Semaglutide & Heart Health: Weight Loss Not Sole Driver of Benefit in SELECT Trial

New analyses from the SELECT trial indicate that the cardiovascular benefits of semaglutide, a medication used for weight management and originally developed to treat diabetes, are not solely attributable to weight loss. Researchers found that while weight loss does contribute to these benefits, a significant portion is linked to changes in waist circumference, a measure of central adiposity. The findings, published in The Lancet, suggest a more complex relationship between semaglutide, body composition, and cardiovascular health than previously understood.

The prespecified analyses examined data from the SELECT trial, which included individuals with established cardiovascular disease and obesity, but without diabetes. Researchers investigated whether the drug, administered weekly at a dose of 2.4 mg, reduced rates of all-cause death, cardiovascular death, and non-cardiovascular death. They also explored whether sex influenced the drug’s efficacy and safety.

The study revealed that rates of all-cause death, cardiovascular death, and non-cardiovascular death were lower in participants treated with semaglutide compared to those receiving a placebo. Interestingly, baseline bodyweight did not appear to influence the risk of major adverse cardiovascular events (MACE). However, a smaller waist circumference at the start of the trial was associated with a lower risk in the placebo group.

The relationship between weight loss and cardiovascular benefit was not straightforward. While early percentage weight change did not demonstrate a linear benefit, a quadratic pattern emerged. Participants who lost 5% or more of their bodyweight experienced a disproportionately higher rate of non-cardiovascular mortality.

“This groundbreaking study demonstrates that semaglutide, perhaps by improving cardiometabolic health, has far-reaching benefits beyond what we initially imagined,”

Harlan Krumholz, MD, SM, FACC

These findings build upon previous research indicating that semaglutide’s cardiovascular benefits extend beyond its effects on weight. According to research published in the Journal of the American College of Cardiology (JACC), six substudies demonstrated benefits including a reduced risk of death, fewer serious COVID-19-related events, and improvements in heart failure symptoms.

The researchers noted that approximately one-third of the benefit observed in the SELECT trial was mediated by changes in waist circumference. This suggests that reducing central adiposity—fat around the abdomen—plays a crucial role in the drug’s cardiovascular effects. The remaining two-thirds of the benefit are likely attributable to other mechanisms, which require further investigation.

The study also examined the impact of semaglutide on COVID-19 outcomes. While the drug did not reduce the incidence of COVID-19 infection, participants treated with semaglutide who subsequently contracted the virus experienced fewer COVID-19-related adverse events and a lower risk of death from the illness.

The findings underscore the potential for GLP-1 agonists, a class of drugs to which semaglutide belongs, to revolutionize cardiovascular care. However, researchers emphasize the need for continued investigation to fully understand the complex interplay between these medications, body composition, and cardiovascular health. Further research is needed to determine the optimal strategies for utilizing these drugs to maximize cardiovascular benefits and minimize potential risks.

The analyses highlight the importance of considering individual patient characteristics, such as baseline waist circumference, when assessing the potential benefits of semaglutide. The unexpected finding of increased non-cardiovascular mortality among those losing 5% or more of their bodyweight warrants further scrutiny to identify potential contributing factors and refine treatment approaches.