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Highlights From AHA 2023—New Risk Calculator, Semaglutide and CVD, and More | Cardiology | JAMA
Semaglutide stole the show at the American Heart Association’s Scientific Sessions meeting in Philadelphia this November. Much-anticipated results from the SELECT (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity) trial demonstrated a cardiovascular benefit of the glucagon-like peptide 1 (GLP-1) receptor agonist among people with obesity or overweight without diabetes. The conference also unveiled a new cardiovascular (CVD) risk calculator called PREVENT (Predicting Risk of Cardiovascular Disease Events) that incorporates what’s now being referred to as cardiovascular-kidney-metabolic health.
To discuss these and other clinical highlights, JAMA Associate Editor Gregory Marcus, MD, a cardiologist and professor of medicine at the University of California San Francisco, sat down with conference chair Amit Khera, MD, MSc, a professor in the Department of Internal Medicine at UT Southwestern Medical Center, where he’s also the director of preventive cardiology.
The following interview has been edited for clarity and length.
Dr Marcus:To start out, I thought we could touch base on some of the late-breaking clinical trials and perhaps first focus on this trial called SELECT, which studied a GLP-1 agonist in a randomized trial, enrolling obese patients without a history of diabetes. They didn’t just look at weight loss, but importantly, differences in a composite outcome of cardiovascular death, nonfatal MI [myocardial infarction], and nonfatal stroke, with the GLP-1 agonist demonstrating superiority. It would be great to get your thoughts on that study and how it might apply to clinical medicine going forward.
Dr Khera:This was really a practice-changing study. I was fortunate to be the editorialist for the article, so I got to spend some time with it, to think through what’s new here for your readers and for medicine in general.
These GLP-1 receptor agonists are everywhere, as weight loss agents, as diabetes medications. So what’s different here? We have evidence that if you treat patients with diabetes with semaglutide, you will lower cardiovascular events. We knew that, but we didn’t know is in the absence of diabetes, would you see the same thing.
That’s what this is: patients with cardiovascular disease without diabetes that happen to be overweight or obese—BMI [body mass index] above 27—randomized to semaglutide vs placebo, a huge study, and as you pointed out, a 20% relative risk reduction. There’s a lot to unpack. But just big picture, we can’t lose the big message that in patients with cardiovascular disease, this is a new treatment option—a medicine that targets the obesity pathway, which is different than lipid pathways and blood pressure and antiplatelets. So it’s really exciting, but there’s definitely a lot to think about and unpack around this.
Dr Marcus:We can dig into more details. I’m curious how you think about one concern that’s come up, that these drugs, because they’re so effective, might prevent the sort of motivation of behavior change and lifestyle risk-factor modification we would normally hope to promote.
Dr Khera:I’m a preventive cardiologist, so this is front and center to my thinking. Just to remind ourselves, this was a study in patients with cardiovascular disease who happened to be overweight and obese. This was not an obesity trial in patients with cardiovascular disease. That’s not the same thing because we don’t know if [the results] had anything to do with the weight loss. We do appreciate that the weight loss was 9.4%, but it’s unclear whether or not the risk reduction tracked linearly with the reduction in weight, whether it’s that vs improvements in risk factors vs GLP-1s themselves. If you look, the curves separate very early before there’s any weight loss. So there’s something happening before people are losing weight.
So first is just being cautious about what this was. The other point I couldn’t agree with more is that again, as a practicing clinical preventive cardiologist, we always have patients who say, “Well, I’m going to eat that steak and take my statin.” And that’s your concern. I think the first big message is obesity prevention in the first place. You don’t want to develop overweight and obesity and cardiovascular disease, and lifestyle is paramount to preserve our health.
Number two, it’s not either-or. With these types of drugs, the weight loss is usually more than what was seen in this trial because it’s coupled with lifestyle. The weight loss was actually a little bit less here because it was not a lifestyle intensive as well. So it’s never either-or. It’s both, and obesity prevention first.
Dr Marcus:And as we think about translating this into clinical practice, do you see this falling more on the primary care physician, the cardiologist, the endocrinologist, all the above? And for those who might be now considering prescribing it, what are some things they should be aware of and watch out for?
