SELECT trial deep-dive: semaglutide cuts MACE 20% in obesity without diabetes
Last verified 2026-05-27 · 3 · Completed; primary results reported November 2023 · NCT03574597 ↗
SELECT (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity) was a multicenter, double-blind, placebo-controlled, event-driven phase 3 superiority trial sponsored by Novo Nordisk. It enrolled 17,604 adults aged 45 or older with a BMI of 27 kg/m² or greater and established cardiovascular disease (prior myocardial infarction, prior stroke, or symptomatic peripheral artery disease), explicitly excluding anyone with type 1 or type 2 diabetes. Participants were randomized 1:1 to weekly subcutaneous semaglutide 2.4 mg or matching placebo on top of guideline-directed standard of care. Mean exposure was 34.2 months and mean follow-up was 39.8 months. The trial was designed and powered to ask one question: does treating obesity with a GLP-1 receptor agonist also reduce hard cardiovascular events in people who do not have diabetes? Primary results were published by Lincoff and colleagues in the New England Journal of Medicine on November 11, 2023.
- Enrollment
- 17,604
- Duration
- Mean exposure 34.2 months; mean follow-up 39.8 months (up to 240 weeks)
- Drug
- Semaglutide 2.4 mg (Wegovy)
- Population
- Adults aged 45 or older with BMI ≥27 kg/m² and established cardiovascular disease (prior MI, prior stroke, or symptomatic peripheral artery disease). No history of type 1 or type 2 diabetes; HbA1c <6.5% at screening. Mean baseline BMI ~33 kg/m², mean age 61.6 years, 27.7% female, 71.0% white.
Primary endpoint
Three-point MACE: composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (time-to-first-event)
Treatment arm
569 of 8,803 (6.5%)
Comparator
701 of 8,801 (8.0%)
Treatment difference: Hazard ratio 0.80 (95% CI 0.72–0.90); P<0.001 for superiority
20% relative reduction in three-point MACE with semaglutide 2.4 mg vs placebo. Absolute risk reduction 1.5 percentage points over a mean 39.8 months, number needed to treat ≈67.
Secondary endpoints
| Endpoint | Treatment | Comparator | Difference |
|---|---|---|---|
| Death from cardiovascular causes (component of MACE) Numerical reduction; confidence interval crossed 1.0 in the hierarchical testing sequence so subsequent secondary endpoints were not declared statistically significant. | 223 of 8,803 (2.5%) | 262 of 8,801 (3.0%) | Hazard ratio 0.85 (95% CI 0.71–1.01) |
| Heart-failure composite: heart-failure events plus cardiovascular death Nominal 18% reduction in the composite of heart-failure events plus CV death; not formally significant under the hierarchical testing rule because CV death alone did not cross the boundary. | 290 of 8,803 (3.3%) | 339 of 8,801 (3.9%) | Hazard ratio 0.82 (95% CI 0.71–0.96) |
| Death from any cause (all-cause mortality) Nominal 19% reduction in all-cause death; not formally significant under hierarchical testing but consistent in direction with the primary endpoint. | 375 of 8,803 (4.3%) | 414 of 8,801 (4.7%) | Hazard ratio 0.81 (95% CI 0.71–0.93) |
| Nonfatal myocardial infarction (component of MACE) 28% relative reduction in nonfatal MI — the component contributing most to the MACE result. | 234 of 8,803 (2.7%) | 322 of 8,801 (3.7%) | Hazard ratio 0.72 (95% CI 0.61–0.85) |
| Nonfatal stroke (component of MACE) No meaningful reduction in nonfatal stroke; the MACE benefit was driven by CV death and MI, not stroke. | 138 of 8,803 (1.6%) | 151 of 8,801 (1.7%) | Hazard ratio 0.93 (95% CI 0.74–1.17) |
| Composite nephropathy outcome (persistent macroalbuminuria, ≥50% eGFR decline, eGFR <15, renal replacement, or renal death) 22% relative reduction in the kidney composite; supports broader cardiometabolic benefit. | 1.8% | 2.2% | Hazard ratio 0.78 (95% CI 0.63–0.96) |
| Percentage change in body weight at week 104 Mean weight loss at 2 years was substantially larger than placebo; weight loss continued through ~65 weeks and was largely sustained. | −9.4% | −0.9% | Estimated treatment difference −8.5 percentage points (95% CI −8.8 to −8.2); P<0.001 |
| Percentage change in body weight at week 208 (prespecified long-term analysis) At 4 years, mean weight loss with semaglutide was about 10% and was sustained, regardless of baseline BMI category, sex, race, or region. | −10.2% | −1.5% | Difference −8.7 percentage points; P<0.0001 |
| Waist circumference change at week 208 Sustained reduction in central adiposity over four years. | −7.7 cm | −1.3 cm | P<0.0001 |
Adverse events
| Event | Treatment rate | Comparator rate |
|---|---|---|
| Serious adverse events (any) Fewer serious adverse events with semaglutide, driven primarily by fewer cardiac and infectious events. | 33.4% | 36.4% |
| Permanent discontinuation due to adverse events P<0.001. Gastrointestinal disorders were the most common reason for stopping semaglutide. | 16.6% (1,461) | 8.2% (718) |
| Gastrointestinal disorders (any) Nausea, diarrhea, vomiting, and constipation were the dominant tolerability issues, consistent with the GLP-1 class profile. | 10.0% leading to discontinuation | 2.0% leading to discontinuation |
| Gallbladder-related disorders Cholelithiasis and cholecystitis were modestly more common with semaglutide; consistent with rapid weight loss biology. | 2.8% | 2.3% |
| Acute pancreatitis (adjudicated) No increased risk of pancreatitis with semaglutide in SELECT. | 0.2% | 0.3% |
| Malignant neoplasms No imbalance in overall cancer incidence between arms over a mean ~40 months. | 5.9% | 5.9% |
| Acute kidney injury Numerically lower with semaglutide despite GI losses; consistent with the kidney-composite benefit. | 1.7% | 2.2% |
| Psychiatric disorders (any serious) No signal for suicidal ideation or self-harm in adjudicated events. | 1.4% | 1.5% |
Subgroup analyses
- Prior myocardial infarction at baseline (~70% of cohort): Hazard ratio for MACE consistent with overall result (~0.80)
MACE benefit was present whether or not the participant had a prior MI; no significant treatment-by-subgroup interaction.
