Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as a first-line drug in treating type 2 diabetes mellitus (T2DM).1 GLP-1RAs have also been found to significantly reduce the risk of major adverse cardiovascular events (MACE) in patients with T2DM, as demonstrated by multiple large cardiovascular outcome trials (CVOTs).2,3 The LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial (2016), which aimed to determine the cardiovascular (CV) effects of liraglutide marked a turning point and was the first to show a reduction in major adverse cardiovascular events (MACE).4 Several trials have followed since, such as the SUSTAIN-6 (2016)5 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes), HARMONY (2018)6 (Albiglutide and Cardiovascular Outcomes in Patients with Type 2 diabetes and Cardiovascular Disease) and REWIND trial (2019)7 (Dulaglutide and Cardiovascular Outcomes in Type 2 Diabetes), demonstrating that semaglutide, albiglutide, and dulaglutide respectively, reduced MACE among patients with T2DM and high CV risk. Furthermore, the AMPLITUDE-O (Effect of Efpeglenatide on Cardiovascular Outcomes) trial (2021), also found that efpeglenatide reduced the risk of cardiovascular (CV) events in patients with T2DM.8

GLP-1RAs are also approved for use in weight loss, and in the recently published SELECT (Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity) trial (2023), semaglutide was associated with a decreased risk of MACE, including CV deaths, nonfatal myocardial infarction (MI), and stroke in patients with overweight or obesity.9 Further highlighting the importance of GLP-1RAs in improving CV outcomes, the STEP-HFpEF (Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity) trial (2023) found that semaglutide led to improvements in symptoms, physical limitations, and exercise function in patients with heart failure.10

In the treatment of cardiometabolic diseases, there are many drugs and drug classes that offer protection against CV morbidity and mortality.11,12 In addition, trials on GLP-1RAs demonstrate substantial racial, ethnic, and geographic differences in terms of CV and renal outcomes.13 Current CVOTs usually focus more on general treatment effects and thus the differential impact and disparities of GLP1-RAs on MACE based on sex, race, ethnicity, or geography is not very well established. For this reason, we sought to conduct a systematic review and meta-analyses on all GLP1-RA CVOTs in patients with or without DM, stratifying by demographic and clinical data, to determine the impact of sex, race, ethnicity, and geographical differences on MACE.