Semaglutide lowers cardiovascular risk regardless of blood sugar: ADA meeting

A weekly dose of semaglutide 2.4 mg significantly reduced the risk of major adverse cardiovascular events (MACEs) in people with overweight or obesity and cardiovascular disease but not diabetes, regardless of blood sugar level, according to a clinical trial including researchers from UT Southwestern Medical Center.

The findings, published in Diabetes Care, also show the reduction in MACEs – a combination of heart attacks, stroke, or death from cardiovascular causes – isn’t due to the drug’s effect in lowering blood sugar.

“We showed that even people with completely normal blood sugar have the same benefits in reducing MACEs as people with blood sugar levels in the prediabetes range. This is very important information that helps us understand which patients might benefit from the cardiovascular risk-lowering effects of this medicine,” said first author Ildiko Lingvay, M.D., M.P.H., M.S.C.S., Professor of Internal Medicine in the Division of Endocrinology and in the Peter O’Donnell Jr. School of Public Health at UT Southwestern.

Dr. Lingvay and her international colleagues collaborated in the Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity Trial (SELECT). This is the longest and largest study with semaglutide (a drug better known in the U.S. under its brand name Wegovy), designed to test its effects on MACE risk in people who have overweight or obesity with cardiovascular disease but no diabetes. Semaglutide was originally approved in 2017 by the U.S. Food and Drug Administration (FDA) at a dose of 1.0 mg for adults with Type 2 diabetes and in 2022 for chronic weight management at a dose of 2.4 mg.

The main results of the trial, published last year in tumors , showed a 20% reduction in the risk of MACE in 8,803 participants who took semaglutide, compared with 8,801 participants who took an identical-looking placebo.

How semaglutide works to lower cardiovascular risk has remained an important question. The drug exerts a wide variety of beneficial effects, including reducing blood sugar (glucose), body weight, blood pressure, blood lipids such as cholesterol, and inflammation, any of which can contribute to the reduction in MACE risk.

In the recent analysis, Dr. Lingvay and her colleagues focused on examining whether semaglutide’s glucose-lowering effects might be at least partially responsible for lowering the participants’ MACE risk. To answer this question, they tested the participants’ hemoglobin A1C (HbA1C) – a measure of average glucose over two to three months – at the start of the trial and after the participants had taken semaglutide or the placebo for 20 weeks. At baseline, a third of the participants had HbA1C readings below 5.7%, a level considered normal. However, the remaining two-thirds had readings between 5.7% and 6.5%, in the prediabetes range.

Most people on semaglutide had a significant reduction in their HbA1C levels by the 20-week mark. An analysis of the number of MACEs that occurred during the study period showed those taking the drug had about 20% fewer of these events, regardless of their HbA1C at baseline and subsequent measurements over time. These findings suggest factors other than semaglutide’s glucose-lowering effects are responsible for this reduction in MACE risk, Dr. Lingvay said.

Other recent findings of SELECT to which Dr. Lingvay contributed have shown that weight loss from semaglutide also doesn’t appear connected to the reduction in MACE risk, but a decrease in inflammation from the drug does seem to be partially responsible. She notes that she and other authors will continue to investigate the mechanisms behind semaglutide’s beneficial cardiovascular effects.

In another analysis of the SELECT study recently published in Nature Medicine, Dr. Lingvay and colleagues reported the effect of once-weekly semaglutide on kidney function. The researchers’ results suggested semaglutide also had a beneficial effect on the kidneys.

These studies were funded by Novo Nordisk A/S, the maker of semaglutide. Dr. Lingvay receives personal consulting compensation from Novo Nordisk.

References: Ildiko Lingvay; John Deanfield; Steven E. Kahn; Peter E. Weeke; Hermann Toplak; Benjamin M. Scirica; Lars Rydén ; Naveen Rathor; Jorge Plutzky; Cristobal Morales; A. Michael Lincoff; Michael Lehrke ; Ole Kleist Jeppesen; Grzegorz Gajos; Helen M. Colhoun ; Bertrand Cariou ; Donna Ryan ; SELECT Trial Investigators

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Corresponding author: Ildiko Lingvay, ildiko.lingvay@utsouthwestern.edu

Diabetes Care dc240764

https://doi.org/10.2337/dc24-0764