Justin Ezekowitz, MD, is a professor of medicine at University of Alberta and a cardiologist at the University of Alberta Hospital and Mazankowski Alberta Heart Institute

Justin Ezekowitz, MD

Beyond Weight Loss: How GLP-1 RAs Established a Role in Cardiology in 2025

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are one of the fastest-growing drug families in medicine today. From humble beginnings as a method of insulin and glucagon management in patients with type 2 diabetes (T2D), GLP-1s have expanded into hepatology, cardiology, and even ophthalmology. Their role as an anti-inflammatory agent, coupled with their weight loss capabilities, has rocketed GLP-1 RAs to one of the top drugs in the industry.

Today, GLP-1 RAs are the backbone of endocrinology. But in recent years, they’ve also become a core component in a variety of cardiovascular diseases. Given their management of obesity, which can lead to sharp increases in heart failure risk, coronary artery disease, and stroke, GLP-1s have taken on almost as prominent a role in cardiology as in their home turf of endocrinology.

In June of 2025, the American College of Cardiology issued a statement on weight management drugs, with a spotlight on GLP-1s. In it, they noted semaglutide and tirzepatide, which have been proven substantially more effective in reducing cardiovascular disease risk than lifestyle changes and with fewer risks than procedure-based interventions. Although prior guidance has suggested GLP-1s as a secondary or even tertiary treatment method, this year’s release encourages clinicians to consider them as first-line options for eligible patients.

Additionally, GLP-1s have received several key approvals from the US Food and Drug Administration (FDA), with oral semaglutide being granted an indication for the reduction of major adverse cardiovascular event risk in patients with T2D. Based on the SOUL trial, oral semaglutide’s approval marks the first oral GLP-1 medicine approved for a cardiovascular indication.

Tirzepatide, a dual GIP/GLP-1 agonist, also made significant progress towards an FDA approval of its own, with Eli Lilly’s SURPASS-CVOT trial indicating its efficacy in reducing MACEs in patients with T2D and established atherosclerotic cardiovascular disease. The head-to-head trial compared tirzepatide to dulaglutide and displayed the former’s superior efficacy; risk of heart attack, stroke, or cardiovascular death was substantially lower with tirzepatide.

However, in the face of such rapid advancement, some cardiologists encourage a more skeptical approach. Although great strides have been made in advancing cardiovascular outcomes with GLP-1 treatment, there are still factors limiting their reach. The most prominent of these issues is the number of clinical trials proving their efficacy. Many cardiologists have noted their hope – and expectation – for further case studies of GLP-1 RAs in the hopes of generating irrefutable evidence of their efficacy.

Editor’s Note: Le reports disclosures with Janssen, Pfizer, Novartis, Idorsia, Amarin, and Lexicon. Greene reports disclosures with Amgen, AstraZeneca, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals, Cytokinetics, and others. Ezekowitz reports disclosures with Bayer, Merck, Amgen, Sanofi, Novartis, Cytokinetics, and others. Hansen and Mamic report no relevant disclosures.

Napoli N. American College of Cardiology Issues Guidance on Weight Management Drugs. American College of Cardiology. June 20, 2025. Accessed December 2, 2025. 

https://www.acc.org/About-ACC/Press-Releases/2025/06/20/14/11/American-College-of-Cardiology-Issues-Guidance-on-Weight-Management-Drugs

Novo Nordisk. FDA approves Novo Nordisk’s oral semaglutide for cardiovascular (CV) risk reduction in adults with type 2 diabetes who are at high risk, including those who have not had a prior CV event. PR Newswire. October 17, 2025. Accessed December 5, 2025. 

https://www.prnewswire.com/news-releases/fda-approves-novo-nordisks-oral-semaglutide-for-cardiovascular-cv-risk-reduction-in-adults-with-type-2-diabetes-who-are-at-high-risk-including-those-who-have-not-had-a-prior-cv-event-302588022.html

Eli Lilly. Lilly’s Mounjaro (tirzepatide), a GIP/GLP-1 dual agonist, demonstrated cardiovascular protection in landmark head-to-head trial, reinforcing its benefits in patients with type 2 diabetes and heart disease. July 31, 2025. Accessed December 5, 2025. 

https://investor.lilly.com/news-releases/news-release-details/lillys-mounjaro-tirzepatide-gipglp-1-dual-agonist-demonstrated

Videos

GLP-1 receptor agonists revolutionize treatment in cardiology, offering new hope for heart failure and related conditions beyond weight loss.

