Semaglutide reduced the risk of major adverse cardiovascular events (MACE) by 20% in adults with overweight or obesity and established cardiovascular disease (CVD) but without diabetes, according to findings from the SELECT trial. The results provide evidence that the cardiovascular benefits of semaglutide extend beyond its effects on glucose control and weight reduction. 

Obesity is an established risk factor for CVD and is associated with hypertension, dyslipidaemia, insulin resistance, chronic inflammation, and renal dysfunction. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have therefore attracted increasing interest for their broader cardiometabolic effects. 

SELECT trial demonstrates cardiovascular benefit 

The SELECT trial enrolled 17,604 adults aged 45 years or older with established CVD and a body mass index (BMI) of at least 27 kg/m². Participants had no history of diabetes and were randomly assigned to once-weekly subcutaneous semaglutide 2.4 mg or placebo. 

The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. During a mean follow-up of approximately 40 months, the primary endpoint occurred in 6.5% of participants receiving semaglutide compared with 8.0% receiving placebo. Semaglutide was associated with a hazard ratio of 0.80 (95% confidence interval [CI], 0.72–0.90; P<0.001), corresponding to a 20% relative reduction in MACE. 

The findings were notable because the trial specifically included people without diabetes. This indicates that the cardiovascular effect of semaglutide cannot be explained solely by glucose lowering. 

Improvements in cardiometabolic risk factors 

Semaglutide treatment was accompanied by reductions in body weight and waist circumference, together with improvements in several cardiometabolic parameters, including blood pressure, glycaemic measures, lipid levels, high-sensitivity C-reactive protein (hsCRP), and kidney-related outcomes. 

These changes could contribute to cardiovascular protection. Reduction in central adiposity may improve metabolic function, while lower systemic inflammation could influence vascular and atherosclerotic processes. GLP-1 RAs have also been proposed to affect endothelial function, vascular inflammation, and other pathways involved in atherosclerosis. 

However, the precise mechanisms underlying the cardiovascular benefit remain incompletely understood. 

Mediation analysis provides clues 

A prespecified mediation analysis of SELECT examined whether changes in body weight, waist circumference, hsCRP, glycated haemoglobin (HbA1c), lipid parameters, blood pressure, and renal markers could statistically account for part of the reduction in cardiovascular events. 

The largest estimated individual mediation effects were observed for waist circumference, hsCRP, HbA1c, and body weight. However, the estimates were associated with wide confidence intervals. When the evaluated factors were considered together, the estimated proportion mediated was 31.4% (95% CI, −30.1% to 143.6%), indicating substantial uncertainty. 

These findings suggest that improvements in measured cardiometabolic risk factors may account for only part of the cardiovascular benefit associated with semaglutide. Mediation analysis, however, cannot establish that a particular biomarker or risk factor is directly responsible for the reduction in cardiovascular events. The results should therefore be interpreted as evidence pointing toward potential pathways rather than definitive proof of mechanism. 

Cardiovascular effects may extend beyond weight loss 

The SELECT findings have prompted further investigation into whether the cardiovascular effects of semaglutide are independent of changes in body weight. Subsequent analyses have examined baseline and changes in adiposity measures, with findings suggesting that the reduction in cardiovascular events cannot be attributed entirely to weight loss or baseline adiposity. 

Together, these findings support a multifactorial explanation in which reductions in adiposity and improvements in inflammation, blood pressure, glycaemic status, lipids, and renal function may interact with other biological effects of GLP-1 receptor activation. 

Implications 

The SELECT trial has expanded the evidence for cardiovascular benefits of semaglutide to adults with overweight or obesity and established CVD who do not have diabetes. The findings also highlight the complexity of determining how GLP-1 RAs reduce cardiovascular risk. 

Further research is needed to clarify the contributions of weight loss, changes in fat distribution, inflammation, vascular function, and other biological pathways to the cardiovascular effects of semaglutide. Understanding these mechanisms may provide additional insights into the role of GLP-1 RAs in cardiovascular risk reduction among people with obesity. 

References 

 

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