Incretin-based Therapies: An Update from Literature

Introduction

Incidence of diabetes mellitus is dramatically increasing worldwide, and it has been estimated by the World Health Organization that more than 300 million people will be diagnosed with type 2 diabetes mellitus (T2D) in the next 20 years.1 The disease results in considerable morbidity and mortality, through the development of microvascular complications – retinopathy, nephropathy and neuropathy – as well as macrovascular complications, leading to high incidence of myocardial infarction, stroke and peripheral artery disease. Among the traditional pathophysiological mechanisms underlying the development of T2D are impaired insulin secretion deriving from β-cell failure, decreased glucose uptake by skeletal muscle and increased hepatic glucose production secondary to augmented gluconeogenesis.2 Beyond promoting physical activity and healthy dietetic habits, physicians can currently use several therapeutic options for people who have developed T2D, directed to enhance either insulin secretion or insulin sensitivity.3 Although much has been done to develop and provide new anti-diabetic agents which directly address the pathophysiological mechanisms underlying T2D, their use is often accompanied by a number of adverse side-effects, mainly including hypoglycemia, weight gain and edema. Most importantly, none of them is currently demonstrated to slow β-cell deterioration, a common feature in the natural history of T2D, which inexorably leads to the need for insulin replacement, or to reduce the risk of cardiovascular complications.

Abstract

Type 2 diabetes represents a chronic metabolic disease characterised by insulin-resistance and a progressive decline of pancreatic β-cell glucose-mediated insulin secretion. Beyond traditional therapeutic approaches, which are directed either to improve β-cell dysfunction, or to enhance insulin sensitivity, a relatively new concept of treatment for type 2 diabetes is based on the effects of several intestinal hormones, called incretins, which are normally secreted after a meal and contribute to glucose homeostasis by enhancing insulin secretion and inhibiting glucagon release in pancreatic islets in a glucose-dependent manner. Glucagon-like peptide-1 (GLP-1) is the incretin hormone that mainly enhances glucose-dependent insulin secretion and inhibits glucagon release. The resulting “incretin-based therapies”, based either on the development of mimetics of the GLP-1, or on the inhibition of the incretins degrading enzyme dipeptidyl peptidase 4 (DPP-4), have been reported to improve glycemic control with minimal risk of hypoglycemia in type 2 diabetic patients. Incretin-based therapy can exert several beneficial effects on blood pressure, myocardial function, dyslipidemia and, limited to GLP-1 analogues, body weight. Furthermore, in rodent models of diabetes, but not yet in humans, both GLP-1 receptor agonists and DPP-4 inhibitors have been demonstrated to improve pancreatic islets mass and preserve β-cell function. Along with a safety profile similar to other anti-diabetic agents, these glycemic and extraglycemic effects of incretin-based therapies make them promising therapeutic options in order to reduce the burden of cardiovascular risk, which still represents the major cause of mortality in type 2 diabetic patients.

Keywords

Type 2 diabetes, incretin mimetics, GLP-1, DPP-4