- Sex: female (27.7%) vs male (72.3%): Similar MACE hazard ratios across sexes
No significant interaction; benefit observed in both women and men, though women were under-represented relative to obesity prevalence.
- Baseline BMI 27 to <30, 30 to <35, 35 to <40, ≥40 kg/m²: MACE benefit consistent across all BMI strata
Cardiovascular benefit did not require severe obesity; participants in the overweight range (BMI 27–30) experienced similar relative risk reduction.
- Baseline HbA1c <5.7% vs 5.7%–6.4% (prediabetes): MACE hazard ratios similar across glycemic strata
Benefit observed regardless of prediabetes status; not driven by glycemic improvement alone.
- Age <65 vs ≥65 years: Consistent MACE reduction across age groups
No significant age interaction.
- Region: North America vs Europe vs Asia vs other: Directionally consistent MACE benefit across regions
Trial enrolled across 41 countries; treatment effect was geographically robust.
Clinical significance
SELECT was the trial that turned semaglutide 2.4 mg from a weight-loss product into a cardiovascular drug. The 20% relative reduction in three-point MACE — driven primarily by fewer nonfatal myocardial infarctions and cardiovascular deaths — was observed in a population explicitly without diabetes, isolating the benefit to the obesity-plus-prior-CVD setting. The result led directly to the March 2024 FDA label expansion for Wegovy to reduce the risk of MACE in adults with cardiovascular disease and overweight or obesity, the first GLP-1 receptor agonist approved on a cardiovascular indication outside diabetes. The benefit appeared early (within months) and was preserved across BMI strata, suggesting mechanisms beyond weight loss alone — blood pressure, inflammation, and direct vascular effects are leading candidates. SELECT does not address primary prevention; everyone enrolled already had established cardiovascular disease.
Frequently asked questions
What does MACE mean?
MACE stands for major adverse cardiovascular events. In SELECT, the primary MACE endpoint was a three-component composite: death from cardiovascular causes, nonfatal myocardial infarction (heart attack), or nonfatal stroke — whichever occurred first. It is the standard composite endpoint that the FDA uses to judge whether a drug reduces cardiovascular risk in trials of this type.
Did SELECT show weight loss too?
Yes, but weight loss was a secondary endpoint, not the primary outcome. In the prespecified long-term analysis published by Ryan and colleagues in Nature Medicine (PMID 38740993), mean weight loss at 208 weeks was 10.2% on semaglutide versus 1.5% on placebo. That is less than the ~15% seen in STEP-1 because SELECT enrolled an older population with established cardiovascular disease and ran much longer, so weight regain plateaus matter more than peak nadir.
Does this apply to people without prior cardiovascular disease?
No. SELECT explicitly required established cardiovascular disease at entry — prior heart attack, prior stroke, or symptomatic peripheral artery disease. The 20% MACE reduction is a secondary-prevention finding. Whether semaglutide reduces first cardiovascular events in people with obesity who have not yet had one has not been tested in a dedicated trial.
Does the SELECT result also apply to tirzepatide (Zepbound, Mounjaro)?
Not yet. SELECT studied semaglutide 2.4 mg only. The equivalent cardiovascular-outcomes trial for tirzepatide is SURPASS-CVOT in adults with type 2 diabetes and SURMOUNT-MMO in adults with obesity and cardiovascular disease — both are ongoing and have not yet reported MACE results. Until SURMOUNT-MMO reports, the cardiovascular labeling differs between Wegovy (carries the MACE-reduction indication) and Zepbound (does not).
Did all-cause mortality go down in SELECT?
Numerically, yes — all-cause death was 4.3% on semaglutide versus 4.7% on placebo, a hazard ratio of 0.81 (95% CI 0.71 to 0.93). But under the prespecified hierarchical testing sequence, this result was not declared formally statistically significant because cardiovascular death alone did not cross its testing boundary first. The direction is consistent with the primary MACE finding; the interpretation is more conservative.
What were the main tolerability problems?
Gastrointestinal side effects, primarily nausea, diarrhea, vomiting, and constipation. Adverse events led to permanent discontinuation in 16.6% of the semaglutide group versus 8.2% on placebo, with GI events the dominant driver. Gallbladder-related events were modestly more common with semaglutide (2.8% vs 2.3%). Acute pancreatitis was rare and not increased. Overall serious adverse events were slightly lower with semaglutide.
Sources
References
- 1.Lincoff AM, Brown-Frandsen K, Colhoun HM, et al.; SELECT Trial Investigators Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes N Engl J Med. 2023. PMID: 37952131.
- 2.Ryan DH, Lingvay I, Deanfield J, et al. Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial Nat Med. 2024. PMID: 38740993.
- 3.U.S. Food and Drug Administration FDA approves first treatment to reduce risk of serious cardiovascular problems specifically in adults with obesity or overweight (Wegovy) FDA Press Announcement. 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-reduce-risk-serious-cardiovascular-problems-specifically-adults-obesity
- 4.ClinicalTrials.gov Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity (SELECT) ClinicalTrials.gov registry. 2024. https://clinicaltrials.gov/study/NCT03574597