Vericiguat Improves HFrEF Regardless of Background Therapy, With Justin Ezekowitz, MD

Patients enrolled in the VICTOR trial, an investigation of the efficacy of vericiguat in patients with 

heart failure with reduced ejection fraction (HFrEF)

, exhibited excellent background therapy before initiation, which contributed significantly to the composite primary endpoint of cardiovascular mortality and heart failure (HF)-related hospitalization.

An oral soluble guanylate cyclase stimulator, vericiguat restores impaired nitric oxide signaling in patients with HFrEF. It was approved by the 

 for the treatment of worsening heart failure (HF) based on a reduction in cardiovascular death or HF hospitalization in the 2020 VICTORIA trial.

Heart Failure Society of America Annual Scientific Meeting 2025

 by Justin Ezekowitz, MD, professor of medicine in cardiology at the University of Alberta and co-director of the Canadian VIGOUR Center, investigators examined the quality of background therapy present in the VICTOR trial and how it was related to clinical outcomes.

 sat down with Ezekowitz to discuss the analysis and its implications for patients with HFrEF.

“We had a lot of patients who were on optimal medical therapy, and that’s the first finding: that we really did have an exceptionally good and well-treated patient population in this HFrEF trial,” Ezekowitz told 

. “The second thing to look at was how that was related to the clinical outcome. The primary endpoint was cardiovascular death and heart failure hospitalization, and what we wanted to look at was whether or not it was related to background medical therapy.”

The VICTOR trial was a double-blind, placebo-controlled, parallel group, 1:1 randomized, event-driven investigation of the effects of oral vericiguat 10 mg versus placebo in ambulatory patients with HFrEF and no worsening HF episode. Patients were excluded if they had experienced recent HF worsening, defined as either an HF event that required hospitalization in the last 6 months or urgent outpatient diuretic use in the last 3 months.

Additionally, VICTOR enrolled patients already on background therapy, such as angiotensin-converting enzyme inhibitors (ACEi), angiotensin-receptor blockers (ARB), angiotensin receptor-neprilysin inhibitors (ARNI), beta-blockers, mineralocorticoid receptor antagonists (MRA), and sodium glucose cotransporter inhibitors (SGLT2i). These therapies were then divided into categories of adequate, good, better, and best background therapies based on their individual effectiveness in reducing symptoms of HFrEF.

Ezekowitz and colleagues examined the adherence to these background therapies according to the number of guideline-directed medical therapy (GDMT), as well as the Heart Failure Collaboratory score (mHFC). The primary endpoint was associations between the study treatment and the primary and secondary outcomes of VICTOR.

Ezekowitz and colleagues found a consistent improvement in the composite VICTOR endpoints across all background therapies, regardless of the quality of treatment. Vericiguat improved both cardiovascular mortality risk and HF hospitalization irrespective of preexisting treatment compared to placebo.

“The effect of vericiguat versus placebo was pretty consistent across all ranges of GDMT; those patients on good, adequate, better, and best therapy saw a very consistent result that vericiguat was better than placebo for most of the outcomes we tested,” Ezekowitz said. “I think that’s the take-home message: regardless of where patients are starting, there was additional benefit for cardiovascular death and all-cause mortality from adding in vericiguat.”

Editor's Note: Ezekowitz reports disclosures with Bayer, Merck, Amgen, Sanofi, Novartis, Cytokinetics, and others.

