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

Summary

In 17,604 overweight/obese patients with cardiovascular disease but without diabetes, semaglutide reduced MACE consistently across baseline bodyweight and waist categories. Reductions in waist circumference—especially by weeks 20 and 104—partly mediated benefit (about 33%), whereas weight loss per se showed no linear association, implying mechanisms beyond adiposity.

Key Findings

• Semaglutide reduced MACE across all baseline bodyweight and waist circumference categories in 17,604 patients.
• Lower baseline bodyweight and waist circumference were associated with lower MACE risk in the semaglutide arm (HR 0.96 per 5 kg and 0.96 per 5 cm).
• Waist circumference reduction at week 20 and by week 104 correlated with lower subsequent/in-trial MACE; ~33% of benefit was mediated via waist reduction.
• In placebo, weight loss was paradoxically associated with increased MACE risk; baseline waist, but not weight, associated with risk.

Clinical Implications

Use semaglutide for secondary cardiovascular prevention in appropriate overweight/obese patients irrespective of baseline adiposity or early weight change; measure waist circumference and communicate that benefits are not solely weight-dependent.

Limitations

• Secondary (prespecified) analysis cannot establish causality of mediators
• Industry funding (Novo Nordisk) and limited detail on full follow-up duration in the abstract

Future Directions

Elucidate weight-independent mechanisms (e.g., inflammation, endothelial function), validate waist-mediated effects prospectively, and explore imaging or biomarker endpoints beyond anthropometry.