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Evevident
Original paper
2023NEJMCardiology

SELECT

Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes

RCTObesity / CV prevention

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Overview

In overweight/obesity with established CVD but no diabetes, semaglutide 2.4 mg reduced major adverse cardiovascular events.

Clinical takeaway

SELECT moved semaglutide from weight-loss therapy into cardiovascular secondary prevention for patients with obesity and established CVD without diabetes.

Key result

MACE was lower with semaglutide (HR 0.80; 95% CI 0.72-0.90).

Practice impact

Supports treating obesity as a cardiovascular risk-modifying condition in selected secondary-prevention patients.

Evidence

Study design

Randomized, double-blind, placebo-controlled cardiovascular outcomes trial.

Enrollment

17,604

Follow-up

Mean 39.8 months.

Geography

Multinational

Clinical question

Does semaglutide reduce cardiovascular events in overweight or obese patients with established CVD but no diabetes?

Population

  • Adults >=45 years with preexisting cardiovascular disease and BMI >=27, without diabetes.

Intervention

Once-weekly subcutaneous semaglutide 2.4 mg.

Comparator

Placebo, both added to standard care.

Primary outcome

Three-point MACE: CV death, nonfatal MI, or nonfatal stroke.

Semaglutide 2.4 mg reduced major adverse cardiovascular events in patients with obesity and established cardiovascular disease but no diabetes.

Hazard ratio / 0.8 / CI 95% CI 0.72-0.90 / p=<0.001

Key results

  • Primary MACE: 6.5% with semaglutide vs 8.0% with placebo; HR 0.80; 95% CI 0.72-0.90; p<0.001.
  • Discontinuation for adverse events was more common with semaglutide (16.6% vs 8.2%), driven by gastrointestinal symptoms.
  • Semaglutide produced substantially greater weight loss than placebo.

Harms

  • Gastrointestinal adverse events led to more discontinuations with semaglutide (16.6% vs 8.2%).
  • As with other GLP-1 receptor agonists, cholelithiasis is a recognized risk.

Clinical Use

When to cite

  • When discussing GLP-1 therapy for secondary cardiovascular prevention in patients with overweight or obesity even without diabetes.

Practice impact

  • Supports treating obesity as a cardiovascular risk-modifying condition in selected secondary-prevention patients.

Applicability

  • Most applicable to adults with overweight or obesity and established cardiovascular disease but without diabetes.

Limitations

  • Secondary-prevention population only; does not address primary prevention.
  • Long-term access, tolerability, and cost are major implementation barriers.
  • The mechanism of cardiovascular benefit is only partly explained by weight loss.

Common misinterpretations

  • Do not attribute the entire cardiovascular benefit to weight loss; event-curve separation preceded maximal weight change.
  • SELECT enrolled patients with established cardiovascular disease, so it does not establish primary-prevention benefit.

Related evidence

LEADER - Same Drug Class

Citation

Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023;389(24):2221-2232. doi:10.1056/NEJMoa2307563

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.