A widely used diabetes and obesity drug has shown strong cardioprotective effects in high-risk patients, providing new momentum for its role in reducing cardiovascular mortality.
Study: Long-term cardiovascular safety and efficacy of glucagon-like peptide-1 (GLP-1) receptor agonists in high-risk cardiovascular populations: a systematic review and meta-analysis. Image credit: Studio Romantic / Shutterstock.com
In a recent study published in Cardiodiabetology – Endocrinology Report, Researchers evaluated the long-term cardiovascular safety and efficacy of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in high-risk populations.
Increasing cardiovascular load and expanding role of GLP-1 therapy
Cardiovascular disease (CVD) accounts for more than 17.9 million deaths each year and is the leading cause of death worldwide. Despite the development and approval of new therapeutic agents, the presence of diabetes and obesity remains the main cause of cardiovascular risk, especially in high-risk populations, compared to other major risk factors.
GLP-1RA was originally developed for glycemic control in type 2 diabetes, and subsequent large-scale trials confirmed cardiovascular effects in high-risk populations. Nevertheless, the role of GLP-1RAs in broader populations where high-risk cardiovascular risk has not been established remains unclear, highlighting the need for large-scale clinical trials beyond high-risk cardiovascular groups.
Study design and selection criteria
The current study was conducted in accordance with the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was registered in the Prospective Register of Systematic Reviews (PROSPERO). All reviewed studies were obtained after searching PubMed, Embase, and the Cochrane Library for articles published between January 2015 and May 2025 that met the search criteria.
Eligible studies include randomized controlled trials (RCTs) with at least 3,000 participants and a minimum follow-up of 12 months. All study participants were 18 years or older with CVD or significant cardiovascular risk factors, including type 2 diabetes, obesity, hypertension, and dyslipidemia. GLP-1RAs such as liraglutide, semaglutide, and dulaglutide were evaluated compared to placebo.
Data extraction was performed independently by two reviewers using a standardized template. Study outcomes included major major cardiovascular events (MACE), nonfatal myocardial infarction, cardiovascular mortality, all-cause mortality, nonfatal stroke, heart failure, and hospitalization for adverse events.
Statistical analysis used pooled hazard ratios (HRs) and 95% confidence intervals (CIs) from random-effects models. Risk of bias was assessed using the Cochrane Risk of Bias 2 (RoB2) tool and certainty of evidence was assessed using the Grading of Recommendations Appraisal, Development and Evaluation (GRADE).
Reduced MACE, mortality and hospitalization risk
A total of 11 cardiovascular outcome trials involving 91,490 participants were included in the review, with a mean follow-up of 2.7 years. A pooled analysis confirmed that GLP-1RAs significantly reduced MACE compared to placebo, demonstrating that GLP-1RA users were 14% less likely to experience heart attack, stroke, and cardiovascular death. Cardiovascular disease mortality decreased by 13%, and all-cause mortality decreased as well.
After GLP-1RA treatment, the risk of both non-fatal myocardial infarction and non-fatal stroke was significantly reduced. Hospitalizations for heart failure also decreased slightly. However, this result was reported in a limited number of trials, and sensitivity analyzes showed inconsistent statistical significance, suggesting a potential benefit in cardiac function and disease progression.
These results are consistent across multiple sensitivity and subgroup analyses. For example, excluding studies that included prediabetic populations did not change the overall results, indicating that the cardiovascular benefits of GLP-1RA therapy are stronger among high-risk populations and are not solely driven by individual study subgroups. Post hoc subgroup analyzes also suggested a more pronounced effect of semaglutide, but this finding should be interpreted with caution as hypothesis generating rather than evidence of superiority.
GLP-1RA demonstrated a favorable safety profile, with no significant increases in severe hypoglycemia or acute pancreatitis observed throughout the study. Nevertheless, mild symptoms such as nausea, vomiting, and diarrhea may occur and consistently become more common with treatment.
Some limitations should be considered. This analysis was based on aggregated trial-level data rather than individual patient data, and variations in study population, trial design, and baseline cardiovascular risk may have influenced the observed results.
conclusion
GLP-1RAs significantly reduce major cardiovascular events, mortality, and other clinically significant complications in high-risk populations while maintaining a strong safety profile. Gastrointestinal side effects remain a concern. However, based on current evidence, the benefits of GLP-1RA appear to outweigh these risks.
However, additional large-scale randomized trials are needed. Incorporating GLP-1RA into standard clinical practice For high-risk individuals, it may change the management of patients with metabolic dysfunction and cardiovascular disease, but further evidence is needed to define its role beyond these populations.
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Reference magazines:
- Peter, K., Roka, O., Sepp, E., et al. (2026). Long-term cardiovascular safety and efficacy of glucagon-like peptide-1 (GLP-1) receptor agonists in high-risk cardiovascular populations: a systematic review and meta-analysis. Cardiovascular Diabetology – Endocrinology Report 12. DOI: 10.1186/s40842-026-00295-3. https://link.springer.com/article/10.1186/s40842-026-00295-3
