Is It Time for Cardiologists to Treat Obesity?

Cardiologists Michelle O'Donoghue and Nicholas Marston discuss the "game changer" trial at AHA showing that GLP-1 agonist semaglutide reduced CV events in patients with ASCVD and overweight/obesity.
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Michelle L. O'Donoghue, MD, MPH: Hi. This is Dr Michelle O'Donoghue, reporting for Medscape. I'm here at the American Heart Association conference in Philadelphia, and one of the big breaking stories here is the primary results of the SELECT trial.
Joining me today to discuss the trial and its implications is Dr Nicholas Marston, who specializes in preventive medicine. He's a clinical trialist with the TIMI study group and a cardiologist at Brigham and Women's Hospital. Thank you for joining me.
Nicholas A. Marston, MD, MPH: Thanks, Michelle. It's huge news - really, a game changer on so many levels.
O'Donoghue: For those who are not yet familiar with the SELECT study, can you tell us what it looked at and who it studied?
SELECT Trial Findings
Marston: Absolutely. It was a phase 3 cardiovascular outcomes trial in 17,000 patients. Importantly, these patients all had a BMI of ≥ 27; they had obesity or they were overweight. They also had atherosclerotic cardiovascular disease (ASCVD), defined by a prior myocardial infarction, stroke, or peripheral artery disease, and, importantly, they did not have diabetes.
Previous studies were in patients with diabetes. These patients did not have diabetes; their hemoglobin A1c had to be below 6.5%. They then randomized these patients 1:1 to either semaglutide or placebo. The follow-up was over 3 years for a primary endpoint of myocardial infarction, stroke, or CV death as a composite outcome. And as you mentioned, these were very exciting results: They found a 20% reduction in the primary endpoint. It drew applause today at the late-breaking session.
O'Donoghue: Yes, it's rare that people break into applause, but this really is a game changer. Semaglutide has been out there a while; it was thought of primarily as a diabetes medication. The fact that there was weight loss associated with its use has helped increase its use. But now we have a secondary prevention trial of people with obesity who have established cardiovascular disease but do not have diabetes, and the drug reduces major adverse cardiovascular events. There was even a reduction in all-cause mortality.
Marston: That was huge and got another reaction from the audience. We've used these drugs for a long time, but they've had a lot of fanfare now because the higher doses of semaglutide cause weight loss. We've known that these drugs show cardiovascular event reduction in patients with diabetes, and now we're expanding that to patients without diabetes. Obesity was thought of as a risk factor, but we didn't really have a good way to treat it previously. If you think about treating coronary disease, you think about lipids, hypertension, diabetes, inflammation, and now weight management and treating obesity. It's a game changer.
Semaglutide Mechanism of Action
O'Donoghue: Semaglutide is a glucagon-like peptide 1 (GLP-1) receptor agonist. What do we know about how the drug works? What is reported to be the possible mechanism?
Marston: It's probably multiple mechanisms. One that we know is that it slows down your gut and that decreases appetite, and you end up eating a lot less. When we look at the side effects, gastrointestinal (GI) symptoms are one of the most common; 10% of patients in SELECT had GI symptoms: nausea. vomiting, bloating. That's part of how this work. Patients don't think about food as much, they aren't eating as much, and then they lose weight. And that seems to have some downstream effects on things like blood pressure, lipids, and inflammation, all of which could contribute to this reduction in cardiovascular events.
O'Donoghue: It's interesting to think whether a lot of the benefit that we see with the drug is in terms of blood pressure coming down, inflammation really coming down quite impressively. That was one of the things that struck me - these people had very high C-reactive protein (CRP) levels at baseline and the levels came down quite a bit with treatment.
Marston: It was an almost 40% reduction of high-sensitivity CRP; this is on par with what we saw with a statin in the JUPITER trial and canakinumab in CANTOS. That's got to be an important pathway.
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