Semaglutide and major adverse cardiovascular events in patients with and without DM: A systematic review and meta-analysis.
Semaglutide shows a significant reduction in cardiovascular events, but practitioners should consider the associated gastrointestinal risks and high cost-effectiveness ratios.
Where it sits
this study against the rest of the albiglutide corpusSummary and findings
This meta-analysis evaluated the effect of semaglutide on major adverse cardiovascular events (MACE) in a population of 25,067 participants across 11 randomized controlled trials. Semaglutide was associated with a 32% reduction in MACE compared to placebo or active control. Safety findings indicated increased risks of gastrointestinal disorders and gallbladder events.
Abstract
Semaglutide, a once-weekly glucagon-like peptide-1 receptor agonist (GLP-1 RA), has been associated with cardiovascular benefits, whereas the consistency of its effect across various clinical settings, as well as its safety-economic profile, remains uncertain. MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, ClinicalTrials.gov and WHO International Clinical Trials Registry Platform were searched up to January 2025 and identified 11 randomized controlled trials (12 comparisons; 25,067 participants) comparing semaglutide with placebo or active control. Using a DerSimonian-Laird random-effects model, semaglutide reduced major adverse cardiovascular events by 32% [pooled odds ratio (OR)=0.68; 95%; confidence interval 0.52-0.91; 95% prediction interval 0.44-1.04]. Point estimates remained unchanged after censoring all STEP obesity trials (OR=0.70) or both heart-failure trials (OR=0.66), indicating a negligible institution-level effect. Mixed-effects meta-regression analysis revealed greater benefit with lower body weight, LDL- and total cholesterol levels, and lesser benefit with higher age, HbA1c and blood pressure (all P<0.01). Safety pooling found higher risks of any gastrointestinal (GI) disorder [relative risk (RR)=1.47], gallbladder events (RR=2.37), and discontinuation due to GI intolerance (RR 2.32). A total of seven out of 11 trials enrolled ≥75% White patients, none of whom were from low-income countries, limiting generalizability. Besides, U.S. cost-utility models published in the literature report incremental cost-effectiveness ratios of US$ 180,000-260,000 per quality-adjusted life-year, above conventional willingness-to-pay thresholds. Overall, semaglutide demonstrated marked cardiovascular risk reduction at all doses and across all populations, with low statistical heterogeneity. However, this benefit must be weighed against GI intolerance, limited racial and geographic representation and uncertain cost-effectiveness outside high-income regions. Future trials must oversample underrepresented minorities, extend to low- and middle-income regions, and include formal economic evaluations to further refine population-specific benefit-risk profiles and value estimates.
Background
This paper addresses the cardiovascular effects of semaglutide, a GLP-1 receptor agonist, in patients with and without diabetes mellitus (DM). Prior research has suggested cardiovascular benefits of GLP-1 RAs, but the consistency and safety profile of semaglutide across different populations remain uncertain. Understanding these effects is crucial for evaluating the drug's overall benefit-risk profile in clinical practice.
Methods
The study conducted a systematic review and meta-analysis of 11 randomized controlled trials, encompassing 25,067 participants. The analysis compared semaglutide with placebo or active control, utilizing a DerSimonian-Laird random-effects model. Primary outcomes included major adverse cardiovascular events, while secondary outcomes focused on safety profiles and economic evaluations.
Results
Semaglutide was associated with a 32% reduction in major adverse cardiovascular events, with a pooled odds ratio of 0.68 (95% CI 0.52-0.91). The analysis also revealed significant increases in the risk of gastrointestinal disorders (RR=1.47), gallbladder events (RR=2.37), and discontinuation due to gastrointestinal intolerance (RR=2.32).
Interpretation
The findings indicate a statistically significant reduction in cardiovascular events with semaglutide, but the clinical significance may be limited by the high cost and increased risk of gastrointestinal issues. The study's limitations, including a lack of diversity in the population and potential biases in funding sources, suggest caution in applying these results broadly. Future research should aim to include more diverse populations and assess long-term economic implications.
Key findings
- 32% reduction in major adverse cardiovascular events (MACE) with semaglutide, OR=0.68, 95% CI 0.52-0.91.
- Higher risk of any gastrointestinal disorder, RR=1.47.
- Higher risk of gallbladder events, RR=2.37.
- Higher risk of discontinuation due to gastrointestinal intolerance, RR=2.32.
- Incremental cost-effectiveness ratios of US$ 180,000-260,000 per quality-adjusted life-year.
Limitations
- Limited racial and geographic representation.
- High cost-effectiveness ratios reported (US$ 180,000-260,000 per QALY).
- Potential biases due to industry funding.
- Short follow-up period for assessing long-term outcomes.