Cardiovascular safety and benefits of GLP-1 receptor agonists

ABSTRACT

Introduction: Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) constitute a class of drugs for the treatment of type 2 diabetes, and currently, six different GLP-1RAs are approved. Besides improving glycemic control, the GLP-1RAs have other beneficial effects such as weight loss and a low risk of hypoglycemia. Treatment with the GLP-1RA lixisenatide has been shown to be safe in patients with type 2 diabetes and recent acute coronary syndrome. Furthermore, liraglutide and semaglutide have been shown to reduce cardiovascular (CV) disease (CVD) risk in type 2 diabetes patients with established and/or high risk of CVD. The CV safety of the remaining GLP-1RAs in type 2 diabetes patients with established and/or high risk of CVD remains uncertain, but ongoing CV outcome trials (CVOTs) will elucidate this within a few years.

Areas covered: The aim of this review is to provide an overview of the existing GLP-1RAs with a particular focus on their clinical effects on CV risk factors and their CV safety and benefits.

Expert opinion: Data on the CV risks and benefits associated with GLP-1RA treatment in patients with type 2 diabetes and high risk of CVD are emerging – and look promising (especially for liraglutide and semaglutide). Data from ongoing CVOTs will be crucial for the positioning of the individual GLP-1RAs in the treatment of patients with type 2 diabetes and high risk of CVD. However, the long-term CV safety and the potential of GLP-1RAs to prevent CVD in type 2 diabetes patients with less risk of CVD (e.g. newly diagnosed patients) remain uncertain.

KEYWORDS:

• Cardiovascular safety
• glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs)
• type 2 diabetes

Article highlights

• Currently, six GLP-1RAs (exenatide BID, exenatide QW, lixisenatide, liraglutide, dulaglutide and albiglutide) are available and other GLP-1RAs are under late-stage clinical development (e.g. semaglutide and ITCA 650).

• In addition to glycemic control, the GLP-1RAs have been shown to improve CV risk factors (body weight, systolic blood pressure and blood lipids) with different effectiveness.

• The precise mechanisms behind these actions are unknown, but could depend on individual pharmacokinetics and pharmacodynamics. Whether and how these beneficial effects translate into better CV outcomes are unknown.

• Compared to placebo, lixisenatide is associated with a neutral CV risk profile in type 2 diabetes patients with recent acute coronary syndrome.

• Compared to placebo in type 2 diabetes patients with established CVD and/or a high risk of CVD, both liraglutide and semaglutide improve CV outcomes, driven by reduced CV-related mortality and non-fatal stroke, respectively. The mechanisms behind these actions are unknown.

• The pending CVOTs evaluating the GLP-1RAs exenatide QW, dulaglutide and albiglutide will be crucial for positioning the GLP-1RA class in the treatment of type 2 diabetes patients with a high risk of CVD.

• The long-term CV safety of GLP-1RAs in type 2 diabetes patients with less risk of CVD (e.g. newly diagnosed patients and younger patients without complications and with a relatively benign CV risk profile) are unknown.

This box summarizes key points contained in the article.

Declaration of interest

Within the last 36 months f. Knop has received lecture fees from, been part of Advisory Boards of, consulted for and/or received unrestricted research funding from AstraZeneca, Boehringer Ingelheim, Eli Lilly, MSD/Merck, Novo Nordisk, Sanofi and Zealand Pharma. T Vilsboll has received lecture fees from, been part of Advisory Boards of, consulted for ansd/or received unrestricted research funding from Agen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, MSD/Merk, Novo Nordisk and Sanofi. 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.

Additional information

Funding

This paper was not funded.