Ezekowitz J, Butler J, Zannad F. Vericiguat efficacy and safety across baseline background therapy in contemporary ambulatory patients with HFrEF enrolled in the VICTOR trial. Presented at the Heart Failure Society of America Annual Scientific Meeting 2025. Minneapolis, MN. September 26-29, 2025.s

Vericiguat did not meet its primary endpoint but lowered the risk of cardiovascular death in patients with heart failure. European Society of Cardiology. August 30, 2025. Accessed October 17, 2025. 

https://www.escardio.org/The-ESC/Press-Office/Press-releases/Vericiguat-did-not-meet-its-primary-endpoint-but-lowered-the-risk-of-cardiovascular-death-in-patients-with-heart-failure

Reddy YNV, Butler J, Anstrom KJ, et al. Vericiguat Global Study in Participants with Chronic Heart Failure: Design of the VICTOR trial. Eur J Heart Fail. 2025;27(2):209-218. 

Ezekowitz spotlights improvement in cardiovascular mortality and heart failure hospitalization despite a failure to achieve the primary endpoint of VICTOR.

Expert Perspectives: Top News in Heart Failure from HFSA Annual Scientific Meeting 2025

The Heart Failure Society of America Annual Scientific Meeting 2025,

 incorporating over 50 scientific sessions and hundreds of abstract presentations from leading researchers, saw a slew of exciting trial updates and insights from some of the best minds in cardiology.

During the conference, the editorial team at 

 sat down with several of these experts, collecting their thoughts on the most significant developments in 

’s approval of finerenone, the upcoming decision on aficamten, and the recent VICTOR, SUMMIT, and MAPLE- and ODYSSEY-HCM trials were highlighted.

The clinicians included in this summary are:

Ronald Witteles, MD, professor of cardiovascular medicine at Stanford University and co-director of the Stanford Amyloid Center and the Stanford Multidisciplinary Sarcoidosis Program

Barry Borlaug, MD, professor of cardiology at Mayo Clinic

Justin Ezekowitz, MD, professor of medicine at University of Alberta and cardiologist at the University of Alberta Hospital and Mazankowski Alberta Heart Institute

Ahmad Masri, MD, director of the Oregon Health & Science University Hypertrophic Cardiomyopathy Center and Knight Cardiovascular Institute Cardiac Amyloidosis Program

Javed Butler, MD, MPH, professor and chair of the department of medicine and Patrick H. Lehan Chair of Cardiovascular Research at the University of Mississippi Medical Center

Benjamin Hansen, MD, postdoctoral research fellow at the Department of Intensive Care at Copenhagen University Hospital - Rigshospitalet

Henri Roukoz, MD, associate professor of medicine, cardiovascular division, and section chief of electrophysiology, director of complex and congenital ablation at the University of Minnesota

Petra Mamic, MD, instructor of cardiovascular medicine at Stanford University Medicine

Stephen Greene, MD, cardiovascular disease fellow at Duke University Medical Center

Viet Le, DMSc, PA-C, associate professor of research at Intermountain Health

Milind Desai, MD, director of the center for hypertrophic cardiomyopathy and vice chair of education of the Heart Vascular Thoracic Institute at the Cleveland Clinic

I may be biased, but to me, ATTR amyloidosis is still the biggest story in heart failure. You’re talking about a disease that, a decade ago, most people hadn’t heard of. Maybe there would be one session every few years at the meetings, which was sparsely attended, but there was little interest, it was wildly underdiagnosed, and there were no therapies for it. Now we’re in an era where we realize this disease is not that rare, that if you look at the right patient populations, particularly older men with heart failure, thick hearts, and atrial fibrillation, you will pick up a lot of this. And it’s easy to diagnose; most patients can be diagnosed non-invasively. And now we have 3 FDA-approved treatments for ATTR 

, we have multiple other treatments approved for ATTR polyneuropathy, and multiple other agents in phase 3 trials. It is a super dynamic area, and it’s one that I think is particularly gratifying because it went from a fundamental understanding of the pathophysiology of the disease that led directly to the therapies. In the world of ATTR amyloidosis, the therapies have been designed to do exactly what they do, and in a rare thing in medicine, they pretty much all work.


