Safety and tolerability of glucagon-like peptide-1 receptor agonists: unresolved and emerging issues

ABSTRACT

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a mainstay of treatment options for type 2 diabetes. They contribute to lowering blood glucose levels, generally have a favorable tolerability profile, and can be used alone or in combination with other antidiabetic agents. Based on the duration of their effects, GLP-1 RAs can be divided into two classes: short-acting and long-acting. Differences exist between these sub-classes, and between each drug, in terms of pharmacokinetic and pharmacodynamic profiles. Therefore, prescribers cannot necessarily assume GLP-1 RA ‘class effects’, especially in terms of tolerability.

Areas covered: This article reviews the published data on the safety and tolerability of currently available GLP-1 RAs and, recognizing the importance of safety profiles when selecting the appropriate treatment for each patient, examines the clinical implications of the differences between the drugs in this class. Cardiovascular safety, gastrointestinal tolerability, and tolerability in elderly patients are discussed as specific areas of interest to prescribers selecting between GLP-1 RAs for their patients.

Expert opinion: Although further research is needed, the current evidence offers the potential to tailor treatment more accurately to each patient. Ultimately, this may improve adherence and persistence, thereby improving glycemic control and, in turn, reducing the risk of macro- and micro-vascular complications.

KEYWORDS:

• Glucagon-like peptide-1 receptor agonists
• incretin effect
• incretins
• tolerability and safety
• type 2 diabetes

Article highlights

• GLP-1 RAs, which can be used alone or in combination with other antidiabetic agents, contribute to lowering blood glucose levels and are generally well tolerated.

• GLP-1 RAs can be broadly divided into two classes: short-acting and long-acting. Pharmacokinetic and pharmacodynamic differences exist between these sub-classes, and between individual drugs.

• The apparent differences between the various GLP-1 RAs in terms of cardiovascular safety, gastrointestinal tolerability, and general tolerability in the elderly may result from differences in the structures of the molecules, although this remains to be confirmed.

• Few direct safety and tolerability comparisons can be made between the GLP-1 RAs as only a small number of studies (mostly open label with short durations) directly compare the different drugs.

This box summarizes key points contained in the article.

Declaration of interest

D Raccah has served on an advisory panel and as speaker for AstraZeneca, Eli Lilly, Janssen, Novartis, Novo Nordisk, and Sanofi. The author has 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.

Additional information

Funding

Editorial assistance for this publication was provided by Mark Greener (for Caudex, Oxford, UK) and Lisa Tatler (Caudex, Oxford, UK), and was funded by Sanofi.