Semaglutide, the popular anti-obesity medication originally developed to treat diabetes, continues to show cardiovascular benefits beyond weight loss, including reducing risk of death, reducing serious COVID-19-related events and improving heart failure (HF) symptoms, according to six new substudies published in JACC. The research was simultaneously published with presentations at the ESC Congress 2024 in London.

"This portfolio of publications, derived from three major trials, significantly advances our understanding of the wide-ranging benefits of GLP-1 agonists, while also highlighting key questions that remain," said JACC Editor-in-Chief Harlan Krumholz, MD, SM, FACC. "These groundbreaking medications are poised to revolutionize cardiovascular care and could dramatically enhance cardiovascular health."

In two new substudies of the SELECT Trial, which included people who had overweight or obesity according to their BMI and had established cardiovascular disease but not diabetes, researchers looked at whether once weekly semaglutide (2.4 mg) reduced rates of all-cause death, cardiovascular death and noncardiovascular death, including death from COVID-19, and whether sex impacts the efficacy and safety of the drug.

In the mortality substudy, rates of all-cause death, cardiovascular death and noncardiovascular death were lower in people taking semaglutide vs. placebo. While semaglutide did not reduce incident COVID-19, among participants who developed COVID-19, those who were treated with semaglutide had fewer COVID-19-related adverse events or died from COVID-19.

"This groundbreaking study demonstrates that semaglutide, perhaps by improving cardiometabolic health, has far-reaching benefits beyond what we initially imagined," said Krumholz. "The ability of semaglutide to significantly lower cardiovascular and COVID-19-related adverse events underscores the transformative potential of targeting obesity and improving cardiometabolic health as a strategy to protect against a broad spectrum of health threats."

In the sex differences substudy, researchers found females experienced fewer major adverse cardiovascular events compared to males, but semaglutide consistently reduced the risk of adverse cardiovascular outcomes regardless of sex.

In a new substudy from the FLOW trial, researchers looked at the effects of semaglutide on HF in patients with both type 2 diabetes and chronic kidney disease. Semaglutide (1 mg) was previously shown to reduce the risk of major kidney disease events in this high-risk group. In the new substudy, once weekly semaglutide (1 mg) was shown to reduce the risk of time to first composite HF event (new onset or worsening HF leading to unscheduled hospital admission or urgent visit, with initiation of or intensified diuretic/vasoactive therapy) or cardiovascular death and HF events and cardiovascular death alone.

Semaglutide can also improve HF outcomes by impacting the pathophysiology of HF with preserved ejection fraction (HFpEF) patients based on three new substudies from the STEP-HFpEF program. Specifically, semaglutide (2.4 mg) improved obesity-related HF symptoms in people with inflammation and both with and without atrial fibrillation (AFib), plus improved cardiac structure and function.

In the inflammation substudy, researchers looked at patients in the STEP-HFpEF program with obesity-related HFpEF to determine the effect of semaglutide on HF symptoms and physical limitations in people with varying levels of inflammation at baseline. Inflammation was measured by levels of high-sensitivity C-reactive protein (hsCRP), which is a protein produced by the liver in response to inflammation or infection. Semaglutide improved HF-related symptoms, physical limitations and exercise function and reduced body weight in all categories of baseline hsCRP (<2, ≥2 to <10, and ≥10 mg/L), and improved inflammation regardless of baseline hsCRP or amount of weight loss.

In the atrial fibrillation (AFib) subanalysis, researchers examined the efficacy and safety of semaglutide in people with and without AFib within the STEP-HFpEF program and found that once weekly semaglutide (2.4 mg) was associated with even greater improvements in HF-related symptoms and physical limitations in those with vs. without AFib, though improvements were seen in both groups.

In the echocardiography substudy, researchers found that once weekly semaglutide (2.4 mg) improved multiple domains of cardiac structure and cardiac function, including improved left atrial volume, left ventricular diastolic function and right ventricular size, compared with placebo.

"We do not yet fully understand how GLP1RA work, but these and other studies are showing that weight loss alone cannot completely account for the many kidney, metabolic, and kidney benefits that these agents provide," said Neha Pagidipati, MD, MPH, FACC, JACC associate editor.

For all the latest GLP-1RA-related articles and resources published by JACC, visit JACC's Obesity Hub.