Semaglutide and cardiovascular outcomes by baseline and changes in adiposity measurements: a prespecified analysis of the SELECT trial
- Design
- Randomized trial · 17604 participants · Hard outcome
- Match to healthy normal-weight adults aged 55–75
- Different populationAll BMI >= 27; consistency across BMI categories cannot be extrapolated below 27.
- Could weight loss explain it?
- Specifically testedCardioprotective effect independent of baseline adiposity and of weight loss; only a small association with waist reduction (about a third of benefit). Suggests mechanisms beyond adiposity reduction within an obese population.
Adjusted for: time-varying weight change, time-varying waist circumference - Study tier
- Study tier 2Prespecified analysis of a large RCT with a mediation model; supports but does not prove weight-independence.
- Assessment
- Version 2 · curated · Sep 13, 2026
Study facts come from the paper. Population match, weight-loss explanation and study tier are our judgments, made against the reference group of healthy normal-weight adults aged 55–75.
A prespecified SELECT analysis found the cardiovascular benefit of semaglutide was similar whatever the starting weight and did not track how much weight people lost; only about a third was explained by waist reduction. Evidence that the benefit is not simply weight loss, within people who all had BMI 27 or higher.
01Findings
What the study reported
- Drugs
- Semaglutide
- Dose
- 2.4 mg weekly
- Route
- subcutaneous
- Comparator
- placebo
- Primary outcome
- Prespecified: MACE by baseline adiposity and by early adiposity change
- Effect
- Benefit consistent across baseline BMI and waist categories; no linear trend between week-20 weight loss and later MACE; ~33% of benefit mediated via waist reduction (HR 0.86 after time-varying waist adjustment)
- 95% confidence interval
- Not extracted
- Follow-up
- 45 years
- Adverse events
- Not extracted
- Limitations
- Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.
Who was studied
- Age min
- 45
- Bmi min
- 27
- Obesity status
- BMI >= 27 required
- Diabetes status
- excluded
- Cvd status
- established CVD
- Sample size
- 604
Study quality details
- Study design
- Randomized controlled trial
- Sample size
- 604
- Randomization
- yes
- Blinding
- not stated
- Comparator
- placebo
- Follow up duration
- 45 years
- Outcome type
- hard
- Replication
- not assessed (auto)
- Consistency with other evidence
- not assessed (auto)
- Population applicability
- INDIRECT
- Statistical precision
- CI reported: 95% CI 0·94-0·99]
- Risk of bias
- prespecified but observational mediation analysis within RCT
- Funding conflicts
- yes
- Peer review status
- yes
02Funding
Funding and conflicts
- Funding
- Novo Nordisk
- Industry funded
- Yes
- Manufacturer
- Novo Nordisk
- Sponsor role
- Sponsor analysed.
- Author conflicts
- Authors report Novo Nordisk and other relationships; sponsor co-authors.
- Independent replication
- unknown
- Notes
- Authors declare relationships with the drug's manufacturer: Novo Nordisk
Funding is shown on every study and never used to score it.
03Claims
Claims this study bears on
- GLP-1 receptor agonist therapy provides a net clinical benefit to healthy normal-weight adults aged 55-75.Mixed
Within SELECT, benefit was consistent across baseline BMI categories (all >= 27) and largely independent of weight loss; cannot extrapolate below BMI 27.
- The cardiovascular benefit of GLP-1 receptor agonists is not explained by weight loss.Supports
Prespecified SELECT analysis: benefit independent of baseline adiposity and early weight loss; ~33% mediated by waist circumference change.
04Source
The source, as retrieved
Abstract
[BACKGROUND] The SELECT trial found semaglutide reduced major adverse cardiovascular events (MACE) in patients with overweight or obesity with cardiovascular disease but without diabetes. We report a prespecified analysis of the SELECT trial on the relationships between baseline adiposity measures, treatment-induced adiposity changes, and subsequent MACE risk. [METHODS] Patients aged at least 45 years, with a BMI of at least 27 kg/m2 were enrolled in 41 countries (804 sites) and randomised 1:1 to once-weekly semaglutide 2·4 mg or placebo. The primary outcome was time to first MACE (composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke). Adiposity measures included weight and waist circumference. In this analysis, risk of MACE occurring after 20 weeks was assessed between patients by adiposity changes in the first 20 weeks and, in a separate analysis, all in-trial MACE were assessed between patients by adiposity changes over 104 weeks. This trial is registered with ClinicalTrials.gov, NCT03574597. [FINDINGS] Semaglutide significantly reduced MACE incidence compared with placebo among 17 604 patients enrolled in SELECT, with consistent benefits across all baseline weight and waist circumference categories. In the semaglutide group, analyses for linear trends showed lower baseline bodyweight and waist circumference were associated with lower incidence of MACE-an average 4% reduction in risk per 5 kg lower bodyweight (hazard ratio [HR] 0·96 [95% CI 0·94-0·99]; p=0·001) and per 5 cm smaller waist circumference (0·96 [0·93-0·99]; p=0·004). In the placebo group, lower baseline waist circumference (0·96 [0·94-0·99]; p=0·007), but not bodyweight (0·99 [0·97-1·01]; p=0·28), was associated with a lower MACE risk and weight loss was paradoxically associated with increased MACE risk. In those receiving semaglutide there was no linear trend linking weight loss at week 20 to subsequent MACE risk, but greater waist circumference reduction at week 20 was associated with lower subsequent MACE risk, and waist circumference reduction by week 104 was associated with lower in-trial risk of MACE. An estimated 33% of the observed benefit on MACE was mediated through waist circumference reduction (HR 0·86 [95% CI 0·77-0·97] after adjustment for time-varying changes in waist circumference). [INTERPRETATION] The cardioprotective effects of semaglutide were independent of baseline adiposity and weight loss and had only a small association with waist circumference, suggesting some mechanisms for benefit beyond adiposity reduction. [FUNDING] Novo Nordisk.
Where this record came from
| Source | Retrieved | Identifier |
|---|---|---|
| pubmed | Sep 13, 2026 | 41138739 first ingestion |