MANAGEMENT OF ENDOCRINE DISEASE: Are all GLP-1 agonists equal in the treatment of type 2 diabetes?

Abstract

GLP-1, a peptide hormone secreted from the gut, stimulating insulin and suppressing glucagon secretion was identified as a parent compound for novel treatments of diabetes, but was degraded (dipeptidyl peptidase-4) and eliminated (mainly by kidneys) too fast (half-life 1–2 min) to be useful as a therapeutic agent. GLP-1 receptor agonist has been used to treat patients with type 2 diabetes since 2007, when exenatide (twice daily) was approved in 2007. Compounds with longer duration of action (once daily, once weekly) and with increasingly better efficacy with respect to glycaemic control and body weight reduction have been developed, and in a recent ADA/EASD consensus statement, were recommended as the first injectable diabetes therapy after failure of oral glucose-lowering medications. Most GLP-1 receptor agonists (lixisenatide q.d., liraglutide q.d., exenatide q.w., dulaglutide q.w., albiglutide q.w., semaglutide q.w., all for s.c. injection, and the first oral preparation, oral semaglutide) have been examined in cardiovascular outcomes studies. Beyond proving their safety in vulnerable patients, most of whom had pre-existing heart disease, liraglutide, semaglutide, albiglutide, and dulaglutide reduced the time to first major adverse cardiovascular events (non-fatal myocardial infarction and stroke, cardiovascular death). Liraglutide, in addition, reduced cardiovascular and all-cause mortality. It is the purpose of the present review to describe clinically important differences, regarding pharmacokinetic behaviour, glucose-lowering potency, effectiveness of reducing body weight and controlling other cardiovascular risk factors, and of the influence of GLP-1 receptor agonist treatment on cardiovascular outcomes in patients either presenting with or without pre-existing cardiovascular disease (atherosclerotic, ischemic or congestive heart failure).

Differential GLP-1R binding and activation by peptide and non-peptide agonists

“…These peptides have been engineered to enhance pharmacokinetic profiles over the rapidly cleared native GLP-1 peptides, while maintaining potency at the GLP-1R. Nonetheless, there are differences in clinical efficacies of these drugs and some are also able to reduce body weight in obese patients, improve cardiovascular outcomes, and may have benefit for the treatment of neurodegenerative disorders (Brown et al, 2018;Grieco et al, 2019;Nauck and Meier, 2019). To date, the structures of active state GLP-1R:Gs complexes bound to either the native GLP-1 peptide or a G protein biased agonist, exendin-P5 (ExP5) have been determined using cryo-EM (Liang et al, 2018b;Zhang et al, 2017).…”

Benefits of the fixed‐ratio combination of insulin glargine 100 units/mL and lixisenatide (iGlarLixi) in Japanese people with type 2 diabetes: A subgroup and time‐to‐control analysis of the LixiLan JP phase 3 trials

“…[11][12][13][14] GLP-1 RAs enhance glucose-induced insulin secretion and suppress postprandial glucagon levels. [15][16][17] In addition, some GLP-1 RAs delay gastric emptying, thereby contributing to the suppression of postprandial glucose elevation. 17 DPP-4 inhibitors are the most widely prescribed oral hypoglycaemic drugs in Japan, and GLP-1 RA treatment is widely used, often as an addition to BI when this therapy has been ineffective in optimizing glycaemic levels.…”

GLP-1 receptor agonists in the treatment of type 2 diabetes: role and clinical experience to date

“…The benefits of GLP-1RAs extend beyond their well-established effects on glycemic control. Indeed, these agents have demonstrated a variety of nonglycemic clinical effects, including weight loss and decreased systolic blood pressure [21,[24][25][26].…”

“…While these agents share a common mechanism of action, there are a number of key differences between them, which can include duration of action, dosing frequency and regimen, and administration device (Table 1), allowing for individualization of treatment for patients. In terms of the duration of action on the GLP-1 receptor, agents in this class can be categorized as either short-acting (exenatide and lixisenatide) or long-acting (dulaglutide, exenatide extended-release, liraglutide, and semaglutide) [23,25,34]. Short-acting agents primarily reduce postprandial glucose by delaying gastric emptying, whereas long-acting agents have a greater effect than short-acting agents on fasting glucose, and offer the advantages of smaller fluctuations in plasma drug concentrations, improved gastrointestinal tolerability, and more convenient dosing regimens [23,34].…”