Dr Khera:I think all of the above. And the reason is, number one, cardiovascular disease is so prevalent. So 82% of the patients in the trials had coronary artery disease. That’s 20 million Americans. So whether you’re a cardiologist, endocrinologist, or primary care doctor, you’re engaging with patients like this.
The second thing is overweight and obesity represents 72% of the population. So I’m going to say it in a few ways. One is that it’s incumbent upon all of us to help lower risk further. And one of the things that’s come up about fractionated care that patients get is it’s one medicine here, one doctor there, and it’s almost impossible then to treat the whole patient. So I think whatever touch point [the patient has], we have to contribute.
I’m not a hypocrite. As a cardiologist, I’ve been prescribing GLP-1s for a few years now. I think the main challenge is going to be cost. These are quite costly medications. So we do appreciate that so many people cannot access these medicines. And it happens to be those that are most vulnerable, those that are socioeconomically underprivileged. The other part to this is societally, the cost is going to be astronomical, and so we’re going to have to think through how we approach that.
Dr Marcus:And are there toxicities or contraindications that clinicians should be aware of?
Dr Khera:There certainly are, and I think the biggest one, and it came out in the trial, fully anticipated, was gastrointestinal [GI]. Ten percent of the individuals couldn’t tolerate the medicine because of gastrointestinal issues. And we’ve known that. That was sort of the main one. Serious adverse events, interestingly, were slightly less. There’s certain people that have certain familial endocrine neoplasias that have to know about this medicine, but that’s quite rare.
So really it’s the GI ones. The way you approach that—I learned this from our endocrine colleagues—is you start low and go slow. So you start at the lowest possible dose and really titrate every several weeks. I think this is where team-based care comes in. We’re very fortunate to have a pharmacist where we work and that individual really helps us in doing this because it takes some coordination, but it’s very effective when you have a good team.
Dr Marcus:Great. Before we move on to the next trial, anything else you think the audience might be interested to know about this trial or these now increasingly used drugs?
Dr Khera:Well, stay tuned because we’ve talked about semaglutide. Tirzepatide, another one, just got FDA [US Food and Drug Administration] approval for obesity. It was [previously] approved for diabetes. That one’s not been tested for cardiovascular outcomes. There are numerous ones in the pipeline that involve GLP-1, but other axes as well. So I think we all just are going to have to get comfortable with these and also be sort of excited about a new opportunity in the treatment of our patients. But the challenge is the evidence. And the other is cost, access, and whom.
Dr Marcus:We look forward to seeing progress in this arena. Moving on to ORBITA-2 [Objective Randomized Blinded Investigation with Optimal Medical Therapy of Angioplasty in Stable Angina], which was a study of about 300 patients, all of whom had stable angina and were on really little to no antianginal medications. They were randomly assigned to undergo percutaneous intervention [PCI] or not, resulting in mainly a substantial improvement in symptoms, specifically anginal symptoms, among those who underwent the percutaneous intervention. What are your thoughts about this trial?
Dr Khera:We’ll spend a second on ORBITA 1, the prelude.
Percutaneous coronary intervention has been around for so long, and the focus historically has been does it lower heart attacks and strokes. We know in stable patients, based on ISCHEMIA [International Study of Comparative Health Effectiveness With Medical and Invasive Approaches] and COURAGE [Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation], that it really doesn’t for most individuals. But the thought is, and is shown in those trials, it improves angina, and that’s important for quality of life for our patients.
But here’s the rub. All of these prior trials did not have sham. And you’re thinking, “Well, how do you do a sham cath [catheter] procedure?” Well, you can and if you take someone, lay them on the table, puncture their groin, spend hours with them afterwards and say, “I just did this thing for you,” it’s entirely conceivable that they may sense that their engine is better.
ORBITA 1 was one of the first studies that actually did a sham PCI procedure. I give them a lot of credit. This is a very creative study where they did this sham procedure to say, “Does PCI actually improve angina?” And the take home from that study, and there’s some nuances, was maybe not. They did not see improvements of angina relative to the sham procedure when they got the coronary artery opened with the PCI. That was groundbreaking in the sense that it really threw the field for a loop.
