The positive results from the SELECT trial for the glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were hailed as ushering in a "new era for patients with obesity." In the trial of overweight and obese patients with cardiovascular disease (CVD), but no diabetes, semaglutide showed meaningful reductions in cardiovascular death, myocardial infarction, and stroke compared with placebo.
"I definitely see increasing adoption of GLP-1 RAs by cardiologists and expect the number to increase now that the data support its use in secondary prevention," says Nicole L. Lohr, MD, PhD, chair of the American College of Cardiology (ACC) Board of Governors, and Mary G. Waters, chair of cardiovascular medicine at UAB, Birmingham.
But many cardiologists are more hesitant. "I think there's going to be an increasing urgency for cardiologists to start prescribing these drugs, but I don't think the comfort to do so is that widespread at this point," says American Heart Association (AHA) volunteer Chiadi Ndumele, MD, PhD, an associate professor at Johns Hopkins Medicine in Baltimore and chair of the AHA's recent presidential advisory on cardiovascular-kidney-metabolic health.
"Weight loss hasn't been a central focus in our practice until recently, with the advent of these more powerful agents. There's a need for more education around not only the use of these agents, but also around initiating weight loss discussions in a nonjudgmental way that reflects the complexity of obesity as a condition with multifactorial causes."
The process will take time and may be similar to what happened with statins, he suggests. "Statins started in the endocrinology space, but as their cardiovascular benefits became more clear, they were increasingly adopted by cardiologists, primary care physicians, and others."
Eugene Yang, MD, chair of the ACC Prevention of CVD Council and codirector of UW Medicine's Cardiovascular Wellness and Prevention Program in Seattle, agrees that GLP-1 uptake by cardiologists will likely be slow. "It's a bit premature to start prescribing right away," he said. "Semaglutide hasn't been approved for secondary prevention at this point, and until it's approved specifically for that indication, I don't think many cardiologists will prescribe it."
Side Effects 'Concerning'
Beyond the requisite approval, Yang is concerned about side effects such as gastroparesis, severe nausea, and vomiting. "I'm not sure cardiologists are going to feel comfortable helping patients deal with these effects."
Because GLP-1 RAs are already being used widely in primary care, he says, "I personally would work in collaboration with either my primary care colleagues or with endocrinologists."
Ambarish Pandey, MD, an associate professor of internal medicine (cardiology) and medical director of the heart failure with preserved ejection fraction (HFpEF) program at UT Southwestern Medical Center, Dallas, is already prescribing semaglutide to patients with HFpEF and obesity. "In terms of side effects, I just tell patients what to expect," he says.
Pandey prepares patients for appetite reduction, early satiety and fullness, abdominal discomfort, nausea, and other gastrointestinal symptoms. "Then I start low and slowly titrate to achieve enough weight loss. If they're having adverse effects on a higher dose, I use a lower dose."
The approach is working well for most patients, he says. "Obviously there's some initial getting used to the drug, but once that has happened, patients like it because they see improvements in their exercise capacity and quality of life."
But GLP-1 RAs are also associated with increased heart rate, which "is never good news," notes Howard Weintraub, MD, a professor of medicine at NYU Grossman School of Medicine in New York City and clinical director of the NYU Center for the Prevention of Cardiovascular Disease. At least some of the elevation may be masked by beta-blocker use, he suggests. "The mechanism is not well elucidated, but it is something we're going to need to keep an eye on, because we don't want to get ambushed."
Cost, Access 'Significant Barriers'
All the cardiologists Medscape Medical News spoke with agreed that cost and access will be significant barriers to widespread prescribing, at least for now.
"Prescribing for individuals at very high cardiovascular risk will probably give a reasonable amount of bang for your buck. But individuals with more adverse social determinants of health, who are more likely to have challenges with obesity and related complications, are also least likely to be able to pay the exorbitant costs out of pocket. So, this is also an important health equity issue," Ndumele says.
Furthermore, he adds, where GLP-1 RAs will fit for those with a lower absolute CVD risk "is still a clear question."
"Access comes two ways," Weintraub says. "One is the supply, which continues to be an issue. You can't sell the drug if you don't have it."
The other access route is the insurance companies. "Will they throw down a gauntlet and make cardiologists prove that a patient failed other obesity drugs before they can prescribe a GLP-1 RA? Some of the old obesity drugs are not only unpleasant to use, but they're ineffective and may have bad cardiac signals."
If the new drugs are approved for secondary prevention, patients will want them and doctors will want them, he says. The demand will be "huge," and it's not clear how it will be handled.
