BACKGROUND AND PURPOSE:

• In the SELECT trial, semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) reduced major cardiovascular events (MACE) in patients with obesity and preexisting cardiovascular conditions in participants without diabetes
• Deanfield et al. (The Lancet, 2025) examined whether factors beyond weight loss and waist circumference contribute to reductions in MACE risk

METHODS:

• Prespecified secondary analysis of a randomized, double-blind, placebo-controlled trial
  • SELECT trial
  • 41 countries
• Participants
  • Individuals ≥45 years
  • BMI ≥27 kg/m2
• Interventions
  • Once-weekly semaglutide with target dose of 2.4 mg 
  • Placebo
• Exposures
  • Adiposity change in the first 20 weeks | 104 weeks
• Study design
  • Adiposity measures included weight and waist circumference
• Primary outcome
  • Risk of MACE after 20 weeks
    • Composite: Cardiovascular death | Non-fatal myocardial infarction | Non-fatal stroke

RESULTS:

• 17,604 patients in SELECT
• Semaglutide reduced the incidence of MACE compared to placebo, regardless of baseline weight and waist circumference
• Within the semaglutide group, lower baseline bodyweight and waist circumference were associated with a lower incidence of MACE
  • Reduction in risk per 5 kg lower bodyweight
    • Hazard ratio (HR) 0.96 (95% CI, 0.94 to 0.99) | P=0.001
  • Reduction in risk per 5 cm smaller waist circumference
    • HR 0.96 (95% CI, 0.93 to 0.99) | P=0.004
• In the placebo group, lower baseline waist circumference but not bodyweight was associated with a lower MACE risk
  • Lower baseline waist circumference
    • HR 0.96 (95% CI, 0.94 to 0.99) | P=0.007
  • Lower baseline bodyweight
    • HR 0.99 (95% CI, 0.97 to 1.01) | P=0.28
• In the placebo group, 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
  • Greater waist circumference reduction at week 20 was associated with lower subsequent MACE risk
• The observed benefit on MACE was mediated through waist circumference reduction, though this was minimized after adjustment for time-varying changes in waist circumference
  • HR 0.86 (95% CI, 0.77 to 0.97)

CONCLUSION:

• Semaglutide lowered cardiovascular risk independent of early weight loss, although there was a linear relationship associated with decreasing waist circumference  
• The authors state

This supports the reconceptualisation of GLP-1RAs as potential cardiovascular disease-modifying agents, with implications for clinical practice and health-care policy

Learn More – Primary Sources:

Semaglutide and cardiovascular outcomes by baseline and changes in adiposity measurements: a prespecified analysis of the SELECT trial