Glucagon‐like peptide‐1 receptor agonists in type 2 diabetes treatment: are they all the same?

Abstract

Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are an important class of drugs with a well-established efficacy and safety profile in patients with type 2 diabetes mellitus. Agents in this class are derived from either exendin-4 (a compound present in Gila monster venom) or modifications of human GLP-1 active fragment. Differences among these drugs in duration of action (ie, short-acting vs long-acting), effects on glycaemic control and weight loss, immunogenicity, tolerability profiles, and administration routes offer physicians several options when selecting the most appropriate agent for individual patients. Patient preference is also an important consideration. The aim of this review is to discuss the differences between and similarities of GLP-1 RAs currently approved for clinical use, focusing particularly on the properties characterising the single short-acting and long-acting GLP-1 RAs rather than on their individual efficacy and safety profiles. The primary pharmacodynamic difference between short-acting (ie, exenatide twice daily and lixisenatide) and long-acting (ie, albiglutide, dulaglutide, exenatide once weekly, liraglutide, and semaglutide) GLP-1 RAs is that short-acting agents primarily delay gastric emptying (lowering postprandial glucose) and long-acting agents affect both fasting glucose (via enhanced glucose-dependent insulin secretion and reduced glucagon secretion in the fasting state) and postprandial glucose (via enhanced postprandial insulin secretion and inhibition of glucagon secretion). Other advantages of long-acting GLP-1 RAs include smaller fluctuations in plasma drug concentrations, improved gastrointestinal tolerability profiles, and simpler, more convenient administration schedules (once daily for liraglutide and once weekly for albiglutide, dulaglutide, the long-acting exenatide formulation, and semaglutide), which might improve treatment adherence and persistence.

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

“…Native GLP-1 has a very short half-life, as it is rapidly degraded by proteases, namely the dipeptidyl peptidase (DPP)-4 enzyme [17][18][19]. To overcome this, GLP-1RAs have been developed that are structurally similar to GLP-1 with regard to their amino-acid sequences, but with modifications that provide stabilization against DPP-4 degradation and/or minimise their renal clearance, thereby increasing their duration of activity (Table 1).…”

Diabetes pharmacotherapy and effects on the musculoskeletal system

“…These contradictory findings could be related to the difference in the number of trials included in the meta‐analyses, different doses, and duration of therapy with GLP‐1R agonists and different analyses used to report comparisons between GLP‐1R agonists. Additionally, recent studies have reported differences in the effects on the gastrointestinal and cardiovascular system with use of short‐acting and long‐acting GLP‐1R agonists . Differential effects with the use of short‐acting versus long‐acting GLP‐1R agonists on the musculoskeletal system could also be responsible for lack of consensus between studies.…”

“…Additionally, recent studies have reported differences in the effects on the gastrointestinal and cardiovascular system with use of short-acting and long-acting GLP-1R agonists. 335 Differential effects with the use of short-acting versus longacting GLP-1R agonists on the musculoskeletal system could also be responsible for lack of consensus between studies. glucosuria.…”

Glucagon‐like peptide‐1 receptor agonists and risk of bone fracture in patients with type 2 diabetes: A meta‐analysis of randomized controlled trials

“…Moreover, it was reported that GLP‐1 might enhance bone mineral density and improve bone quality by promoting bone formation and inhibiting bone resorption . GLP‐1 RAs are a new class of anti‐diabetic drugs that mimic the effects of native GLP‐1, lead to robust glycemic control and weight loss, and different GLP‐1 RAs differ in several aspects owing to the difference in molecular structures . However, the effects of GLP‐1 RAs on bone fracture remains unclear.…”

“…12,13 GLP-1 RAs are a new class of anti-diabetic drugs that mimic the effects of native GLP-1, lead to robust glycemic control and weight loss, and different GLP-1 RAs differ in several aspects owing to the difference in molecular structures. 14 However, the effects of GLP-1 RAs on bone fracture remains unclear. Although many clinical trials and observational studies investigated the association between bone fracture and GLP-1 RAs, the results are inconsistent.…”