Pandey agrees that getting the drug without "good insurance" to cover the cost is a big challenge. " As more of these drugs become available, hopefully the cost will come down, and hopefully access will grow as companies are able to scale up production."
Add-On or Substitute?
Anticipating approval, Yang says it's not yet clear where the GLP-1 RAs stand among the various available cardiovascular therapies.
"Based on the results of SELECT, one could argue that maybe it's more important to get the weight down and reduce blood pressure versus adding another cholesterol-lowering medication, for example, especially if a patient is already on a statin and ezetimibe. But maybe their low-density lipoprotein cholesterol is not exactly below the threshold of the current guideline. And maybe they're overweight or prediabetic, and they can lose 10% or 15% of their body weight with a GLP-1 RA. You may have to pick and choose."
That said, he adds, "Who's going to be able to afford all of this? Some patients would be taking a PCSK9 inhibitor, bempedoic acid because their lipids are not optimized, then a GLP-1 receptor. Right there, we're talking about at least $2000 a month for those three medications. That's not feasible."
"This is one of the things I've worried about, given all the drugs some of our patients are on," Weintraub says. "The data on cholesterol-lowering drugs are so monumental, it's hard to say you can do without it. The same is true of blood pressure-lowering medication. So to my mind, a GLP-1 RA is going to have to be an add-on."
"The only good news is that unlike in the heart failure arena, patients are not paying for other drugs on top of it," he says. "Statins, ACE inhibitors, ARBs, and beta-blockers are all generic; they're not going to leave a huge hole in the patient's pocket when the donut hole [Medicare payment gap] comes around. So in this case, if the GLP-1 RAs get included, which I hope they will, the added cost may not be that horrible."
What About Lifestyle Changes?
Everyone agreed that the drugs are not a substitute for lifestyle changes.
"I have seen many patients who take these medications, reach plateaus, and when discontinued, gain back the weight. I counsel patients to view the medication as an aid, and not necessarily a magic wand," Lohr says.
Ndumele agrees. "I advocate a lifestyle-first approach," he says. "I imagine there will be busy clinicians who will prescribe medications as a first line, but that's not going to be our most effective approach."
The major challenge to such an approach, he says, is that lifestyle support has to be ongoing. "It's not the kind of thing that just happens in a yearly doctor's visit appointment, and it's been under-supported in most coverage and reimbursement strategies."
In his clinical practice, which includes ongoing support for lifestyle changes, Ndumele is seeing far greater weight loss than was shown in SELECT. "I think there's a real benefit to having the two approaches come together," he says.
Yang also favors an emphasis on lifestyle. "The success rate of a lifestyle approach may be low, but that doesn't change the importance of it. We need to figure out better ways to do it." Leveraging technology is one way, he suggests, such as cellphone reminders to walk more or alerts to tell you when to sleep.
"I also encourage patients to monitor their own blood pressure, and they do." Yang acknowledges that his patient population is highly educated with access to resources to purchase the technological devices. However, he adds, "if the clinician is negative, and doesn't really believe these interventions will work, the patient can sense that, and then they won't work." It's up to the clinician to promote the importance of these lifestyle changes in order to be successful. Is it discouraging at times? Yes. But don't let the patient know."
Pandey approaches the issue differently. "Our healthcare system is such that patients don't get to see us that often, so I think we should start the lifestyle intervention, but also start the medication at the same time, in parallel, because we don't have time to take a stepwise approach."
"Lifestyle interventions are better received if patients see positive improvements, and the medication actually induces a positive improvement," he says. He is concerned that if a lifestyle first approach doesn't work "that can affect the willingness to try future therapies. And we don't want to lose like 6 or 8 months just trying lifestyle when they could have benefited from the weight-loss medication, as well."
Lohr, Ndumele, and Yang report no conflicts of interest. Weintraub reports being an investigator in the SELECT trial and a consultant for NovoNordisk. Pandey reports receiving research support from the National Institutes of Health; grant funding from Applied Therapeutics and Gilead Sciences; honoraria outside of the present study as an advisor/consultant for Tricog Health Inc, Lilly USA, Rivus, Cytokinetics, Roche Diagnostics, Axon therapies, Medtronic, Edwards Lifesciences, Science 37 Novo Nordisk, Bayer, Merck, Sarfez Pharmaceuticals, Emmi Solutions; and has received nonfinancial support from Pfizer and Merck; and serving as a consultant for Palomarin Inc. with stocks compensation.
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