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Semaglutide and cardiovascular risk reduction: a mediation analysis of the SELECT trial
Key result
Semaglutide reduces MACE through mechanisms not fully explained by changes in known risk factors.
- 31.4% mediation
- 95% CI -30.1, 143.6
Why the study?
The mechanisms by which semaglutide reduces major adverse cardiovascular events in adults with pre-existing cardiovascular disease and elevated BMI without diabetes are not fully understood.
Does semaglutide reduce MACE through changes in body weight, waist circumference, hsCRP, HbA1c, lipids, blood pressure, eGFR, and UACR in adults with pre-existing CVD and BMI ≥27 kg/m2 without diabetes?
Population
Adults with pre-existing cardiovascular disease and BMI ≥27 kg/m2 without diabetes
Comparison
Subcutaneous semaglutide 2.4 mg weekly vs placebo
Design
Randomized placebo-controlled trial (SELECT)
Follow-up
24 months
Authors
Discussion
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Member takes
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“Our analyses could not fully ascribe the effects of semaglutide on cardiovascular disease to known risk factors with any certainty. Whether we combine all risk factors together or look at some subsets of the risk factors, no more than half of the reduction in heart disease could be explained by the changes in these risk factors. These results suggest that semaglutide should be considered a cardiovascular disease reduction drug and not just a weight loss drug.”
SVSubodh VermaProfessor of surgery, University of Toronto
“The conclusion of this paper is appropriately humble. Known risk factor changes could not, with any confidence, explain all of the GLP-1RA effects on major adverse cardiovascular events.”
SVSubodh VermaProfessor of surgery, University of Toronto
“By all accounts, the remarkable story of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in cardiovascular medicine has been one of serendipity. Two years ago, in the European Heart Journal, we wrote that the journey of semaglutide was one such story—a drug born to lower glucose that has become the most versatile weapon against cardiometabolic-, kidney- and obesity-related diseases”
Overview
Mechanisms underlying semaglutide's MACE reduction remain incompletely explained; leaves open unidentified pathways beyond measured risk factors.
EHJ · SELECT mediation analysis. Weight and known risk factors don't fully explain semaglutide's MACE reduction. Semaglutide and cardiovascular risk reduction: a mediation analysis of the SELECT trial The mechanisms by which semaglutide reduces major adverse cardiovascular events in adults with pre-existing cardiovascular disease and elevated BMI without diabetes are not fully understood. Does semaglutide reduce MACE through changes in body weight, waist circumference, hsCRP, HbA1c, lipids, blood pressure, eGFR, and UACR in adults with pre-existing CVD and BMI ≥27 kg/m2… A mediation analysis of the SELECT trial could not fully ascribe the reduction in MACE with semaglutide to known risk factors, with joint mediation estimated at 31.4% (95% CI -30.1 to 143.6). Semaglutide significantly improved all evaluated potential mediators (P < .05), with individual mediation point estimates highest for waist circumference (64.0%, 95% CI… Joint multivariable mediation for all candidates combined was 31.4% (95% CI -30.1 to 143.6), and 46.0% (95% CI -6.0 to 161.0) when excluding body weight and waist… Where experts stand: Helen Colhoun (Professor, University of Edinburgh · University…): “Our analyses could not fully ascribe the effects of semaglutide on cardiovascular disease to known risk factors with any certainty.” From their public comments on the paper Read the evidence. See where experts stand. synapsesocial.com/papers/6ab6904a68a7ce8912ee884d
Key Points
- Determine the extent to which changes in established cardiometabolic risk factors mediate the 20% reduction in major adverse cardiovascular events (MACE) achieved by semaglutide.
- Evaluated 24-month changes in body weight, waist circumference, hsCRP, HbA1c, lipids, blood pressure, eGFR, and urinary albumin-to-creatinine ratio among adults with pre-existing cardiovascular disease and BMI ≥27 kg/m² without diabetes.
- Applied the Vansteelandt repeated regression counterfactual mediation method to estimate individual and combined proportions of MACE reduction mediated by these biomarkers.
- Semaglutide significantly improved all evaluated potential mediators (P < .05), with individual mediation point estimates highest for waist circumference (64.0%, 95% CI 27.5 to 179.6) and hsCRP (42.1%, 95% CI 17.9 to 110.5), though confidence intervals were wide.
- Joint multivariable mediation for all candidates combined was 31.4% (95% CI -30.1 to 143.6), and 46.0% (95% CI -6.0 to 161.0) when excluding body weight and waist circumference due to model unreliability.
Study Design
Type
RCT
Blinding
Placebo-controlled
Randomization
Randomized
Structured PICO
Does semaglutide reduce MACE through changes in body weight, waist circumference, hsCRP, HbA1c, lipids, blood pressure, eGFR, and UACR in adults with pre-existing CVD and BMI ≥27 kg/m2 without diabetes?
P
Population
Adults with pre-existing cardiovascular disease and body mass index ≥27 kg/m2 without diabetes, evaluated for mediators of cardiovascular risk reduction over 24 months.
I
Intervention
Subcutaneous semaglutide (target dose 2.4 mg) weekly
C
Comparator
Placebo
O
Outcome
Mediation of major adverse cardiovascular events (MACE) risk reduction by changes in body weight, waist circumference, hsCRP, HbA1c, lipids, blood pressure, eGFR, and UACRcomposite
Main Result
Effect estimate: 31.4% mediation (95% CI -30.1, 143.6)
The cardiovascular benefits of semaglutide in the SELECT trial cannot be fully explained by changes in known risk factors such as body weight, waist circumference, or hsCRP, suggesting additional mechanisms of cardiovascular protection.
Limitations
- Wide confidence intervals for all mediation estimates
- Unreliability of estimates for body weight and waist circumference, potentially due to differing relationship of body weight and waist change to MACE between treatment arms
- Wide confidence intervals for mediation estimates
- Unreliability of estimates for body weight and waist circumference due to differing relationships to MACE between treatment arms
Cite This Study
Colhoun et al. (2026) conducted an RCT in Pre-existing cardiovascular disease and overweight/obesity without diabetes. Semaglutide vs. Placebo was evaluated on Joint mediation for all potential mediators combined for MACE risk reduction (31.4% mediation, 95% CI -30.1, 143.6). A mediation analysis of the SELECT trial could not fully ascribe the reduction in MACE with semaglutide to known risk factors, with joint mediation estimated at 31.4% (95% CI -30.1 to 143.6).