Heterogeneity amongst GLP-1 RA cardiovascular outcome trials results: can definition of established cardiovascular disease be the missing link?

Abstract

Atherosclerotic cardiovascular diseases are the leading cause of adverse outcomes in patients with type 2 diabetes, and all new anti-diabetic agents are mandated to undergo cardiovascular outcome trials (CVOTs). Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are incretin mimetics that reduce blood glucose levels with a low associated risk of hypoglycaemia. CVOTs with different GLP-1 RAs yielded different results in terms of major cardiovascular composite outcome (MACE), with some trials showing superiority in the treatment arm, whereas other simply displayed non-inferiority. More importantly, the significance of each component of MACE varied between drugs. This begs the question of whether these differences are due to dissimilarities between drugs or other factors, namely trial design, are at the root of these differences. We analyse the trial designs for all CVOTs with GLP-1 RAs and highlight important differences between them, namely in terms of definition of established cardiovascular disease, and discuss how these differences might explain the disparate results of the trials and preclude direct comparisons between them. We conclude that a fair comparison between GLP-1 RA CVOTs would involve post-hoc analysis re-grouping the patients into different cardiovascular risk categories based upon their baseline clinical parameters, in order to even out the criteria used to classify patients.

HOW did GLP-1RAs bring about a paradigm shift in the guidelines of managing T2DM: A path to gluco-cardio Centricity

“…Although there was a difference in the results obtained across all the trials, some CVOTs provided superiority in the treatment arm, while others only demonstrated non-inferiority ( Table 1 ). 1 …”

“…These results showed that GLP-1RAs are associated with better CV outcomes. 1 Composite CV outcomes from several multicentre, double-blinded, randomised, placebo-controlled trials involving different GLP-1RAs namely lixisenatide, liraglutide, semaglutide, exenatide, albiglutide, dulaglutide and oral semaglutide have demonstrated a non-inferiority in reducing the CV outcomes. Among all of the GLP-1Ras included in an overview, liraglutide, subcutaneous semaglutide, albiglutide and dulaglutide demonstrated a significant reduction in the overall composite CV outcomes.…”

“…Diabetes is one of the most prevalent, chronic, and devastating metabolic disorder, associated with an ominous diagnosis. 1 According to the recent findings by the International Diabetes Federation (IDF), about 537 million people are living with diabetes in the World. Globally, type 2 diabetes mellitus (T2DM) accounts for the vast majority (around 90%) of type of diabetes.…”

“…More importantly, the significance of each component of MACE varied between different drugs. 1 Several other CVOTs have highlighted that GLP-1RAs confer protection against major CV diseases events in patients with established atherosclerotic CV disease (ASCVD). GLP-1RAs also help to reduce the risk of hospital admission to hospital for heart failure and reduce CV and all-cause mortality with the advantage of having a lower risk for dangerous hypoglycaemia and multiple postulated mechanisms which may be beneficial in reducing CV-related outcomes.…”

EVOO’s Effects on Incretin Production: Is There a Rationale for a Combination in T2DM Therapy?

“…All agents within this class not only demonstrate significant reductions in HbA1c but also a favourable effect on weight and a lower risk of hypoglycaemia. Treatment with GLP-1 receptor agonists is also recommended as a first option in patients with T2DM at onset, especially in those at risk of cardiovascular disease, due to an important effect on both the primary and secondary prevention of ischemic disease [ 30 ]. In particular, liraglutide, dulaglutide and semaglutide have been shown to reduce major cardiovascular events.…”