The recent FDA decision will likely mean more Medicare patients gain access to the blockbuster weight loss drug, experts say. Meanwhile, results continue to roll in for GLP-1 agonists for conditions beyond diabetes and obesity.
Pictured: Collage of vascular system and heart/Taylor Tieden for BioSpace
Earlier this month, the FDA approved Novo Nordisk’s Wegovy (semaglutide) to help reduce the risk of cardiovascular death, heart attack and stroke in people with higher BMIs, opening a new indication for the blockbuster drug. With Wegovy competitor tirzepatide, marketed by Eli Lilly as Zepbound for weight loss, also currently in trials for cardiovascular indications, the decision could mark a milestone on the path toward using GLP-1 agonists for conditions that go far beyond diabetes and weight loss.
“If you have cardiovascular disease, and your body mass index is well above normal, then these drugs should be considered, particularly in people who are very high risk,” Steve Nissen, a cardiologist at the Cleveland Clinic, told BioSpace.
From Diabetes Treatment to Weight-Loss Sensation
Both semaglutide and tirzepatide activate receptors for GLP-1, a molecule secreted by the gut after meals that increases insulin secretion and signals fullness. These drugs were thus first marketed as Ozempic and Mounjaro, respectively, for type 2 diabetes.
In addition to mimicking GLP-1, tirzepatide also activates receptors for another post-meal signal known as glucose-dependent insulinotropic polypeptide (GIP). Other drugs that work similarly include Eli Lilly’s Trulicity for type 2 diabetes and Viking’s VK2735, in development for various metabolic diseases.
While this class of drugs has a long track record in diabetes treatment, it’s received a tsunami of attention in the last few years for its potential to drive weight loss in both diabetic and non-diabetic patients. Most recently, GLP-1 agonists figured prominently in an Oprah Winfrey weight-loss special that aired March 18. Wegovy was approved for weight loss in 2021, and Zepbound for the same indication in 2023.
GlobalData projects that GLP-1 agonists will become the most lucrative class of drugs in the world this year and that the market for them will continue to grow rapidly, at a rate of more than 19% per year through 2029.
Additional Cardiovascular Benefits Beyond Weight Loss Questioned
Even before Ozempic became a household name, drugmakers were collecting data needed to expand the market for GLP-1 agonists still further. In 2016, Novo Nordisk reported a reduction in the risk of fatal cardiovascular events and nonfatal stroke or heart attack—collectively known as major adverse cardiac events (MACE)—in type 2 diabetes patients who took semaglutide. And in a statement emailed to BioSpace, a company spokesperson noted that a trial of semaglutide for weight loss published in 2021 found changes in biomarkers pointing to a cardiovascular benefit of the drug.
Then last year, Novo’s SELECT trial, whose topline results were announced in August and published in December, found a 20% reduction in MACE outcomes compared with placebo in overweight or obese patients who had cardiovascular disease but not diabetes. The SELECT results formed the basis of the FDA’s label expansion decision earlier this month.
The authors of the SELECT trial suggested that weight loss did not fully explain the cardiovascular benefits they found for semaglutide. But Nissen disagrees. “It’s the weight loss, period,” he said. “It’s spin, the idea that there’s some magical benefit beyond weight loss. . . . We have reason to believe that [because of] the bariatric surgical data. . . . The cardiovascular benefits [from the surgery] are clear cut, and just as large as they are with medications.” Nissen was not involved in SELECT but is an investigator on an ongoing trial of tirzepatide for cardiovascular outcomes known as SURMOUNT-MMO.
Lilly, meanwhile, reported in 2019 that Trulicity lowered the risk of MACE in people with type 2 diabetes and cardiovascular risk factors, compared with placebo. The company is currently conducting two trials on tirzepatide’s effects on cardiovascular outcomes, SURPASS-CVOT in type 2 diabetes patients and SURMOUNT-MMO in people who are overweight or obese with cardiac risk factors but who do not have type 2 diabetes. A Lilly spokesperson said the company expects to have data from SURPASS-CVOT next year and from SURMOUNT-MMO in 2028.
Both Novo and Lilly have also trialed GLP-1 agonists in a different cardiac indication, heart failure with preserved ejection fraction (HFpEF). In results reported last September, Novo found that, compared with placebo, semaglutide improved a variety of outcomes in patients with obesity and HFpEF. The company spokesperson said it has filed for HFpEF as a new indication. Lilly is expecting results from its trial of tirzepatide for HRpEF in obese patients later this year.
A Coverage Loophole?
Medicare is prohibited by law from covering weight-loss treatments, so classifying Wegovy instead as a cardiac drug could open the door to coverage for patients who have both heart disease and obesity or overweight. “I think the most obvious implication [of label expansions to cardiovascular indications] is basically a get-around for Medicare to cover obesity, maybe indirectly,” said Andy Hsieh, an analyst at William Blair who covers Viking.
Indeed, the Centers for Medicare and Medicaid Services (CMS) announced on Thursday that it will cover Wegovy for the reduction of the risk of heart attack, stroke and other related cardiovascular issues in patients who have preexisting heart disease.
Meanwhile, Congress is considering a bill that would enable coverage of weight-loss drugs under Medicare Part D, and the CBO recently predicted that the CMS will negotiate the cost of Wegovy, and that it will eventually be subject to negotiations under the Inflation Reduction Act.
Some private insurers have been reluctant to cover GLP-1 agonists for weight loss in light of their high costs—Wegovy’s list price is $1,350 per month, and Zepbound’s is $1,060. And in January, North Carolina’s state health plan made a highly publicized decision to stop covering GLP-1 weight loss drugs, citing ballooning costs. Hsieh believes the effect of the label expansion on private health coverage of Wegovy will likely be less clear cut than with Medicare, but said, “it could push the needle because ultimately the gold standard of pharmacologic intervention is improved mortality. . . . And this is a very definitive outcome that in this composite endpoint [MACE], you do see a benefit there.”
Nissen said GLP-1 agonists should be considered as “an important adjunct” to other, established drugs to lower cardiovascular risk, such as statins. He added that he anticipates physicians’ hesitancy to adopt new therapies but that he doesn’t think that will ultimately hold these drugs back. “The problem we face whenever we do research like this is clinical inertia,” he said. “There will be a slow uptake, but there will be an uptake.”
On the Horizon
Ultimately, the applications of GLP-1 agonists may extend beyond diabetes, weight loss and cardiovascular health. Earlier this month, Novo released topline data pointing to both cardiovascular and kidney-health benefits elicited by semaglutide in patients with type 2 diabetes and chronic kidney disease. A retrospective study published last month found that semaglutide improved scores associated with metabolic dysfunction‐associated steatohepatitis (MASH) independent of weight loss. Semaglutide and tirzepatide have both been trialed for MASH. And Novo is currently studying whether there is a benefit for semaglutide in Alzheimer’s disease.
“The pharmaceutical landscape is undergoing a transformative shift, as GLP1 agonists are poised to surpass PD-1 antagonists as the best-selling drugs from 2024 onward,” said pharma analyst Kevin Marcaida of GlobalData in a statement. “This shift could reflect a changing demand away from oncology toward addressing metabolic disorders.”
Shawna Williams is a freelance writer and editor based in New York City. She can be reached at shawna.williams@biospace.com or on LinkedIn.