The SUMMIT trial is probably the biggest news. It wasn’t a lot of events, it wasn’t a big trial, but it was a statistically significant improvement with a drug that was developed for weight loss, and it’s really ushering in a new era. HFpEF is a disease that’s driven by adiposity and everything that comes with that, such as visceral adiposity, pro-inflammatory and profibrotic effects, and many others. It’s opening the door for a lot of different drugs and potentially even devices that can target this cardiometabolic axis.


 2025 has been a pretty banner year for some trials: the VICTOR trial, being the largest recent clinical trial, has been quite important; the completion of DAPA-ACT, being the last real SGLT2 trial, showing that, when in combination with the meta-analysis, there is an advantage to starting those drugs early on. I think seeing the secondary analysis from some trials, such as the SUMMIT trial and the MRI of adipose tissue, is really interesting because it shows there’s a change in the structure and function of the myocardium that really is interesting. We’ve had so many great smaller trials as well, though, so it’s hard to pick one. There’s so much good stuff going on.


 Focusing on hypertrophic cardiomyopathy specifically, I think the 2 recent trials that were published, MAPLE-HCM and ODYSSEY-HCM, are really important findings in this space. MAPLE-HCM showed that beta blockers, as represented by metoprolol, are detrimental to patients with obstructive hypertrophic cardiomyopathy. This challenges a practice of 60-plus years of using beta blockers as first-line therapy. You don’t see reversals in approach frequently, because you don’t see these first-time agents challenged frequently. ODYSSEY-HCM, on the other hand, while it wasn’t a positive trial, showed that you have to be careful in your evaluation of patients with hypertrophic cardiomyopathy. You have to be mindful that you can’t just use 1 trial in a specific population and expand the drug treatment to other populations without investigation. This is a drug that was successful in obstructive hypertrophic cardiomyopathy with some safety issues that were managed and dealt with that wasn’t successful in non-obstructive HCM, and the safety signal was much worse. The trial wasn’t positive, but it reminded us that we have to be really careful when applying an extension of the current use of drugs, and we have to strive to stay with evidence-based medicine as much as we can with our newer therapies.


 The biggest story so far is that the field continues to move forward. We had a lot of positive data that has come out of either smaller primary studies or secondary analyses of larger studies with the obesity trials. That is becoming the solid, certified data that evidence generation needs, which has led to a lot of ongoing studies. The other is smaller studies that have shown that aldosterone modulation in ways other than MRA, like aldosterone synthase inhibitors, may be very helpful. And third, there’s a lot of compelling data that has come out about prevention of heart failure in high-risk populations.


 If I were to call out just one big news, it’s the role of vericiguat. I think that’s something of a hot topic right now, so I guess that’s something we really need to look further into to see its role in this population of well-treated outpatients with difficult-to-treat or advanced heart failure.


I would say how widely the SGLT2 inhibitors are being used and the increase in the indication to cover HFpEF patients. The second part is rhythm control and afib in heart failure, which is still a dominant thing from the EP standpoint.


This past year, we’ve had incredible studies published about gut microbiome in the context of heart failure, which have really put certain gut microbial metabolites on the map for their roles in heart failure. I think where we have come from 2024 to 2025 has really informed my research in a huge way.


There’s some things to pick from, but one thing that’s very notable is the FDA approval of finerenone as an evidence-based treatment for HFpEF, not just diabetic kidney disease anymore. The FINEARTS trial was presented last year, but FDA approval now really solidifies this in my mind that we have another pillar for HFpEF. SGLT2 inhibitors were the first definitively proven therapy for patients with HFpEF, and despite making up more than half of our heart failure population, we had no evidence-based therapy, no disease-modifying therapy to offer them. Now we have another therapy that I would argue strongly is definitively proven for improving hard clinical outcomes. I think we need to embrace that.

