Effectiveness and Safety of GLP-1 Receptor Agonists in Cardiovascular Outcomes: A Systematic Review and Meta-Analysis

Abstract

Abstract

Background:
Cardiovascular disease (CVD) continues to be the primary cause of illness and death in people with type 2 diabetes mellitus (T2DM). Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a relatively new therapeutic class for diabetes and have been suggested to offer cardiovascular protection. Their overall impact on major cardiovascular outcomes and safety, however, remains an important area of clinical evaluation.

Objectives:
This systematic review and meta-analysis was conducted to assess the cardiovascular benefits and safety profile of GLP-1 RAs in individuals at high cardiovascular risk, including those with T2DM.

Methods:
Relevant literature published between January 2016 and June 2025 was searched systematically in PubMed, Scopus, Cochrane Library, and ClinicalTrials.gov in line with PRISMA guidelines. Randomized controlled trials (RCTs) reporting cardiovascular endpoints such as major adverse cardiovascular events (MACE), cardiovascular mortality, and safety outcomes were included. Data synthesis was performed using a random-effects model, and heterogeneity was examined with the I² statistic.

Results:
Eight RCTs enrolling 60,572 patients met the eligibility criteria. GLP-1 RAs were associated with a significant reduction in MACE compared with placebo (Hazard Ratio [HR] = 0.88, 95% Confidence Interval [CI]: 0.82–0.94, p < 0.001). Stroke incidence was reduced by 15% (HR = 0.85, 95% CI: 0.76–0.95), while cardiovascular mortality declined by 13% (HR = 0.87, 95% CI: 0.80–0.96). Safety analysis indicated a higher risk of mild gastrointestinal adverse effects (Risk Ratio [RR] = 1.56, 95% CI: 1.41–1.72) but no increase in severe hypoglycemia (HR = 0.95, 95% CI: 0.87–1.04).

Discussion:
This analysis highlights that GLP-1 RAs provide substantial cardiovascular benefits in patients with T2DM at elevated risk, particularly through lowering MACE, stroke, and cardiovascular death. Although gastrointestinal intolerance occurs more frequently, it is generally mild and manageable, and the absence of increased severe hypoglycemia reinforces their safety. These findings support the use of GLP-1 RAs not only for glycemic control but also as part of an integrated strategy to reduce cardiovascular burden in diabetes care.

Conclusion:
GLP-1 receptor agonists demonstrate meaningful cardiovascular protection with an acceptable safety profile. Their dual role in glucose regulation and cardiovascular risk reduction makes them promising agents in the combined management of T2DM and CVD.