Summary:
In patients with obesity and cardiovascular disease without diabetes (n=17,604) from the SELECT trial, once-weekly semaglutide 2.4 mg reduced MACE consistently across all baseline adiposity categories, with only 33% of the benefit mediated through waist circumference reduction compared to placebo, though weight loss magnitude showed no linear relationship with MACE reduction, suggesting cardioprotective mechanisms beyond adiposity.
| PICO | Description |
|---|---|
| Population | Patients aged ≥45 years with BMI ≥27 kg/m² and established cardiovascular disease without diabetes (n=17,604) enrolled in SELECT trial across 804 sites in 41 countries. |
| Intervention | Once-weekly subcutaneous semaglutide 2.4 mg. |
| Comparison | Placebo injection once weekly (1:1 randomization). |
| Outcome | MACE reduction consistent across baseline adiposity categories. In semaglutide group: 4% lower MACE risk per 5 kg lower baseline weight (HR 0.96, p=0.001) and per 5 cm smaller waist (HR 0.96, p=0.004). No linear trend linking weight loss to MACE, but waist reduction at weeks 20 and 104 associated with lower MACE. 33% of benefit mediated by waist reduction. |
Clinical Context
The SELECT trial established semaglutide as the first obesity medication to demonstrate cardiovascular event reduction in patients without diabetes. The 20% reduction in MACE (cardiovascular death, non-fatal MI, non-fatal stroke) was groundbreaking, but the mechanisms underlying this benefit remained unclear. Did cardiovascular protection come from weight loss, metabolic improvements, direct vascular effects, or some combination?
Understanding the relationship between adiposity changes and cardiovascular outcomes has important implications. If benefits are purely weight-mediated, any effective weight loss intervention should provide similar protection. If benefits occur independently of weight loss, semaglutide’s cardiovascular effects may involve unique mechanisms warranting investigation.
This prespecified analysis examined MACE risk across baseline adiposity measures (weight and waist circumference) and evaluated whether treatment-induced changes in these measures mediated the observed cardiovascular benefit. The inclusion of both weight and waist circumference is important, as waist circumference better reflects visceral adiposity—the depot most strongly linked to cardiometabolic risk.
Clinical Pearls
1. Benefit Across All Adiposity Levels: Semaglutide reduced MACE consistently regardless of baseline weight or waist circumference. This is clinically important—patients with lower BMI (≥27-30) benefit as much as those with higher BMI, supporting broad use of semaglutide for cardiovascular risk reduction in eligible patients.
2. Waist Circumference More Predictive Than Weight: Lower baseline waist circumference predicted lower MACE risk in both treatment groups, while lower baseline weight was only predictive in the semaglutide group. This reinforces waist circumference as a superior marker of cardiovascular risk compared to weight or BMI alone.
3. Weight Loss Alone Doesn’t Explain Benefit: Critically, weight loss at week 20 showed no linear association with subsequent MACE reduction in the semaglutide group. This striking finding suggests that semaglutide’s cardiovascular protection operates through mechanisms beyond simple weight reduction.
4. Waist Reduction Partially Mediates Effect: While weight loss didn’t predict outcomes, waist circumference reduction did associate with lower MACE risk. An estimated 33% of semaglutide’s benefit was mediated through waist reduction, leaving 67% attributable to other mechanisms—likely direct anti-inflammatory, anti-atherosclerotic, or metabolic effects.
Practical Application
When prescribing semaglutide for cardiovascular risk reduction, emphasize that benefits extend beyond weight loss. Patients who achieve modest weight loss should not be considered treatment failures—cardiovascular protection likely occurs through multiple mechanisms. This messaging may improve adherence among patients discouraged by perceived inadequate weight loss.
Consider measuring waist circumference in addition to weight as a monitoring parameter. Waist reduction better reflects visceral fat loss and was the adiposity measure most associated with MACE reduction in this analysis.
For patients with established cardiovascular disease and overweight/obesity without diabetes, semaglutide provides cardiovascular protection across the adiposity spectrum. Do not restrict use to patients with higher BMI—those with BMI 27-30 derive similar relative benefit.
Broader Evidence Context
This analysis addresses a fundamental question in obesity medicine: is weight loss itself cardioprotective, or are specific interventions uniquely beneficial? The finding that weight loss magnitude didn’t predict MACE reduction challenges the assumption that “a calorie is a calorie” and suggests GLP-1 agonists have distinct cardiovascular mechanisms.
Potential weight-independent mechanisms include direct anti-inflammatory effects (reduced CRP, IL-6), improved endothelial function, reduced atherosclerotic plaque inflammation, and metabolic effects on lipids and blood pressure that exceed what weight loss alone would predict.
This has implications for other weight loss interventions. Bariatric surgery and other medications may need dedicated cardiovascular outcomes trials rather than assuming weight loss equivalently translates to cardiovascular benefit.
Study Limitations
Mediation analysis cannot prove causation. Weight and waist circumference are imperfect measures of adiposity (don’t capture visceral vs subcutaneous distribution). Paradoxical association of weight loss with increased MACE in placebo group suggests confounding by illness-induced weight loss. Analysis of changes at week 20 may miss effects of later adiposity changes. Residual confounding possible despite adjustment.
Bottom Line
Semaglutide’s cardiovascular benefit in SELECT occurred independently of baseline adiposity and was not explained by weight loss magnitude, with only 33% of the MACE reduction mediated through waist circumference changes, suggesting substantial cardioprotective mechanisms beyond adiposity reduction that may include direct vascular and anti-inflammatory effects.
Source: Deanfield J, et al. “Semaglutide and cardiovascular outcomes by baseline and changes in adiposity measurements: a prespecified analysis of the SELECT trial.” Lancet. 2025;406(10516):2257-2268. Read article
