Is It Time for Cardiologists to Treat Obesity?

This transcript has been edited for clarity.

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.

O'Donoghue: Another interesting point is that the clinical benefit in terms of reducing cardiovascular events appeared very early after starting this drug. It seemed to occur even faster than the weight loss trajectory; they continued to lose weight until about 12 months.

Marston: Yes — you wonder whether this is all through weight loss and the downstream effects, or perhaps some of this is working independently of the weight loss. The separation of the curves suggests that one of those potential pathways is blood pressure. It was a small reduction, but it's 3 mm Hg, and that would perhaps explain about a third of the cardiovascular risk reduction that we see.

O'Donoghue: As a preventive cardiologist, we often have conversations with patients about weight. This study really lends credence to the idea that weight loss really does have a very important role in and of itself, in terms of reducing somebody's cardiovascular risk profile.

Marston: I think it changes the paradigm of how we think about obesity. Antiobesity specialists have been saying that obesity is a disease for a long time. SELECT is validating because it shows that it can be treated, and hopefully this will help make physicians recognize it more and put it up there with the other risk factors, because now we have something to do about it.

O'Donoghue: The implications are quite broad if we think about how many patients there are who are either overweight or have obesity, and have established cardiovascular disease. That's a lot of people who hypothetically could be on this drug.

Marston: Absolutely. We use these drugs in the cardiology clinic for patients with diabetes, but actually a minority of patients with ASCVD have diabetes, and a lot of them are overweight or have obesity, so it really does expand who we're going to be treating in the clinic.

Challenges: Cost and Tolerability

O'Donoghue: Certainly cost will be one challenge. We'll have to see where insurers land in terms of being able to get the drug approved for a broader patient population. You mentioned the GI tolerability. What other side effects do clinicians need to be thinking about if they're going to be prescribing this?

Marston: It's an injectable therapy so there are injection-site reactions. The GI tolerability is probably the biggest one. There was about a fivefold increase in the treatment arm vs the placebo arm, and then there were small but significant increases in biliary tract disease as well as nutritional disorders. I think we want to see more data on that. It's nice to have this longer-term follow-up data. We've been using these drugs for a long time, and overall, the long-term safety profile is very good.

O'Donoghue: It's interesting to think about whether this is a broader class effect or how much might this be drug specific. Semaglutide just happens to be the first therapy in that class to specifically study this broader patient population.

Marston: Right. And another thing I would note about tolerability is that the percentage of patients that came off therapy during the trial was not insignificant — about 25%. A lot came off in the placebo arm as well — over 20% — so it wasn't too different. Not all patients are going to tolerate these drugs, but if they do, it seems to work really well.

O'Donoghue: I'd like to see if the amount of weight loss correlated with the cardiovascular benefit. Did people who didn't even lose a pound have any cardiovascular benefits? And also the interplay with inflammation; I'm very interested to see if CRP levels may identify those patients who benefit the most.

Marston: We can anticipate the additional analyses the investigators are going to do. I'm sure we're going to continue to see follow-up studies and analyses from SELECT, which is exciting.

O'Donoghue: The whole class is a very exciting one, when you think that several years ago, the concern about weight loss therapies was that they would cause excess risk for cardiovascular events, right? But here we've got the opposite. It's really flipped. Now with a weight loss therapy, we also have the additional benefit of reducing cardiovascular events, so it's a great option for many patients.

Marston: Patients are excited about it because of the weight loss, and now cardiologists are excited about it because of the cardiovascular risk reduction. It's going to be a good match in terms of both parties wanting to get patients on it. Sometimes patients aren't as excited as we are about lowering their LDL-C, but with weight loss, they're gonna be excited.

O'Donoghue: I'm sure there'll be a lot of great studies to come from this and a lot more to watch for. Thanks again for joining me today.

Marston: Thank you for having me.

O'Donoghue: Signing off for Medscape, this is Dr Michelle O'Donoghue.

Michelle O'Donoghue is a cardiologist at Brigham and Women's Hospital and senior investigator with the TIMI Study Group. A strong believer in evidence-based medicine, she relishes discussions about the published literature. A native Canadian, Michelle loves spending time outdoors with her family but admits with shame that she's never strapped on hockey skates.

Follow theheart.org | Medscape Cardiology on X (formerly known as Twitter)

Follow Medscape on Facebook, X (formerly known as Twitter), Instagram, and YouTube

Comments

Commenting is limited to medical professionals. To comment please Log-in.

Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.