Clinical pharmacology of glucagon-like peptide-1 receptor agonists

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are an important asset in the armamentarium for the treatment of type 2 diabetes mellitus (type 2 DM). Incretin failure is a critical etiopathogenetic feature of type 2 DM, which, if reversed, results in improved glycaemic control. GLP-1 RAs are injectable peptides that resemble the structure and function of endogenous incretin GLP-1, but as they are not deactivated by the dipeptidyl peptidase-4 (DPP-4), their half-life is prolonged compared with native GLP-1. Based on their ability to activate GLP-1 receptor, GLP-1 RAs are classified as short-acting (exenatide twice-daily and lixisenatide once-daily), and long-acting (liraglutide once-daily and the once-weekly formulations of exenatide extended-release, dulaglutide, and albiglutide). Semaglutide, another long-acting, once-weekly GLP-1 RA, was recently approved by the FDA and EMA. Although all of these agents potently reduce haemoglobin A1C (HbA1c), there are unique features and fundamental differences among them related to fasting and postprandial hyperglycaemia reduction, weight loss potency, cardiovascular protection efficacy, and adverse events profile. It is imperative that current evidence be integrated and applied in the context of an individualised patient-centred approach. This should include not only glucose management but also targeting as many as possible of the pathophysiologic mechanisms responsible for type 2 DM development and progression.

Glucagon-Like Peptide-1 Receptor Agonists in Type 2 Diabetes: Their Use and Differential Features

“…When blood glucose levels are high, activation of the GLP-1 receptors by GLP-1RAs stimulates insulin secretion and lowers inappropriately high glucagon secretion in a glucose-dependent manner, thereby improving glycaemic control. When blood glucose levels are low, GLP-1RAs do not stimulate insulin secretion and do not impair glucagon secretion, which also helps maintain glycaemic control by reducing the risk of hypoglycaemia [17][18][19][20]. Reduced feelings of hunger and lowered energy intake also help patients lose weight.…”

“…Individual GLP-1RAs differ with regard to their pharmacological profiles and duration of activity due to several factors, including the rate of absorption, degree of binding to albumin/plasma proteins, degree of protection against metabolic degradation and rate of renal clearance (Table 1) [17][18][19][20]. Based on their duration of activation of the GLP-1 receptor, exenatide IR and lixisenatide are classified as short-acting GLP-1RAs, whereas liraglutide, dulaglutide, exenatide ER and semaglutide are classified as long-acting GLP-1RAs (Table 1).…”

“…Based on their duration of activation of the GLP-1 receptor, exenatide IR and lixisenatide are classified as short-acting GLP-1RAs, whereas liraglutide, dulaglutide, exenatide ER and semaglutide are classified as long-acting GLP-1RAs (Table 1). [17][18][19][20]. Unlike long-acting GLP-1RAs, short-acting GLP-1RAs are associated with substantial delays in gastric emptying [19].…”

“…Given the pharmacological differences between individual GLP-1RAs (Table 1), the drugs in this class may have differences in their effectiveness [18][19][20]22]. However, there are few RCTs that directly compare the relative efficacy of drugs in this class ( Table 2).…”

“…Due to their effects in delaying gastric emptying, shortacting GLP-1RAs had greater effects on post-prandial glucose levels than long-acting ones. However, the longacting GLP-1RAs offer the pharmacological advantage of reducing plasma glucose levels across the 1-day or 1-week administration intervals [18,20,22]. In a metaanalysis of RCTs comparing a GLP-1RA with placebo or another GLP-1RA [23], dulaglutide, exenatide, liraglutide and lixisenatide improved HbA 1c and fasting plasma glucose levels relative to placebo (semaglutide data were not available at the time of the meta-analysis).…”