Early weight loss during semaglutide therapy may not predict later reductions in major cardiovascular events, according to a recent study.
In a prespecified analysis of the SELECT trial, researchers investigated the relationship between baseline adiposity, treatment-induced changes in body fat, and cardiovascular outcomes in adults with overweight or obesity but without diabetes.
The randomized, double-blind, placebo-controlled phase 3 trial, published in The Lancet, enrolled 17,604 participants aged at least 45 years with a body mass index of at least 27 kg/m² and established atherosclerotic cardiovascular disease. Conducted at 804 sites across 41 countries, study participants were randomized 1:1 to receive once-weekly subcutaneous semaglutide 2.4 mg or placebo and followed for a mean of 39.8 months. The primary endpoint was the time to first major adverse cardiovascular event (MACE), defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.
Baseline data showed that higher body mass index categories were associated with younger age, female sex, higher blood pressure, and increased inflammatory burden, as measured by high-sensitivity C-reactive protein. Semaglutide significantly reduced MACE incidence compared with placebo, with consistent benefit across all baseline adiposity categories. Each 5 kg lower baseline bodyweight or 5 cm smaller waist circumference was associated with an hazard ratio of 0.96 for MACE.
At 20 weeks, participants receiving semaglutide had a 6.4% mean reduction in bodyweight and a 5.0 cm decrease in waist circumference, compared with 0.8% and 1.1 cm, respectively, for placebo. However, the magnitude of early weight loss did not predict cardiovascular outcomes. Patients treated with semaglutide who lost at least 5% of their baseline weight had a MACE incidence of 2.0 events per 100 person-years, similar to those with less than 5% weight loss. By contrast, waist circumference reduction correlated with improved cardiovascular outcomes (hazard ratio, 0.91), accounting for roughly one-third of the MACE risk reduction (adjusted HR, 0.86).
"However, mediation analyses estimated that waist circumference reduction accounted for no more than 33% of the MACE effect," noted lead author John Deanfield, MB BChir, of the Institute of Cardiovascular Sciences, University College London, London, UK, and colleagues.
Serious adverse events were comparable between groups. Placebo recipients with at least 5% weight loss had higher all-cause mortality, with greater non-cardiovascular and overall deaths observed in this group.
Full disclosures can be found in the published study.
Source: The Lancet
