Wegovy confers reductions in cardiovascular risk, regardless of weight loss

Key takeaways:

• In the SELECT trial, there were no linear trends between weight loss with semaglutide and reduction in CV risk.
• Higher waist circumference loss at 20 weeks was tied to greater CV risk reduction.

Once-weekly semaglutide 2.4 mg conferred a greater reduction in major adverse cardiovascular events than placebo, regardless of change in body weight, according to an analysis of the SELECT trial published in The Lancet.

As Healio previously reported, in the primary analysis of the SELECT trial, adults who received once-weekly subcutaneous semaglutide 2.4 mg (Wegovy, Novo Nordisk) had a lower risk for major adverse CV events than those who received placebo. In the new analysis, researchers found the CV benefits with semaglutide were consistent regardless of how much weight participants lost during the study. However, those who had a greater decrease in waist circumference with semaglutide had a larger reduction in major adverse CV event risk.

“This work has implications for how semaglutide is used in clinical practice,” John Deanfield, MB, Bchir, FRCP, FESC, FACC, professor of cardiology at University College London, consultant cardiologist at Barts Heart Centre and director of the National Institute for Cardiovascular Outcomes Research, said in a press release. “You don’t have to lose a lot of weight, and you don’t need a high BMI to gain CV benefit. If your aim is to reduce cardiovascular disease, restricting its use to a limited time only and for those with the highest BMIs doesn’t make sense.”

The SELECT trial enrolled 17,604 adults aged 45 years and older with a BMI of 27 kg/m2 or higher and established atherosclerotic CVD. Participants were randomly assigned to receive once-weekly semaglutide or placebo. In this secondary analysis, researchers analyzed how major adverse CV event risk at 20 and 104 weeks differed by body weight and waist circumference change.

Most adiposity changes occur early

Risk for major adverse CV events decreased by 4% for each 5 kg of lower baseline body weight in the semaglutide group (HR = 0.96; 95% CI, 0.94-0.99; P = .001) but not the placebo group. Each 5 cm reduction in baseline waist circumference was tied to lower risk for major adverse CV events in both the semaglutide (HR = 0.96; 95% CI, 0.93-0.99; P = .004) and placebo groups (HR = 0.96; 95% CI, 0.94-0.99; P = .007).

At 20 weeks, the semaglutide group had a 5.6 percentage point greater decline in body weight and a 3.9 cm greater decrease in waist circumference than the placebo group. Adiposity changes at 20 weeks accounted for 71% of weight loss and 68% of waist circumference decline in the semaglutide group during the study. Of first major adverse CV events reported, 11.2% occurred during the first 20 weeks, favoring the semaglutide group (HR = 0.58; 95% CI, 0.41-0.81).

Weight loss not tied to CV risk

Both the semaglutide and placebo groups had no linear trends between weight loss and major adverse CV event risk as 20 weeks. Greater weight circumference decrease was tied to lower risk for major adverse CV events at 20 weeks in the semaglutide group (HR = 0.91; 95% CI, 0.84-0.98; P = .02).

Semaglutide’s effect on major adverse CV event risk was not mediated by time-varying weight loss. However, change in waist circumference at 20 weeks had a 33% mediation effect on semaglutide’s reduction in major adverse CV event risk.

“Abdominal fat is more dangerous for our CV health than overall weight and, therefore, it is not surprising to see a link between reduction in waist size and CV benefit,” Deanfield said in the release. “However, this still leaves two-thirds of the heart benefits of semaglutide unexplained.”

Deanfield said the findings “reframe” how semaglutide is benefiting heart health in patients. However, he added that health care professionals should consider potential adverse events and weigh them against the drug’s benefits.

“Investigations of side effects become especially important given the broad range of people this medicine and others like it could help,” Deanfield said in the release.

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