Sonya Collins
Semaglutide, a GLP-1 receptor agonist, has lowered the risk of CV events for untold patients with T2D. But does the drug offer the same protective effects to the growing number of people without diabetes who now take the drug for weight loss? New research says “yes.”
In the SELECT trial, semaglutide 2.4 mg (Wegovy) lowered the risk of adverse CV events in patients with overweight and obesity and without diabetes by 20%, according to trial results that were published on December 14, 2023, in NEJM.
“Prescribers of this drug can do so with the idea that they are improving glycemic control, improving glucose, and also reducing CV risk, while at the same time the medications have the benefit of weight loss, but they’re not necessarily linked,” said Michael Lincoff, MD, an interventional cardiologist at Cleveland Clinic and a coauthor of the study.
The SELECT trial
The trial included 17,604 adults at more than 800 sites in 41 countries. Study participants were 45 years or older, had a BMI of 27 or more, and had established CVD but no history of diabetes. Half the patients (8,803) received semaglutide and the other half (8,801) received a placebo.
The study’s primary endpoint was any major adverse CV event, including CV death, nonfatal myocardial infarction, or nonfatal stroke. Among patients in the semaglutide group, 569 experienced a CV event. In the placebo group, 701 had an event, meaning patients in the interventional arm were 20% less likely to experience CV events. Their risk of myocardial infarction was reduced by 28%, need for coronary revascularization by 23%, and death by CV causes by 15%.
Launched in 2018, the trial was the largest and longest-running study of the drug, according to Lincoff.
Is weight loss the cause?
In the SELECT trial, patients in the interventional arm lost about 9% of their body weight. In trials that include dietary counseling and lifestyle modification, Lincoff said, participants on semaglutide may lose up to 15% of their body weight. These findings raise the question as to whether the weight loss alone directly causes the CV benefits.
“It’s almost certainly not entirely linked directly to the weight loss or the magnitude of weight loss,” Lincoff said.
First, the CV benefits of the drug were apparent early in the study before substantial weight loss was seen. Patients did not reach peak weight loss until week 65. Also, other similar drugs have lowered the risk for CV events in patients with diabetes without weight loss.
“There’s no way to say that it only happens in people who do or do not lose weight or that it depends on how much weight you lose,” Lincoff said. But, he noted, it may be fair to speculate that the drug could offer similar, though less dramatic, heart benefits to patients who are overweight or obese without pre-existing CVD, though that group has not yet been studied.
What’s the mechanism?
A number of processes that occur in the body during weight loss also protect heart health. Reduction in dysfunctional fat, better glucose control, lower BP, reduced inflammation, and an improved lipid profile are the direct effects of semaglutide. The GLP-1 receptor that the drug targets, Lincoff explained, is present in the heart muscle, blood vessels, the brain, the stomach, the pancreas, and other tissues involved in metabolic syndrome.
“It’s not only through changes such as BP and inflammation, but the drug may have direct effects as well.”
Counseling points
Pharmacists are no doubt seeing a major increase in prescriptions for semaglutide. CNN reported last fall that 1.7% of Americans were prescribed semaglutide in 2023—a 40-fold increase over the last 5 years, according to an analysis by Epic Research of millions of EHRs, which was shared exclusively with CNN.
Pharmacists should be prepared to counsel patients new to the drug on its adverse effects and realistic weight-loss expectations. Semaglutide’s most common adverse effects include nausea and diarrhea. Previous studies have uncovered a risk of pancreatitis, but the SELECT trial did not show this result. Patients should understand that weight loss will eventually plateau and that discontinuing the drug typically leads to weight gain. ■