TOPLINE

In adults with obesity and established cardiovascular disease (CVD), semaglutide was associated with improvements in several risk factors. However, those changes only accounted for part of the reduced risk for major adverse cardiovascular events (MACE) noted in the SELECT trial. 

METHODOLOGY

• In the SELECT trial, patients with obesity and CVD who received semaglutide had a 20% relative reduction in the risk for MACE. Researchers performed a mediation analysis to identify which treatment-related changes explained that benefit.
• The study included 17,604 adults aged 45 years or older with a BMI of 27 or higher who had CVD and were free of diabetes. The mean age of patients was 62 years, and 72% were men.
• Patients were randomly assigned to receive either once-weekly subcutaneous semaglutide (titrated to a 2.4 mg target dose over 16 weeks) or matching placebo.
• Researchers tracked repeated measurements of 12 potential mediators, including body weight, waist circumference, blood pressure, and levels of high-sensitivity C-reactive protein (hsCRP), A1c, and lipids, at multiple timepoints through at least 24 months.
• The primary endpoint was MACE, defined as nonfatal myocardial infarction or nonfatal stroke, or cardiovascular death. The mean follow-up duration was 39.8 months.

TAKEAWAY

• Semaglutide was associated with significant improvements in all 12 risk factors evaluated (P < .05).
• Waist circumference accounted for an estimated 64.0% of the benefit of semaglutide (95% CI, 27.5-179.6), hsCRP levels for 42.1% (95% CI, 17.9-110.5), A1c levels for 29.0% (95% CI, -20.7 to 120.5), and body weight for 19.5% (95% CI, -33.0 to 110.7). All estimates had wide CI values.
• Combining eight key risk factors explained 31.4% of the benefit of semaglutide (95% CI, -30.1 to 143.6). Variables other than body weight and waist circumference explained 46.0% of the benefit (95% CI, -6.0 to 161.0).

IN PRACTICE

"While it remains possible that a greater % of mediation is due to waist circumference or weight change than the point estimates we have obtained here, our analyses cannot convincingly show that the effect of semaglutide on MACE in SELECT is totally accounted for by body weight or waist circumference change or change in the other CV risk factors measured," the researchers wrote.

SOURCE

The study was led by Helen M. Colhoun, University of Edinburgh in Edinburgh, Scotland. It was published online on September 23 in European Heart Journal.

LIMITATIONS

The study had not been designed or powered to assess mediation. Several mediator measurements were missing, partly because of the COVID pandemic. The mediation analyses relied on strong, untestable assumptions, such as the absence of unmeasured confounders.

DISCLOSURES

The study received funding from Novo Nordisk. Several authors reported being employees and/or stakeholders of Novo Nordisk. Many authors reported having financial ties such as receiving consulting or advisory fees, speaker honoraria, travel support, or research grants from various companies, including the funder. Detailed disclosures are in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.