Research involving key contributions from the Brigham and Women’s Hospital shows that semaglutide, a member of the GLP-1 receptor agonist (GLP-1RAs) drug class approved to treat diabetes and weight loss, had an additional benefit: reducing the incidence of major cardiovascular events among those with overweight or obesity but not diabetes.

Published in The New England Journal of Medicine, SELECT (Semaglutide Effects on Cardiovascular Outcomes in Obesity without Diabetes) is a landmark trial for many reasons, including providing the most definitive evidence to date for obesity as a modifiable risk factor for heart disease.

Jorge Plutzky, MD, director of the Brigham’s Preventive Cardiology Section, played an instrumental role on the steering committee of the international, double-blind, randomized trial. He has a long-standing interest in studying the connection between weight loss and cardiovascular disease, both in the clinic and his laboratory.

“As a preventive cardiologist, I see firsthand the significant cardiovascular burden associated with overweight and obesity and the resulting health benefits of even moderate weight loss,” Dr. Plutzky says. “With such a large percentage of society having issues with overweight or obesity, it is crucial that we understand how the metabolic issues associated with obesity, like high triglycerides, diabetes, and inflammation, are connected to cardiovascular disease—and how we can treat these issues to improve outcomes.”

Building on Previous Work in Diabetes

Previous studies have proven that semaglutide and other GLP-1RAs reduce the risk of adverse cardiovascular events in patients with diabetes. However, the role of semaglutide in reducing that risk for those with overweight or obesity, but not diabetes, had been unknown. In fact, although the cardiovascular risk of obesity had long been suspected, no previous trials had shown that heart disease could be reduced using a drug that causes weight loss.

The SELECT study was run by a team of cardiologists, endocrinologists, obesity specialists, statisticians, and other investigators from 804 clinical sites in 41 countries. Separate from Dr. Plutzky’s involvement in guiding the overall SELECT trial, the Brigham was also one of those clinical trial sites. Led by endocrinologist Vanita Aroda, MD, the Brigham team studied more than 17,000 patients over 34.2+13.7 months. Half of the patients received a weekly 2.4 mg dose of subcutaneous semaglutide, while half received a placebo. All patients were 45 years or older when enrolled and had a high cardiovascular risk because of prior heart disease and a body mass index of 27 or greater but not diabetes.

A primary cardiovascular endpoint event (death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke) was 20% less likely to occur in those on semaglutide as compared to those on placebo. Even though SELECT was not oriented toward trying to achieve the greatest weight loss possible, patients in the semaglutide group also saw on average a 9.4% decrease in body weight. In addition, they experienced positive changes in multiple biomarkers of cardiovascular risk, including blood pressure, waist circumference, glycemic control, nephropathy, and levels of lipids and the inflammatory marker high-sensitivity C-reactive protein (hsCRP).

“Earlier weight loss drugs and lifestyle modifications have generally failed to substantially reduce body weight and improve cardiovascular outcomes such as incidence of heart attack or the need for coronary stenting,” Dr. Plutzky says. “Semaglutide is different, with previous studies showing an average 15.2% reduction in body weight among patients with overweight or obesity who did not have diabetes. The SELECT study adds to those benefits by showing an unequivocal reduction in cardiovascular events as well, even in those who did not have diabetes.”

Not only did the SELECT study prove that semaglutide has benefits for a larger population than before, but it also supports the concept of obesity as a disease with a linear relationship to cardiovascular disease risk, Dr. Plutzky adds.

Digging Deeper: Further Study Analysis Underway

Dr. Plutzky’s work with SELECT study data is not complete. One of the essential questions he is next exploring is whether the improved cardiovascular outcomes seen with semaglutide are strictly due to weight loss or to other mechanisms of the drug. He is also deeply involved in ongoing analysis of study data to identify parameters, including changes in individual biomarkers, that better predict risk and response to therapy.

“We’re also interested in looking at the relationship between the weight lost, other parameters, and cardiovascular risk,” he says. “Was there a difference among the different reasons why a patient qualified for entry into SELECT? What were the effects on specific cardiovascular outcomes?”

As Dr. Plutzky continues to investigate more nuanced advantages of semaglutide, he encourages cardiologists and their patients to consider its benefits on heart health as well as the support this provides for the potential benefits of losing weight in general.

He also envisions expanding interest among cardiologists and internists in using semaglutide, which previously had been considered more of a diabetes drug. This interest may also extend to other medical specialties, given the impact obesity has on so many different disorders. As a result of SELECT, semaglutide is no longer just a “diabetes” drug or an “obesity” drug; it is now a drug that improves outcomes for which a variety of clinicians are responsible.

Brigham Leads in Big Picture and Boots on the Ground

The Brigham’s leadership through all phases of the SELECT study and previous studies of semaglutide—from big-picture conceptualization to boots-on-the-ground trial execution—is a testament to its focus on advancing science to better treat patients, Dr. Plutzky notes.

“Our rich tradition of excellence in clinical trials and the evidence they produce has changed the way patients are treated here at the Brigham and around the world,” he says. “We are honored to play a key role in improving patient outcomes for a growing health problem and look forward to driving future phases of research.”