Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes
- Design
- Randomized trial · 17604 participants · Hard outcome
- Match to healthy normal-weight adults aged 55–75
- Different populationAll participants had established atherosclerotic disease and BMI >= 27 (mean 33.4); no normal-weight participants. Age range overlaps the target. Absolute benefit (1.5 percentage points over ~3.3 years) was measured in a high-risk secondary-prevention group.
- Could weight loss explain it?
- PossiblyPrimary paper does not separate weight-loss effects; prespecified analyses (records for PMID 41138739 and 42610271) later examined adiposity and hs-CRP mediation.
- Study tier
- Study tier 1Large, event-driven, double-blind, placebo-controlled trial with adjudicated hard outcomes. Certainty is high for the enrolled population; the sponsor designed and analysed the trial.
- 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.
In 17,604 adults with prior heart disease or stroke and BMI of 27 or more but no diabetes, weekly semaglutide reduced the combined rate of cardiovascular death, heart attack and stroke from 8.0% to 6.5% over about 3.3 years. Twice as many people stopped the drug because of side effects, mostly gastrointestinal. This is strong evidence for people like those enrolled; it says nothing directly about people of normal weight.
01Findings
What the study reported
- Drugs
- Semaglutide
- Dose
- 2.4 mg once weekly
- Route
- subcutaneous
- Treatment duration
- mean exposure 34.2 months
- Comparator
- placebo
- Primary outcome
- Composite of CV death, nonfatal MI, nonfatal stroke (time to first event)
- Effect
- HR 0.80 (6.5% vs 8.0%)
- 95% confidence interval
- 0.72 to 0.90
- P value
- <0.001
- Follow-up
- mean 39.8 months
- Adverse events
- Adverse events leading to permanent discontinuation 16.6% vs 8.2% (P<0.001), mainly gastrointestinal. Serious adverse events lower with semaglutide (33.4% vs 36.4%, from full text).
- Limitations
- Secondary-prevention population with obesity; cannot inform primary prevention or normal-weight adults. Weight loss and CV benefit not separated in the primary report.
Who was studied
- Mean age
- 61.6
- Age min
- 45
- Bmi mean
- 33.4
- Bmi min
- 27
- Obesity status
- overweight/obesity required (BMI >= 27); mean BMI 33.4
- Diabetes status
- excluded (no history of diabetes)
- Cvd status
- established cardiovascular disease required
- Ckd status
- not an entry criterion
- Sample size
- 17604
- Inclusion exclusion
- Age >= 45, BMI >= 27, prior MI/stroke/PAD, no diabetes
Study quality details
- Study design
- Randomized controlled trial
- Sample size
- 17604
- Randomization
- yes
- Blinding
- double-blind
- Comparator
- placebo
- Follow up duration
- mean 39.8 months
- Outcome type
- hard
- Replication
- consistent with T2D CVOTs (LEADER, SUSTAIN-6, REWIND); no independent replication in non-diabetic obesity
- Consistency with other evidence
- consistent with class effect
- Population applicability
- INDIRECT
- Statistical precision
- narrow CI, 1270 primary events
- Risk of bias
- low for outcome ascertainment; 16.6% discontinuation on drug
- Funding conflicts
- manufacturer funded, sponsor employees co-authored
- Peer review status
- yes
Methodological notes
Event-driven superiority design; 1270 primary events. Funded and analysed by Novo Nordisk.
02Funding
Funding and conflicts
- Funding
- Novo Nordisk
- Industry funded
- Yes
- Manufacturer
- Novo Nordisk
- Sponsor role
- Sponsor designed the trial with the steering committee, collected data and performed analyses (per trial methods; verify in the protocol/disclosures).
- Author conflicts
- Steering committee members report consulting/grant relationships with Novo Nordisk and other companies; sponsor employees are co-authors (see published disclosure forms).
- Independent replication
- no (single trial in this population); class consistency from T2D trials
- Notes
- Pivotal industry trial. Design quality is high; interpretation of secondary analyses should account for sponsor involvement.
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.No direct human evidence
SELECT required BMI >= 27 and established CVD; mean BMI 33.4. Does not include normal-weight adults.
- The cardiovascular benefit of GLP-1 receptor agonists is not explained by weight loss.Supports
SELECT primary result: HR 0.80 for MACE in obesity without diabetes.
- GLP-1 receptor agonists cause serious gastrointestinal and biliary adverse events.Supports
SELECT: discontinuation for adverse events 16.6% vs 8.2%, mainly GI.
04Source
The source, as retrieved
Abstract
[BACKGROUND] Semaglutide, a glucagon-like peptide-1 receptor agonist, has been shown to reduce the risk of adverse cardiovascular events in patients with diabetes. Whether semaglutide can reduce cardiovascular risk associated with overweight and obesity in the absence of diabetes is unknown. [METHODS] In a multicenter, double-blind, randomized, placebo-controlled, event-driven superiority trial, we enrolled patients 45 years of age or older who had preexisting cardiovascular disease and a body-mass index (the weight in kilograms divided by the square of the height in meters) of 27 or greater but no history of diabetes. Patients were randomly assigned in a 1:1 ratio to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in a time-to-first-event analysis. Safety was also assessed. [RESULTS] A total of 17,604 patients were enrolled; 8803 were assigned to receive semaglutide and 8801 to receive placebo. The mean (±SD) duration of exposure to semaglutide or placebo was 34.2±13.7 months, and the mean duration of follow-up was 39.8±9.4 months. A primary cardiovascular end-point event occurred in 569 of the 8803 patients (6.5%) in the semaglutide group and in 701 of the 8801 patients (8.0%) in the placebo group (hazard ratio, 0.80; 95% confidence interval, 0.72 to 0.90; P<0.001). Adverse events leading to permanent discontinuation of the trial product occurred in 1461 patients (16.6%) in the semaglutide group and 718 patients (8.2%) in the placebo group (P<0.001). [CONCLUSIONS] In patients with preexisting cardiovascular disease and overweight or obesity but without diabetes, weekly subcutaneous semaglutide at a dose of 2.4 mg was superior to placebo in reducing the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke at a mean follow-up of 39.8 months. (Funded by Novo Nordisk; SELECT ClinicalTrials.gov number, NCT03574597.).
Where this record came from
| Source | Retrieved | Identifier |
|---|---|---|
| pubmed | Sep 13, 2026 | 37952131 first ingestion |