I’d also like to encourage people to think that it’s not an either-or when we talk about the “pillars of therapy,” and I don’t want to make the same mistakes that we made in HFrEF. We have multiple evidence-based therapies; you need to be willing to initiate them simultaneously and not get distracted with this specific medication sequence. People need both for prognosis comparable to cancer, not either-or.


GLP-1s are one of these unifying therapies across multiple diseases, and I think as we think back to 2025, we’re just having this confluence of heart failure from the diabetic space. Everyone is reporting clinical data trending towards benefit with GLP-1s. I think this is such a great jump-off point. So many different industry partners are looking into this, and before 2025, they were thinking about it. But now I think the community is much more aware. I look forward to seeing where those fit in the space of heart failure, but also in cardiovascular, kidney, and metabolic health.


I think the continued evolution of high-quality randomized controlled trial data in the context of cardiomyopathy, not just hypertrophic obstructive cardiomyopathy. Gene therapy is rapidly evolving, and you’re going to hear a lot about it. The other important thing is the utilization of novel artificial intelligence techniques to make early and precise diagnoses in these spaces. A rising tide lifts all boats, so they say; there’s a major tide that is lifting a lot of boats right now.

The quotes contained in this video summary were edited for clarity.

Editor's Note: Le reports disclosures with Pfizer, Novartis, Janssen, Idorsia, Amarin, and Lexicon. Greene reports disclosures with Amgen, Bayer AG, Boehringer Ingelheim, Bristol-Myers Squibb, AstraZeneca, Corcept, and others. Butler reports disclosures with Abbott Laboratories, Amgen, Bristol-Myers Squibb, Cytokinetics, Medtronic, Merck, and others. Masri reports disclosures with Pfizer, Ionis Pharmaceuticals, AstraZeneca, Cytokinetics, BioMarin, Akros, and others. Desai reports disclosures with Bristol-Myers Squibb, Medtronic, Cytokinetics, Edgewise, Viz-Al, and Tenaya Therapeutics. Borlaug reports disclosures with Amgen, Novo Nordisk, Eli Lilly, Edwards LifeSciences, Boehringer Ingelheim, AstraZeneca, and others. Witteles reports disclosures with Pfizer, Alnylam Pharmaceuticals, Bridge Bio, Janssen, AstraZeneca, and Alexian Pharmaceuticals. Roukoz, Hansen, Mamic, and Ezekowitz report no disclosures.

US FDA Approves KERENDIA (finerenone) to Treat Patients with Heart Failure with Left Ventricular Ejection Fraction ≥40% Following Priority Review. Bayer. July 14, 2025. Accessed October 3, 2025. 

https://www.bayer.com/en/us/news-stories/fda-approves-kerendia

Packer M, Zile MR, Kramer CM, et al. Interplay of Chronic Kidney Disease and the Effects of Tirzepatide in Patients With Heart Failure, Preserved Ejection Fraction, and Obesity: The SUMMIT Trial. J Am Coll Cardiol. 2025;85(18):1721-1735. 

Hegde SM, Wang X, Garcia-Pavia P, et al. Effect of Aficamten Compared With Metoprolol on Echocardiographic Measures in Symptomatic Obstructive Hypertrophic Cardiomyopathy: MAPLE-HCM. J Am Coll Cardiol. Published online August 27, 2025. 

Desai MY, Olivotto I, Abraham T, et al. Effects of Mavacamten on Cardiac Biomarkers in Nonobstructive Hypertrophic Cardiomyopathy: Insights From the ODYSSEY-HCM Trial. J Am Coll Cardiol. Published online August 25, 2025. 

This set of interviews collects perspectives from 11 leading clinicians in the heart failure field, cataloguing the biggest news from 2025.

Justin Ezekowitz, MD

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