Semaglutide reduces major adverse cardiovascular events by 20% in overweight or obese adults with pre-existing heart disease, but traditional risk factors like weight, blood pressure, and cholesterol explain less than a third of this benefit, according to a mediation analysis of the SELECT trial published in the European Heart Journal.
SELECT Trial Findings and the Mediation Analysis
The landmark SELECT trial evaluated 17,604 adults aged 45 years or older with a body mass index of 27 or higher and established cardiovascular disease without diabetes. Participants received either a weekly subcutaneous target dose of 2.4 milligrams of semaglutide or a placebo, with a mean follow-up of 39.8 months. The primary trial established that semaglutide lowered the incidence of major adverse cardiovascular events—defined as cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke—from 8.0% in the placebo group to 6.5%.
To determine how much of this cardioprotective effect stemmed from conventional risk factor improvements, researchers conducted a pre-specified counterfactual mediation analysis using the Vansteelandt repeated regression method. The analysis examined 12 candidate mediators measured repeatedly through at least 24 months, with mediation estimated at 36 months.
Contribution of Traditional Cardiovascular Risk Factors
In the multivariable model combining body weight, blood pressure, cholesterol, and blood glucose, conventional risk factors produced a joint mediation point estimate of 31.4%. Based on these calculations, approximately 68.6% of the treatment effect was not accounted for by the included measures, though statistical uncertainty prevented this proportion from being regarded as precise.
When evaluated in individual counterfactual models, changes in waist circumference yielded the largest estimated mediation at 64.0%. High-sensitivity C-reactive protein followed at 42.1%, glycated hemoglobin at 29.0%, and body weight at 19.5%. Additional factors showing smaller mediation point estimates included triglycerides at 18.6%, urinary albumin-to-creatinine ratio at 14.6%, systolic blood pressure at 14.3%, and low-density lipoprotein cholesterol at 10.9%.
Unidentified Pathways and Future Research
Because nearly 69% of the cardiovascular benefit remained unexplained by traditional risk factors, the study authors suggested that other unmeasured pathways contribute to semaglutide’s protective effects. Proposed mechanisms include direct vascular and anti-inflammatory impacts, though the researchers emphasized that these possibilities remain speculative. The findings highlight the need for further research to isolate the exact biological pathways driving GLP-1 receptor agonist benefits beyond standard metabolic and anthropometric improvements.
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