Recent updates on GLP-1 agonists: Current advancements & challenges

by 996668pwpadmin 未分类

Abstract

Glucagon-like peptide (GLP)-1 is an incretin hormone exhibiting several pharmacological actions such as neuroprotection, increased cognitive function, cardio-protection, decreased hypertension, suppression of acid secretion, increase in lyposis, and protection from inflammation. The most potent actions are glucose-dependent insulinotropic and glucagonostatic actions, stimulation of β-cell proliferation, enhanced insulin secretion and reduced weight gain in patients with type-2 diabetes pertaining to blood glucose control. Despite all these actions, its short half-life (around 2∼min) and degradation by a dipeptidyl peptidase-4 enzyme (DPP-4) limits the therapeutic utility of GLP1. In this review, we have discussed DPP IV-resistant analogs of GLP-1 currently present in clinical trials such as Exenatide, Liraglutide, Semaglutide, Efpeglenatide, Exenatide ER, Ittca 650 (Intarcia), Dulaglutide, Albiglutide, and Lixisenatide. Moreover, we have also discussed in detail the pharmacology, signaling mechanisms, and pharmacokinetic properties (Cmax, Tmax, T1/2, Vd, and Bioavailability) of DPP IV-resistant analogs of (GLP-1). Interestingly, GLP-1 agonist drugs have shown better potential to treat type-2 diabetes mellitus (T2DM) as compared to currently used drugs in clinics without causing the side effects of hypoglycemia and weight gain.

Introduction

Oral glucose administration elicits a larger insulin secretion than intravenous glucose when glucose levels are matched. This is called the incretin effect. It is attributed to an augmented glucose-stimulated insulin secretion induced by the gut incretin hormones released after oral glucose, the most important being glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) [1]. GLP-1 is a 30 amino acid peptide which is a product of the proglucagon gene in the intestinal L-cells and released after meal ingestion [1]. GLP-1 is the endogenous ligand of the G (Gαs) protein coupled GLP-1 receptors, which are expressed in a number of organs, including the pancreatic beta cells. Activation of the GLP-1 receptors elevates cAMP levels through the action of adenylate cyclase; cAMP in turn activates protein kinase A and Epac 1 and 2, resulting in a stimulation of insulin secretion in a glucose-dependent manner [2].

GLP-1 also increases beta cell mass through stimulated neogenesis and proliferation and inhibited apoptosis, as shown in rodents [3]. Furthermore, GLP-1 inhibits glucagon secretion, which, as the stimulation of insulin secretion, is exerted in a glucose-dependent manner [4]. Other effects of GLP-1 include inhibition of gastric emptying [5] and induction of satiety with reduction in food intake [6]. Since all these effects are of potential value in the treatment of type 2 diabetes, GLP-1 has been explored as a pharmacological therapy for the disease.

The original evidence that GLP-1 might be a potential target in the treatment of type 2 diabetes was reported in the early 1990s in a study showing that intravenous infusion of GLP-1 to subjects with diabetes reduces the insulin requirement to meal ingestion [7]. The antidiabetic action of GLP-1 was later confirmed in a number of other clinical and experimental studies; a particular important contribution was a study showing improved glycemic control and reduction in body weight after six weeks continuous subcutaneous infusion of GLP-1 in subjects with type 2 diabetes [8]. A challenge in the development of GLP-1 based therapy was that the active form of GLP-1 has a short half-life of only 1–2 min, because it is rapidly inactivated through truncation of the peptide by removal of the N-terminal dipeptide end through the enzyme dipeptidyl peptidase-4 (DPP-4) [1]. Two strategies have been explored to overcome this challenge. One strategy is the use of GLP-1 receptor agonists, which are largely resistant to the action of DPP-4, whereas the other approach is to inhibit the enzyme DPP-4, which prevents the inactivation of GLP-1 and thereby enhances and prolongs the action of the endogenous incretin hormone [9]. Both these approaches are now, after many years of development, established in the clinical management of type 2 diabetes over the world [9].

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