In a study published in The Lancet, researchers explored how baseline adiposity, treatment-induced adiposity changes, and the risk of major adverse cardiovascular events (MACE) relate to the cardiovascular outcomes of semaglutide in people with overweight or obesity and established cardiovascular disease. The GLP-1 receptor agonists, including semaglutide, were developed to improve glycemic control in type 2 diabetes and have demonstrated cardiovascular and weight-related benefits in some populations without diabetes.
Obesity remains a major driver of cardiovascular mortality and morbidity through metabolic, inflammatory, and hemodynamic pathways. However, weight alone does not capture the nuanced distribution of fat, such as visceral adiposity, which has been causally linked to adverse cardiovascular outcomes. The relationship between baseline adiposity, changes in adiposity during therapy, and subsequent MACE risk has remained unclear in GLP-1RA trials.
Key findings
Baseline characteristics showed higher BMI associated with female sex, younger age, and non-Asian nationality, with increasing prevalence of prediabetes, elevated blood pressure, and inflammatory burden across BMI categories. Participants had a mean exposure duration of about 33 to 35 months and a mean follow-up of roughly 40 months. Semaglutide reduced MACE incidence consistently across baseline body habitus categories, with no observed heterogeneity in effect by adiposity measures.
Weight and waist changes
Within each group, participants on semaglutide experienced greater adiposity reductions than those on placebo. By week 20, mean body weight decreased by 6.4% and waist circumference by 5.0 cm in the semaglutide group, versus 0.8% weight loss and 1.1 cm waist reduction in the placebo group.
Early adiposity changes accounted for most, but not all, of the weight and waist reductions observed by week 104 (approximately 68% of waist reduction and 71% of weight loss).
By week 20, first-event MACE had already diverged between groups (hazard ratio [HR] 0.58), suggesting an early treatment effect.
Adiposity and MACE risk
In the semaglutide arm, each 5 kg lower baseline weight was associated with about a 4% further reduction in MACE risk (HR 0.96 per 5 kg), a trend not statistically significant in the placebo arm.
For waist circumference, each 5 cm smaller baseline waist was associated with roughly a 4% lower MACE risk in both arms.
Among participants who lost weight by week 20, the semaglutide group had a lower subsequent MACE incidence than the placebo group. By week 104, placebo participants with the greatest weight loss had higher MACE incidence, whereas semaglutide recipients with the greatest weight reduction had the lowest incidence.
The study observed a linear relationship between greater waist circumference reduction and lower subsequent MACE risk in the semaglutide group. In contrast, non-linear effects in the placebo group were driven by higher MACE incidence among participants with at least 5% weight loss, potentially reflecting unintentional or illness-related weight loss.
Mediation analysis and interpretation
Time-varying weight loss did not mediate semaglutide’s cardiovascular benefit in a linear fashion; however, early waist circumference changes partially mediated the effect, accounting for an estimated 33% of the treatment effect.
In placebo recipients, those with at least 5% weigh
t loss had higher all-cause mortality than those with smaller losses or weight gain, suggesting that weight loss in the placebo group could reflect confounding illness-related factors.
Conclusions and limitations
Semaglutide reduced MACE risk compared with placebo across all baseline waist circumference and weight levels from early in the trial.
Early weight loss alone did not explain cardiovascular benefits after 20 weeks. Waist circumference reduction showed a clearer, linear association with reduced MACE risk.
Mediation analyses indicate that waist circumference reduction partially contributes to semaglutide’s cardioprotective effects, but a substantial portion of benefit remains independent of early adiposity changes.
The predominantly White, male study population may limit generalizability to broader groups.
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