Semaglutide’s CV Effects Only Partially Tied to Weight Loss: SELECT Analysis

The cardiovascular benefits of semaglutide (Wegovy; Novo Nordisk) seem to be independent of both baseline patient adiposity and subsequent weight loss with treatment, suggesting that the glucagon-like peptide-1 receptor agonist (GLP-1 RA) has benefits that go beyond the scale, according to a new prespecified analysis of the SELECT trial.

The new findings, published online this week in the Lancet, show a linear reduction in MACE as both baseline bodyweight and waist circumference decrease, but there was no association between weight loss at 20 weeks and subsequent risk of clinical events.

Researchers estimate that about two-thirds of the MACE reduction with semaglutide was not related to weight at all.

“We were surprised that the cardiovascular benefit was not significantly different across the baseline level of BMI with patients who were only modestly overweight, achieving the same cardiovascular benefit as those with significant obesity,” lead author John Deanfield, MBBChir (University College London, England), told TCTMD in an email. “Furthermore, the cardiovascular benefit was not related to the amount of weight that patients lost while taking semaglutide during the study. This reframes GLP-1 receptor agonists as disease modifying agents rather than as ‘weight loss jabs.’”

Naveed Sattar, MD (University of Glasgow, Scotland), who commented on the study for TCTMD, said he was not surprised to see that many of the effects of semaglutide are not associated with weight.

“Most of the effect of these drugs is probably a direct effect of the drugs on blood vessels and heart tissue, at least for the benefit on preventing strokes and heart attacks,” he said. “Whereas we do know that the weight benefit is definitely the reason why you get less sleep apnea [and] better liver disease measures. It’s the main reason why blood pressure goes down.”

The new study “further reinforces the notion that these incretin therapies have both direct effects right on the heart and in keeping sugar down and possibly the kidneys and they also have indirect effects that benefits their patients via weight loss,” Sattar added. “In some ways these drugs almost seem too good to be true—having direct effects that prevent heart attacks and strokes and having weight loss effects that affect many other things.”

Adiposity Findings

SELECT was the first study to show that treating nondiabetic patients with overweight or obesity significantly cut the risk of MACE when compared with placebo.

In this analysis, MACE was less prevalent in patients with lower baseline adiposity levels overall. Those treated with semaglutide showed a significant trend of less MACE risk per 5 kg lower baseline weight (HR 0.96; 95% CI 0.94-0.99), but this was not observed in those randomized to placebo (HR 0.99; 95% CI 0.97-1.01). A similar trend of a lower risk of MACE was observed for each 5-cm reduction in baseline waist circumference in both the semaglutide (HR 0.96; 95% CI 0.93-0.99) and placebo arms (HR 0.96; 95% CI 0.94-0.99).

The mean change in waist circumference at 20 weeks was -5.0 cm in those on semaglutide and −1.1 cm in controls. The correlation between weight loss percentage and change in waist circumference was significantly greater in those on semaglutide vs placebo (P < 0.0001).

In the semaglutide group, researchers could not find a linear trend tying weight loss at week 20 with subsequent risk of MACE. However, they did show that reducing waist circumference by week 20 was linked with lower subsequent MACE risk and reducing waist circumference by week 104 was associated with a lower in-trial risk of MACE.

They estimate that only 33% of the observed benefit on MACE was mediated through reducing waist circumference.

“Ours is the largest trial undertaken so far and supports the use of these agents not merely to enable patients to lose weight, but also to benefit underlying diseases such as cardiovascular disease,” Deanfield said, adding that he’s like to see “more research on the mechanisms by which GLP-1 RAs achieve weight loss, benefit multiple diseases, and result in behavioral changes that can maintain their health benefit.”