Expanding volumes of data point to mechanisms beyond weight loss and blood sugar control that contribute to cardiovascular benefits in the world’s fastest-growing drug class.
In the last four years, the obesity drug industry has gone from nearly defunct to dominating the pharmaceutical landscape. Initially approved two decades ago for diabetes, it was their efficacy in obesity that brought GLP-1 agonists into the spotlight. Now one major focus is understanding and applying GLP-1s’ heart health benefits.
In March 2024, the FDA approved a label expansion for Novo Nordisk’s Wegovy (semaglutide) to reduce the risk of cardiovascular death, heart attack and stroke in adults with cardiovascular disease and obesity or overweight. The approval was based on the Phase III SELECT trial, which showed that a 2.4 mg injection of Novo’s drug led to a 20% drop in major adverse cardiovascular events compared to placebo when added to standard of care.
An AI proof-of-concept study expanded on SELECT’s findings to determine if GLP-1 use might reduce the risk of major cardiac events in patients without severe preexisting cardiovascular disease. The Dandelion Health study, released in September 2024 as a whitepaper, was seven times larger than Novo’s trial with that inclusion criteria and determined that even those without severe disease had 15% to 20% lower risk scores for major adverse cardiac events after taking a GLP-1 drug for three years. Ultimately, the study found that GLP-1s may be effective as primary prevention against cardiovascular disease for 44 million additional at-risk patients in the U.S. who had not previously been studied.
While companies moving into the GLP-1 space continue to target diabetes and obesity indications first, evidence is accruing for the drugs’ benefits in cardiac outcomes, and multiple players are looking to join Novo in using them to address these indications.
Mounting Cardiac Evidence
The first-in-human trials studying the effects of GLP-1s on cardiovascular outcomes date back to 2016, Daniel Drucker, an endocrinologist and obesity expert at the Lunenfeld-Tanenbaum Research Institute at Mount Sinai in Toronto, told BioSpace. In total, multiple cardiovascular outcomes trials have been conducted with GLP-1s, and “the benefit is pretty consistent,” he said.
“We were pretty confident this is a [drug] class effect. If you have type 2 diabetes and a history of heart disease or are at risk for heart disease, you will see a reduced number of heart attacks, strokes and reduced rates of death” on GLP-1 receptor agonists, Drucker said.
Whether the effect on cardiac health and other comorbidities is due to the weight loss and blood sugar control that GLP-1s provide or other mechanisms has been a point of contention. Bariatric surgery, for example, doesn’t just help people lose weight; it also has a profound effect on type 2 diabetes and cardiovascular disease, Mark Bagnall, CEO of Phenomix Sciences, told BioSpace. For the cardiovascular benefits of GLP-1s, “how much of this is weight loss and how much of this is some specific mechanism that GLP-1s target?” he asked. He said the question remains unresolved but noted that the drugs are known to target multiple areas of the body, suggesting the possibility of mechanisms beyond weight loss.
Though the data are not yet published, Novo has presented additional results from the SELECT trial at meetings that suggest the extent of the cardiovascular benefit is not strictly tied to weight loss or control of blood sugar in type 2 diabetes patients, Drucker said. That evidence would support the idea that other actions of GLP-1 agonists contribute to countering heart disease.
GLP-1 drugs are known to have a direct effect on the endothelial cells that line blood vessels, lymph vessels and the heart, providing a biologically plausible mechanism for the cardiovascular benefit, noted Blai Coll, chief medical officer at Structure Therapeutics.
“When you put everything together—the body weight reduction, blood pressure, lipids, metabolic and direct effect—the common denominator to all those is a reduction in systemic inflammation. That can also bring additional cardiovascular benefits,” Coll told BioSpace.
Additional studies of GLP-1s’ efficacy in cardiovascular indications are underway. Novo conducted a Phase IIIb trial dubbed STRIDE to evaluate the effects of a 1 mg dose of semaglutide versus placebo in patients with symptomatic peripheral artery disease and type 2 diabetes. The primary endpoint is patients’ maximum walking distance, with secondary endpoints of quality of life and cardiometabolic assessments. The trial is complete but results have not yet been shared.
Meanwhile, Lilly is conducting a head-to-head comparison of Zepbound (tirzepatide) against its older GLP-1 Trulicity (dulaglutide) looking at major adverse cardiovascular events in patients with type 2 diabetes and atherosclerotic cardiovascular disease. Trulicity was approved for reduction of cardiovascular event risk in type 2 diabetes patients in 2020.
Lilly is also studying Zepbound in a five-year placebo-controlled study, SURMOUNT MMO, investigating the benefits of the weight loss drug for reducing obesity-related diseases and death in participants with cardiovascular risk factors.
Expanding the Pool
With Zepbound predicted to become the one of the top-selling drugs of all time, it’s no surprise biotech and big pharma companies alike are all vying to get their obesity candidates through the clinic and onto the market. And with the latest estimates forecasting a $200 billion obesity drug market by 2031, there’s room at the table for everyone.
“Traditionally obesity had been discarded as a market,” Drucker said. “Now these medicines are the hottest things, growing at the fastest rates and expected to continue to dominate the pharmaceutical landscape.”
Amgen recently released Phase II data for MariTide, its once-monthly GLP-1 agonist and GIP antagonist injection. The results came in at the lower end of investor expectations with weight loss of up to 20% on average at week 52. Overall, its profile looked similar to Zepbound, but with less frequent dosing, which could give it a leg up in the market. Amgen is pushing MariTide into late-stage development for cardiovascular event risk and other indications. Amgen CEO Robert Bradway noted at a conference in September that an obesity treatment with other applications “represents an exciting opportunity.”
Elsewhere, Structure initiated a Phase IIb dose escalation study last month for its oral GLP-1R selective small molecule. CEO Ray Stevens told BioSpace that after seeing data from the competition, Structure believes it has a potentially best-in-class molecule in terms of off-target safety and efficacy. Alongside weight loss endpoints, the company has an eye on indicators of cardiovascular benefits, collecting data on lipids, blood pressure and metabolic control to include as exploratory data at the end of its 36-week study, Stevens said.
Depending on how the chronic weight management indication goes, Structure has said it may propose an additional cardiovascular outcome trial for the candidate.
What’s Next for GLP-1s
Bagnall emphasized the broad value of GLP-1s. “If body weight loss and side effects are the only two things we really focus on, we got it wrong,” he said. “There are so many other aspects of benefits here.” He highlighted, for example, the ultimate effect he expects GLP-1s and other obesity medicines to have on patients’ overall well-being.
“There are opportunities yet to be exploited in this area,” Drucker said. While the medicines have first been tested against cardiovascular events in people with type 2 diabetes and/or obesity, the next step may be to see if they reduce heart disease in all patient types. “They should work in people who have residual risk for ongoing cardiovascular disease, who may not have any diabetes or any obesity—that’s a hypothesis, and [we] need to have a company take this on.”
The number of clinical studies involving GLP-1s is only increasing as researchers and companies alike pit the drug class against not only cardiovascular disease, but also type 1 diabetes, kidney disease, metabolic liver disease, arthritis, Alzheimer’s, Parkinson’s, cystic fibrosis and even addiction. The NIH’s clinical trials site shows over 400 active trials involving GLP-1 intervention.
With so much attention on the potential uses of this drug class and expanding into oral formulations, Stevens said, “2025 is really going to be the year for small molecules, particularly for GLP-1s.”
