Evolution of Exenatide as a Diabetes Therapeutic

Abstract

Type 2 diabetes (T2DM) is a disease of epidemic proportion associated with significant morbidity and excess mortality. Optimal glucose control reduces the risk of microvascular and possibly macrovascular complications due to diabetes. However, glycemic control is rarely optimal and several therapeutic interventions for the treatment of diabetes cause hypoglycemia and weight gain; some may exacerbate cardiovascular risk. Exenatide (synthetic exendin-4) is a glucagon-like peptide-1 receptor (GLP-1R) agonist developed as a first-in-class diabetes therapy. This review presents an overview of the evolution of exenatide as a T2DM treatment, beginning with the seminal preclinical discoveries and continuing through to clinical pharmacology investigations and phase 3 clinical trials. In patients with T2DM, exenatide enhanced glucose-dependent insulin secretion, suppressed inappropriately elevated glucagon secretion, slowed gastric emptying, and enhanced satiety. In controlled phase 3 clinical trials ranging from 12 to 52 weeks, 10-mcg exenatide twice daily (ExBID) reduced mean HbA 1c by -0.8% to -1.7% as monotherapy or in combination with metformin (MET), sulfonylureas (SFU), and/or thiazolidinediones (TZD); with mean weight losses of -1.2 kg to -8.0 kg. In controlled phase 3 trials ranging from 24 to 30 weeks, a 2-mg once-weekly exenatide formulation (ExQW) reduced mean HbA 1c by -1.3% to -1.9%, with mean weight reductions of -2.3 to -3.7 kg. Exenatide was generally well-tolerated. The most common side effects were gastrointestinal in nature, mild, and transient. Nausea was the most prevalent adverse event. The incidence of hypoglycemia was generally low. By building upon early observations exenatide was successfully developed into an effective diabetes therapy.

Clinical relevance of epigenetics in the onset and management of type 2 diabetes mellitus

“…Synthetic analogs of exendin-4 have been approved for diabetes therapy, and their efficacy is mostly linked to their resistance to degradation by DPP-4, the enzyme that quickly degrades endogenous GLP-1. 114 Later studies suggested that epigenetic effects, such as DNA methylation and/or histone modifications, could mediate the effects of exendin-4 and its synthetic analogs. 115 However, it is not known whether these peptides exert the anti-diabetic effect by inducing epigenetic changes, and their classification as epidrug remains hypothetical.…”

Effects of Glucagon-Like Peptide-1 Receptor Agonists on β-Cell Function in Patients with Type 2 Diabetes

“…In contrast, rosiglitazone was associated with a two-fold increase in insulin sensitivity, while exenatide twice daily had no significant insulin-sensitizing effect. β-cell function was further evaluated using the disposition index, which is calculated from hyperglycemic and glucagon secretion [14], which in turn reduces hepatic glucose production [15]. Furthermore, GLP-1RAs slow gastric emptying, decrease food intake, and promote satiety [14].…”

“…β-cell function was further evaluated using the disposition index, which is calculated from hyperglycemic and glucagon secretion [14], which in turn reduces hepatic glucose production [15]. Furthermore, GLP-1RAs slow gastric emptying, decrease food intake, and promote satiety [14]. Because native GLP-1 and GLP-1RAs were shown to reduce apoptosis and/or increase cellular proliferation and β-cell mass in rodent models of diabetes and insulin resistance [16,17], it was hypothesized that GLP-1RAs may modify β-cell function in patients with T2D.…”

Evaluation of the Dual-Chamber Pen Design for the Injection of Exenatide Once Weekly for the Treatment of Type 2 Diabetes

“…[1][2][3] In 2012, the US FDA approved a long-acting formulation of exenatide for once-weekly administration that can be administered regardless of meal times; 4 European Medicines Agency approval occurred in 2011. The long-acting, sustained release of exenatide is achieved by dispersion of the parent exenatide molecule in poly-(D,L-lactide-co-glycolide) polymer microspheres approximately 0.06 mm in diameter.…”

“…After injection of microspheres into the subcutaneous space, gradual biodegradation of the polymer matrix into CO 2 and H 2 O releases exenatide continuously over an extended duration. With regular once-weekly dosing, mean exenatide levels exceed the minimal effective concentration (50 pg/mL) in 2 weeks and achieve steady state in 6-7 weeks, resulting in consistent concentrations of exenatide.…”