Popular GLP-1 drugs significantly reduce major cardiovascular events,

Commonly used diabetes and obesity drugs show strong cardioprotective effects in high-risk patients, providing new impetus for their role in reducing cardiovascular deaths.

Study: The 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 Cardiovascular Diabetes–Endocrinology Reports, Researchers evaluated the long-term cardiovascular safety and efficacy of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in high-risk populations.

The increasing cardiovascular burden and the expanding role of GLP-1 therapies

Cardiovascular disease (CVD) causes more than 17.9 million deaths each year, making it the leading cause of death worldwide. Despite the development and approval of new therapies, the presence of diabetes and obesity is a significant contributor to cardiovascular risk, particularly in high-risk populations, compared to other major risk factors.

GLP-1RAs were originally developed for glycemic control in type 2 diabetes, with subsequent large-scale trials confirming cardiovascular benefits in high-risk populations. However, the role of GLP-1RAs in broader populations without established high cardiovascular risk remains unclear, emphasizing the need for large-scale clinical trials beyond high cardiovascular risk groups.

Study planning 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 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 included randomized controlled trials (RCTs) with at least 3,000 participants and a minimum follow-up of 12 months. All study participants were 18 years of age or older with established cardiovascular disease or significant cardiovascular risk factors such as type 2 diabetes, obesity, hypertension, or dyslipidemia. GLP-1RAs such as liraglutide, semaglutide, dulaglutide and others were evaluated compared to placebo.

Data extraction was performed independently by two reviewers using standardized templates. Study outcomes included major adverse cardiovascular events (MACE), nonfatal myocardial infarction, cardiovascular mortality, all-cause mortality, nonfatal stroke, and hospitalization for heart failure and adverse events.

Statistical analysis used pooled hazard ratios (HRs) and 95 % confidence intervals (CIs) for a random effects model. Risk of bias was assessed using the Cochrane Risk of Bias 2 (RoB2) tool and certainty of evidence was graded using Grading of Recommendations for Assessment, Development and Evaluation (GRADE).

Lower risk of MACE, mortality and hospitalization

A total of 11 cardiovascular outcome trials involving 91,490 participants, with a mean follow-up period of 2.7 years, were included in the review. The pooled analysis confirmed that GLP-1RAs significantly reduce MACE compared to placebo, showing that GLP-1RA users were 14% less likely to have a heart attack, stroke or cardiovascular death. Cardiovascular mortality was reduced by 13%, with all-cause mortality similarly reduced.

The risk of both nonfatal myocardial infarction and nonfatal stroke was significantly reduced after GLP-1RA treatment. Hospitalization for heart failure was also modestly lower. However, this effect was reported in a subset of trials and showed less consistent statistical significance in sensitivity analyses, suggesting potential benefits on cardiac function and disease progression.

These findings remain consistent in multiple sensitivity and subgroup analyses. For example, exclusion of studies involving prediabetic populations did not change the overall results, indicating that the cardiovascular benefits of GLP-1RA therapy are robust among high-risk populations and are not solely driven by individual subgroups of trials. A post hoc subgroup analysis also suggested a stronger effect with semaglutide, although this finding should be interpreted with caution as hypothesis generation rather than evidence of superiority.

GLP-1RAs demonstrated a favorable safety profile, with no significant increase in severe hypoglycaemia or acute pancreatitis observed in all trials. However, mild symptoms such as nausea, vomiting, and diarrhea may develop and are consistently more common with treatment.

Some limitations should be noted. The analysis was based on pooled trial-level data rather than individual patient data, and variations in study populations, trial design, and baseline cardiovascular risk may have influenced the observed results.

conclusions

GLP-1RAs significantly reduce major cardiovascular events, mortality, and other clinically important complications in high-risk populations while maintaining a strong safety profile. Gastrointestinal side effects are still a concern. However, the benefits of GLP-1RAs appear to outweigh these risks based on current evidence.

However, additional large-scale randomized trials are needed. incorporation of GLP-1RAs into standard clinical practice for high-risk individuals has the potential to transform the management of patients with metabolic dysfunction and cardiovascular disease, although further evidence is needed to define their role beyond these populations.

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