Photo: Vascular system and heart collage/Taylor Teeden biospace

Earlier this month, the FDA approved Novo Nordisk’s Wigovy (semaglutide) to reduce the risk of cardiovascular death, heart attack, and stroke in people with a high body mass index, opening up a new indication for the blockbuster drug. The decision goes far beyond diabetes and weight loss, as Wegovy’s competitor tirzepatide, sold by Eli Lilly as Zepbound for weight loss, is also currently in clinical trials for cardiovascular disease indications. This could be a milestone on the path to using GLP-1 agonists for symptoms.

“If you have cardiovascular disease and your BMI is well above normal, you should consider using these drugs, especially if you are at very high risk,” said Cleveland Clinic cardiologist Steve Nissen. ” he said. biospace.

From diabetes treatment to weight loss sensation

Both semaglutide and tirzepatide activate receptors for GLP-1, a molecule secreted by the intestines after a meal that increases insulin secretion and signals satiety. Therefore, these drugs were initially marketed as Ozempic and Munjaro for type 2 diabetes, respectively.

In addition to mimicking GLP-1, tirzepatide also activates receptors for another postprandial 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, which is being developed for a variety of metabolic diseases.

Although this class of drugs has a long track record in treating diabetes, it has received a surge of attention in recent years due to its potential to promote weight loss in both diabetic and non-diabetic patients. GLP-1 agonists were recently featured prominently in Oprah Winfrey’s weight loss special that aired on March 18th. Wegovy was approved as a weight loss drug in 2021, and Zepbound was approved for the same indication in 2023.

GlobalData predicts that GLP-1 agonists will become the world’s most lucrative class of drugs this year, and the market will continue to grow rapidly at more than 19% annually through 2029.

Additional cardiovascular benefits beyond weight loss are questionable

Even before Ozempic became famous, drug companies were gathering the data they needed to further expand the market for GLP-1 agonists. In 2016, Novo Nordisk found that patients with type 2 diabetes who took semaglutide were at increased risk of fatal cardiovascular events and non-fatal stroke or heart attack (collectively known as major adverse cardiac events (MACE)). reported that it had decreased. And in a statement sent via email, biospacea company spokesperson noted that a trial of semaglutide for weight loss published in 2021 found changes in biomarkers that indicate the drug’s cardiovascular benefits.

And last year, Novo’s SELECT trial, with topline results announced in August and published in December, showed a 20% improvement in MACE outcomes compared to placebo in overweight or obese patients with cardiovascular disease but not diabetes. It was found that it decreased. SELECT results were the basis for FDA’s label expansion decision earlier this month.

The authors of the SELECT trial suggested that weight loss does not fully explain the cardiovascular benefits of semaglutide. However, Nissen disagrees. “It’s weight loss,” he said. “It’s a spin on the idea that there are magical benefits beyond weight loss… We have reason to believe that” [because of] Obesity surgery data. . . .cardiovascular benefits [from the surgery] They are clear and as big as medicine. ” Nissen is not involved in SELECT, but is an investigator in an ongoing trial of tirzepatide for cardiovascular disease known as SURMOUNT-MMO.

Meanwhile, Lilly reported in 2019 that Trulicity reduced MACE risk in people with type 2 diabetes and cardiovascular risk factors compared to a placebo. The company is currently investigating the impact of tirzepatide on cardiovascular outcomes with SURPASS-CVOT, for people with type 2 diabetes, and SURMOUNT-MMO, for people with cardiac risk factors who are overweight or obese but do not have type 2 diabetes. Two tests are being conducted. A Lilly spokesperson said data will be available from SURPASS-CVOT next year and SURMOUNT-MMO in 2028.

Both Novo and Lilly are also testing GLP-1 agonists in a different cardiac indication: heart failure with preserved ejection fraction (HFpEF). In results reported last September, Novo found that semaglutide improved a variety of outcomes in patients with obesity and HFpEF compared to placebo. A company spokesperson said it has filed a new indication for HFpEF. Lilly expects results from a trial of tirzepatide in HRpEF in obese patients later this year.

Loophole in reporting?

Medicare is prohibited by law from covering weight loss treatments, so classifying Wigovy as a heart drug instead opens the door to coverage for patients with both heart disease and obesity or overweight. there is a possibility. “The most obvious meaning is [of label expansions to cardiovascular indications] It’s basically a workaround for Medicare to cover obesity, perhaps indirectly,” said Andy Shea, a William Blair analyst who covers Viking.

In fact, the Centers for Medicare and Medicaid Services (CMS) announced Thursday that it will cover Wegovy for reducing the risk of heart attack, stroke, and other related cardiovascular problems in patients with pre-existing heart disease.

Meanwhile, Congress is considering legislation that would allow coverage of weight-loss drugs under Medicare Part D, and CBO recently announced that CMS will negotiate Wegovy’s costs and ultimately make them subject to negotiations under the Inflation Control Act. I predicted it would happen.

Some private insurance companies are reluctant to cover GLP-1 agonists for weight loss, given their high cost. Wegovy has a list price of $1,350 per month, and Zepbound has a list price of $1,060. Then, in January, North Carolina’s state health plan made headlines with its decision to discontinue coverage of GLP-1 weight loss drugs, citing ballooning costs. Hsieh believes that the impact of Wegobee’s expanded labeling on private health insurance coverage is likely to be less clear-cut than on Medicare, but that “the ultimate criterion for pharmacological intervention is mortality improvement.” Therefore, there is a possibility of needle pricking.” . . . This is a very conclusive result with this composite endpoint. [MACE]I definitely think there are benefits to that. ”

Nissen said GLP-1 agonists should be considered as “important adjuncts” to other established drugs that reduce cardiovascular risk, such as statins. He added that while he expected physicians to be reluctant to adopt new treatments, he did not think that would ultimately preclude the use of these drugs. “The problem we always face when doing studies like this is clinical inertia,” he said. “It’s slow to catch on, but it’s definitely going to catch on.”

on the horizon

Ultimately, the applications of GLP-1 agonists may extend beyond diabetes, weight loss, and cardiovascular health. Earlier this month, Novo announced topline data showing the cardiovascular and renal health benefits caused 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 are both being tested for his MASH. And Novo is currently studying whether there is a benefit to semaglutide for Alzheimer’s disease.

“The pharmaceutical industry is undergoing major changes, with GLP1 agonists overtaking PD-1 antagonists to become the best-selling drugs starting in 2024,” Kevin Marcaida, a pharmaceutical analyst at GlobalData, said in a statement. . “This shift may reflect a shift in demand from oncology to addressing metabolic disorders.”

Shawna Williams is a freelance writer and editor based in New York City. Contact her at shawna.williams@biospace.com or on LinkedIn.