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Abstract
With the advent of dipeptidyl peptidase (DPP)-4 inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) over the past decade, incretin therapy has become established as an important treatment strategy for Type 2 diabetes mellitus (T2DM), with an efficacy and safety profile distinct from that of other anti-hyperglycemic agents. However, our understanding of the optimal clinical use of incretins remains incomplete. This review focuses on the use of GLP-1 RAs in the treatment of T2DM, with reference to the differing dominant mechanisms of action between short- and long-acting GLP-1 RAs and the clinical implications of this difference. The role of GLP-1 and the effects of GLP-1 RAs in various organs other than the pancreas will also be discussed.
Financial & competing interests disclosure
D Yabe has taken part in advisory panels for Sanofi, Novo Nordisk, Inc. and Novartis Pharma AG, and has taken part in speaker’s bureaux for Sanofi, Novo Nordisk Inc., Merck Sharp & Dohme Limited, Takeda Pharmaceuticals USA, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company and Bristol-Myers Squibb Company. Y Seino has acted as medical advisor for Eli Lilly, Sanoi, Novo Nordisk, GlaxoSmithKline, Taisho Pharmaceuticals, Astellas Pharmaceuticals, Becton, Dickinson & Company, Boerhringer Ingelheim, Johnson & Johnson, Takeda Pharmaceuticals and Otsuka Pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Writing and editorial assistance was provided by A Shepherd of Caudex Medical, funded by Sanofi.
Key issues
Patients with Type 2 diabetes mellitus (T2DM) demonstrate an impaired capability to regulate their incretin effect, and correction of this dysfunction with exogenous glucagon-like peptide-1, GLP-1 receptor agonists (GLP-1 RAs), has become established as an important treatment strategy for T2DM, with an efficacy and safety profile distinct from that of other anti-diabetic agents.
The different GLP-1 RAs approved for use in patients with poorly controlled T2DM can be divided into two broad categories according to their relative half-lives as short- and long-acting GLP-1 RAs, which exert their glucose-lowering effects through different dominant mechanistic actions: delayed gastric emptying and enhanced insulin secretion.
Short-acting GLP-1 RAs have limited effects on insulin and glucagon secretion, but have a delaying effect on gastric emptying, which results in pronounced reductions in postprandial plasma glucose (PPG) levels by reducing the rate of glucose absorption from the small intestine.
Long-acting GLP-1 RAs have a limited effect on gastric emptying, but provide reductions in fasting plasma glucose (FPG) and PPG – the latter less robustly than short-acting GLP-1RAs – through amelioration of insulin and glucagon secretion.
The clinical implication of these mechanistic differences is that short-acting GLP-RAs are better suited to improve control of PPG excursions, even in patients with limited residual β-cell function, while long-acting GLP-1 RAs are more appropriate for patients needing control of FPG, in addition to PPG, but require a certain amount of residual β-cell function.
Compared with thiazolidinediones, sulfonylureas and glinides, GLP-1 RAs are associated with a relatively low risk of hypoglycemia, as GLP-1-induced stimulation of insulin is glucose-dependent and is negligible under conditions of hypoglycemia, although caution is advised if GLP-1 RAs are used in combination with sulfonylureas, as they may enhance β-cell sensitivity to this agent.
Both short- and long-acting GLP-1 RAs have a clinically demonstrable benefit in terms of weight, which can be helpful in ameliorating early T2DM and the effects of weight gain from other anti-diabetic therapies, such as insulin.
GLP-1 RAs also have well-documented benefits against risk factors for cardiovascular disease, including hypertension and dyslipidemia.
The most common class of adverse events experienced by patients receiving GLP-1 RAs are gastrointestinal adverse events, and although concerns have been raised about a potential increased risk of acute pancreatitis, thyroid C-cell hyperplasia and tumors, no increased risk has been identified.
GLP-1 RAs represent an attractive option as add-on therapy for patients who may not have adequate glycemic control with their existing treatment regimen, and in particular, the addition of GLP-1 RAs to basal insulin represents a clinically useful treatment option for patients with inadequate PPG control and body weight gain despite well-controlled FPG.
