Incretin-Based Therapy

Introduction

As proposed by De Fronzo in his 2008 Banting Lecture, the defects leading to the onset and the progression of type 2 diabetes mellitus can be described as an “ominous octet” composed not only by the beta-cell, the liver, and the skeletal muscle (the “traditional” culprits) but also the adipocytes, the gastrointestinal tract (in relation to the alleged deficiency in incretin secretion), the alpha-cell (inappropriately high glucagon levels), the kidney (increased glucose reabsorption), and the brain/central nervous system (inappropriate substrates and insulin sensing). This has important clinical implications, namely: (1) management of type 2 diabetes should target the known pathogenic abnormalities characterizing the disease rather than just aim at reducing hemoglobin A; (2) doing so demands the use of a combination of agents aimed at different targets; and (3) since many of the underlying defects are present early in the natural course of the disease, therapy should be initiated as soon as possible to protect the remaining beta-cell function.1 To successfully improve patient outcomes and to minimize the risk of complications, treatment should ideally protect and/or restore beta-cell function and decrease HbA1c, fasting plasma glucose (FPG), and postprandial plasma glucose (PPG) levels without increasing the risk of hypoglycemia or inducing weight gain or other changes potentially negatively affecting cardiovascular risk.2

Abstract

Despite availability of several oral hypoglycemic agents, safe and effective treatment still represents a challenge in type 2 diabetes (T2DM) and a large percentage of patients do not reach the therapeutic goal of a near normal HbA1c value. Incretin-based therapies represent a relatively new treatment approach that may address some of the shortfalls of the traditional treatments. “Incretins” are hormones secreted by the gastrointestinal tract upon food intake. Glucagone like peptide-1 (GLP-1), the first incretin to be described, potentiates glucose-dependent insulin secretion and appears capable, at least in vitro and in animal models, to preserve beta-cell mass and function. Due to its characteristics, GLP-1 is considered a very attractive molecule for treatment of type 2 diabetes. However, native GLP-1 is rapidly degraded by the enzyme dipeptidyl-peptidase IV (DPP-4) and, therefore, it is not suitable for clinical use. This has led to development of the two classes of incretin-based drugs that are presently approved for type 2 diabetes treatment: DPP-4 inhibitors (or incretin enhancers) that are small compounds readily absorbable when assumed orally, which will prolong endogenous GLP-1 half-life and GLP-1-receptor agonists (or GLP-1 mimetics), which are injectable molecule mimicking endogenous GLP-1 action but with a longer half-life. Efficacy, safety, and clinical use of the available compounds of these two classes are discussed in this review. It is concluded that, on the basis of the available evidence, incretin-based therapies do represent a very flexible tool to achieve optimal blood glucose control in type 2 diabetic patients.

Keywords

Incretin, GLP-1, DPP-4 inhibitors, T2DM