When you look back, one of the things was that patients were on a lot of antianginal medicines and those can get crossed over into trials. You can get bias toward the null. A background of a lot of good medicines that frankly most patients don’t end up being on was the environment of the study not really answering the hypothetical question about PCI. So that’s what ORBITA-2 was.
Here they said, “Well, let’s try to do the experiment differently.” Take patients that have angina, and it’s pretty substantial. Most of them have what we call class III, meaning affecting day-to-day quality-of-life issues. And they did the same thing, similar to some of the neat things you’ve done with apps and wearables and sensors. First, in one arm, they made them all stop their antianginals. So the experiment is without antianginals, so an interesting study design. And then they had them use this app to record how much angina were they getting every day and how much medicines were they taking for it.
It’s a little bit of an interesting outcome measure. It’s sort of integrating how many medicines and how bad was the angina. But all told, as you mentioned, at 12 weeks, in those that had the PCI, there was definitely an improvement in angina. That was a primary outcome. There was a little bit of extension of walking on a treadmill. Patient’s quality of life was a bit better. So I think it was an important proof of concept that for our patients, PCI can improve quality of life and symptoms.
Dr Marcus:It’s a nice use of the mobile technology that is now so ubiquitous to capture things in real time, which really helps to mitigate against recall bias. So I would share in congratulating the investigators on this innovative study.
I think one of the criticisms has been, “Well, but they really should be on their antianginal medications.” I think it’s worth pointing out that doesn’t take away from the fact that at least from a mechanistic standpoint, this demonstrates PCI really does seem to reduce anginal symptoms. Then there’s the more clinical applicability side. I’d love to hear your answer to this critique, “Well, but if they had been on their antianginal meds, maybe they wouldn’t have needed that procedure.”
Dr Khera:I think that those are fair criticisms. I think the experiment now clearly shows that PCI can improve symptoms and quality of life.
Now comes a practical part. I’m reasonably conservative as a preventive cardiologist, and I think PCI has a role. But let’s go back for a second. PCI didn’t improve outcomes more, but it wasn’t worse either in those prior studies. Why don’t we ask the patient what they want? You can look them in the eye and say, “PCI can improve your symptoms and can improve your quality of life.” And now it’s sort of patient-centered care about what is it that they value. Some don’t want to take 4 medicines a day.
So I do think this offers patient-centered care, that there are options. I still think antianginals should be primary, but if patients don’t want to take numerous medicines for their quality of life, I think it’s reasonable to have PCI as an appropriate option.
Dr Marcus:I’ll ask about one more of the late breaking clinical trials before we move on to a few other things. And that is ARTESIA [Apixaban for the Reduction of Thrombo-Embolism in Patients with Device-Detected Subclinical Atrial Fibrillation], which falls in my wheelhouse as a cardiac electrophysiologist and is something we struggle with routinely, where we get reports either from some ECG [electrocardiogram] monitor or from a pacemaker, “Oh this patient had 10 minutes of atrial fibrillation. Should we anticoagulate them or not?”
In this study, patients with 6 minutes to 24 hours of Afib [atrial fibrillation] were randomly assigned to either apixaban or a baby aspirin, 81 mg of aspirin. They subsequently found a reduction in stroke and systemic embolism among those receiving the apixaban, but there was more major bleeding in the apixaban arm. Importantly, there was not more intracranial hemorrhage, and if anything, the point estimate, although not statistically significant, favored apixaban. And there was also no difference in fatal bleeding. It really seemed to be driven by GI bleeding.
I would be curious to hear what your takeaways were from this trial.
Dr Khera:This is your area, but I will opine as a general cardiologist. It was a really important study. There was a study published recently called NOAH AFNET 6 [Non-vitamin K Antagonist Oral Anticoagulants in Patients With Atrial High Rate Episodes], which actually showed the opposite, at least that they did not see a benefit of anticoagulant. So to your point, what is the framework here? When on the devices, when we see these brief Afibs, what do they mean and what should we do about them?
