offer significant advantages over small molecule drug targets when it comes to specificity, potency, and more predictable side effects. As exemplified by exenatide, injectable peptides can be important drugs for the treatment of chronic diseases, such as T2DM.

Keywords::

• exenatide
• exendin-4
• GLP-1 receptor agonist
• type 2 diabetes mellitus

Acknowledgments

The authors thank LL Nielsen (LLNielsen Medical Writing LLC, Ramona, CA) for medical writing services; S Brunell for editorial assistance; and J Roth, D Roy, and K Tatarkiewicz for expert scientific input. The authors also thank all the members of the development teams at Amylin Pharmaceuticals, Inc., and Eli Lilly and Co. involved in the large bulk of work that resulted in successful registration of exenatide as a diabetes drug in multiple countries worldwide, and all individuals participating in the preclinical research and clinical trials.

Notes

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