Glucagon-Like Peptide-1 Receptor Agonists in Adult Patients With Type 2 Diabetes: Review of Cardiovascular Outcome Trials

Nov 9, 2019Canadian journal of diabetes

Heart health results of GLP-1 receptor drugs in adults with type 2 diabetes

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Abstract

Recent cardiovascular outcome trials (CVOTs) for glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown varied cardiovascular benefits.

People with type 2 diabetes are at increased risk for cardiovascular events, which are a leading cause of early death in this population.
Some antidiabetes medications previously worsened cardiovascular function, prompting regulatory changes for new treatments to demonstrate cardiovascular safety.
CVOTs were designed to evaluate cardiovascular safety and may also identify cardiovascular protection when properly powered.
Multiple completed CVOTs for GLP-1RAs have shown cardiovascular benefits, but not all GLP-1RAs have demonstrated the same outcomes.
Key differences in study design may explain the varied cardiovascular effects observed among different GLP-1RAs.

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People with type 2 diabetes are at heightened risk for developing cardiovascular (CV) events. CV disease is the leading cause of premature death among adults with type 2 diabetes. Unfortunately, historically, some antidiabetes agents were implicated in worsening CV function, despite improving glycemic and metabolic control. Accordingly, over a decade ago, health regulatory bodies modified approval requirements for novel antidiabetes pharmacotherapies, requiring prospective evaluation of CV safety through cardiovascular outcome trials (CVOTs). To meet regulatory requirements, CVOTs were primarily designed around establishing CV safety by demonstrating noninferiority to placebo in addition to standard of care, without significant differences in blood glucose. If appropriately designed and powered, however, these CVOTs could also determine superiority, and hence CV protection. Although many of these CVOTs were initiated several years ago, the recent reporting of the results for these CVOTs has been pivotal and practice-changing. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are one such class of antidiabetes therapies, wherein multiple GLP-1RA CVOTs, but interestingly, not all, have demonstrated CV benefits. In this review, we provide a comprehensive summary of all the reported CVOTs completed with GLP-1RAs to date. Although it remains unclear why some GLP-1RAs are associated with reducing CV events, whereas others have been consistent with CV safety alone, we highlight and provide an overview of some key differences between the various GLP-1RAs and their respective CVOTs and possible implications of study design differences. We also speculate on potential mechanisms of action for glucagon-like peptide-1 receptor signalling in the CV system.

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Glucagon-Like Peptide-1 Receptor Agonists in Adult Patients With Type 2 Diabetes: Review of Cardiovascular Outcome Trials

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