It is a debate. It’s not the same as clinical Afib, when patients come to your office where we know anticoagulation is imperative in the right patients to lower the risk of stroke. We’re not doing enough there. But subclinical Afib, a briefer episode, may not mean the same thing. And we always know that anticoagulants have a penalty of bleeding, so we can’t just assume we give blood thinners to everyone. So this was a really important study. And to your point, it did say that with these 6- to 24-hour episodes, giving anticoagulation as compared to aspirin did lower the risk of stroke and events like that.
So now it comes to framing, and this is when we come back to shared decision-making. The absolute stroke risk per year was about one-point-something percent. And the difference between the aspirin arm and anticoagulation arm was about 0.4% per year. The number needed to treat was something like over 200. For the bleeding, the number needed to harm was 100 something. Leaving aside how we weigh them, the harm was greater than the benefit if you weigh them one-to-one. And the benefit was, from an absolute perspective, pretty small. So there’s the rub. And yet many patients of course fear a stroke more than a GI bleed. We certainly understand that.
Not to make this even more confusing on the bleeding side but, as you pointed out, the comparator was aspirin. Many would argue that for Afib, we’re not sure if aspirin is helpful and that’s going to make the bleeding seem not as bad, because we’re comparing it to something that causes bleeding. If it was compared to placebo, there might’ve even been more bleeding.
And so there’s a lot to ruminate on. But what does it tell me? If I meet with a patient, I think my take home is when they have these episodes of that duration, that it’s shared decision-making. This may help in lowering stroke if that’s what you fear most. But the absolute risk is pretty small. Absolute benefit is actually pretty small per year. And it has to be individualized. We have to look at the HAS-BLED [hypertension, abnormal kidney/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, and drugs or alcohol concomitantly] score and their bleeding risk. We just can’t do this one-size-fits-all. It does take a lot more thought and nuance, but it’s really important balancing bleeding and stroke risk.
Dr Marcus:I think that’s a really important point. Some people don’t like the shared decision-making. They feel like it’s kind of passing the buck. But I agree, especially when there’s evidence of potential harm and potential benefit, it’s really important to have an in-depth discussion with the patient to understand their goals of care, their concerns, and to make a decision together, especially when there is something close to equipoise as there may be here.
Moving on, anything else from a scientific perspective you’d like to share about the meeting?
Dr Khera:The one thing I wanted to bring up, and it comes back to SELECT, is this concept around cardiometabolic health. The American Heart Association launched a new initiative just a few weeks ago, and more data came out here, called the cardiac-kidney-metabolic health initiative.
What it tells us is that obesity has a lot of adverse consequences in that they’re all interrelated. We’re thinking of not just coronary heart disease but diabetes, heart failure, and also chronic kidney disease. As cardiovascular specialists, we’ve kind of ignored the kidney, but we know chronic kidney disease directly relates to having cardiovascular disease.
And we have lots of therapies now that we didn’t have before to treat kidney disease. I treat chronic kidney disease as a cardiologist. I see it as my job, too. Just a couple of take-homes for the audience about this initiative. There’s a staging system. At stage zero, you don’t have any of the risk factors. Stage one, and this is the one that we all miss, is people with obesity and prediabetes or some impaired fasting glucose. That is a sizable proportion of the population. We ignore that glucose of 100 to 125 and we can’t. Because, to our point about SELECT and developing obesity, this is the canary in the coal mine for these individuals that then go on to have risk factors and then subclinical disease and then clinical disease stages.
The last thing about that that came out at this meeting is a new risk calculator. Now, part of this shared decision-making is you have to know who’s at highest risk for disease. Many may be familiar with the pooled cohort equation that came out in 2013. The new one, called the PREVENT calculator, was just launched here.
What’s different? It’s for ages 30 to 75, while the other one started in the 40s. Second, it looks at 10- and 30 year risks. Nobody was appropriately complaining that the other calculator only looked over the short-term, not the long-term. And particularly when it comes to prediabetes to disease, it could be decades. The long-term risk also incorporates outcomes like heart failure and has some parameters about kidney disease. So it’s a real advance. Seventy-two percent of the population is overweight or obese. It’s an epidemic, and we have to do something more. And I think this is a great way forward.
Published Online: November 22, 2023. doi:10.1001/jama.2023.22707
Conflict of Interest Disclosures: None reported.
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