By Gisany Ravichandran

Graphic design by Raymond Zhang

Cardiovascular diseases (CVDs) are the number one cause of death globally, comprising a group of disorders affecting the heart and blood vessels.¹ Obesity and type 2 diabetes (T2D) increase the risk of CVD through shared cardiometabolic disturbances, such as disruptions to glucose regulation, fat storage, and energy balance.² As the global prevalence of obesity rises, so does the development of CVD and diabetes, contributing to high mortality and morbidity.^3-4 Together, metabolic disturbances and CVD represent a significant and growing healthcare burden.⁴ 

In recent years, medications known as glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have transformed the treatment landscape for diabetes and obesity. Originally developed to improve blood sugar control, these therapies have shown benefits for CVD risk and outcomes.⁵ These insights have inspired a new wave of research aimed at uncovering the mechanisms underlying the intersection of obesity, CVD, and cardiometabolic diseases.⁵ These advances have catalyzed a new era of medicine focused on cardiometabolic health. This emerging field probes the biological connections between metabolic dysfunction and cardiovascular outcomes to identify new strategies for prevention and treatment.

Dr. Subodh Verma is a cardiac surgeon at St. Michael’s Hospital, Professor of Surgery at the University of Toronto, and Tier 1 Canada Research Chair in Cardiovascular Surgery. His research focuses on unveiling the mechanisms underlying the relationship between diabetes, obesity, and cardiovascular stress. Since 2007, he has worked as a cardiac surgeon-scientist, mending human hearts in the operating room, while pioneering global efforts in advancing cardiovascular and cardiometabolic medicine.

Dr. Verma’s research efforts are directly inspired by his clinical work. Operating at the forefront of cardiac surgery and translational research, Dr. Verma identified a fundamental gap in cardiovascular medicine: translating high-quality clinical data into real-world patient and surgical care. In response, he co-founded CardioLink with Dr. David Mazer in 2015. CardioLink was developed to unite international cardiac investigators and clinicians to conduct rigorous, translational clinical trials using cutting-edge techniques to inform surgical and clinical decision-making. Over the past decade, the platform has produced numerous high-impact publications supporting evidence-based practice and improving patient outcomes.

CardioLink has been integral to understanding the impact of GLP-1 RAs, like semaglutide, on CVD. Semaglutide is known to reduce cardiovascular events and promote weight loss in patients with obesity or diabetes; however, the biological mechanisms behind these protective effects remain unclear.⁶ 

To address this, Dr. Verma and his colleagues launched the Semaglutide and Vascular Regeneration (SEMA-VR) CardioLink-15 trial.⁶ The study examined patients with atherosclerotic CVD (ASCVD), a condition where plaque build-up on the arterial walls hardens the arteries.⁷ Healthy blood vessels rely on specialized repair cells, or vascular regenerative (VR) cells to maintain vascular health, but they are diminished in individuals with ASCVD risk factors, including obesity and T2D.⁶ It is known that semaglutide impacts ASCVD risk, though the mechanism remained elusive.⁶ 

Given the role of VR cells in ASCVD, Dr. Verma hypothesized that semaglutide may impact the number and/or function of these cells, contributing to better outcomes. He evaluated the effects of semaglutide on VR cell content using multi-parametric flow cytometry, a technique that tags cells with unique cell-specific markers to distinguish beneficial repair-oriented cells from harmful inflammatory cells.⁶ Dr. Verma and his team demonstrated for the first time that semaglutide increases the number of bone marrow-derived VR progenitor cells. The discovery uncovered a previously unrecognized mechanism by which the drug exerts cardioprotective effects in people with obesity, diabetes, ASCVD, or ASCVD risk factors.⁶ 

Another major focus of Dr. Verma’s research assesses the efficacy of GLP-1 RAs in treating peripheral artery disease (PAD). PAD occurs when fatty plaques build up in the arteries, narrowing the blood vessels. In lower limb PAD, reduced circulation leads to leg pain, trouble walking, and diminished quality of life.⁸ PAD is a severe type of ASCVD that disproportionately affects women and individuals with T2D, often progressing to severe disability or even limb amputation.⁸ Despite its prevalence and severity, effective treatment options are limited.

To address this unmet clinical need, Dr. Verma and his collaborators examined whether semaglutide could improve functional outcomes in people with PAD and diabetes through the Semaglutide and Walking Capacity in People With Symptomatic PAD and T2D (STRIDE) trial.⁹ The study demonstrated that semaglutide significantly improved walking ability and quality of life of these individuals.⁹ “GLP-1 [RAs] are the first kind of hope for these people—it’s a critical advancement in the field,” says Dr. Verma. Building on these findings, he led the post-hoc analysis examining sex differences, which demonstrated that although semaglutide improved functional outcomes regardless of sex, females with PAD have different baseline demographics and treatment histories compared to males.¹⁰ These findings are critical to consider when designing and interpreting future PAD trials.

The collective efforts of Dr. Verma, his team, and their collaborations with investigators worldwide have illuminated the breadth of impact of semaglutide and other GLP-1 RAs in influencing CVD, heart failure, and metabolic health. “It’s the gift that keeps on giving,” Dr. Verma reflects. “We’ve hit a core driver of multiple cardiometabolic comorbidities.” The collaborative framework of CardioLink has also enabled a deeper understanding of the intersection between CVD and metabolic health. “It’s not just a story of [myself]—it’s a story of intense global collaboration. Interrogating overweight and obesity with these therapies has really represented a sea of change in our ability to move the field forward.” These discoveries are not only reshaping treatment, but they are also shifting the focus towards earlier intervention. Dr. Verma’s efforts are not just opening doors to new treatments, they are refining the way CVD and metabolic diseases are studied and managed to optimize patient care. 

“It is a profound privilege to serve as a cardiac surgeon—caring for the human heart in the operating room while advancing solutions for heart failure, atherosclerosis, and PAD from bench to bedside, with impact that extends to patients globally.” 

References

1. Olvera Lopez E, Ballard BD, Jan A. Cardiovascular Disease. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK535419/
2. Park B, Bakbak E, Teoh H, et al. GLP-1 receptor agonists and atherosclerosis protection: the vascular endothelium takes center stage. Am J Physiol Heart Circ Physiol. 2024;326(5):H1159-H1176. doi:10.1152/ajpheart.00574.2023.
3. Powell-Wiley TM, Poirier P, Burke LE, et al. Obesity and Cardiovascular Disease: A Scientific Statement From the American Heart Association. Circulation. 2021;143(21):e984-e1010. doi:10.1161/CIR.0000000000000973
4. Netala VR, Teertam SK, Li H, et al. A Comprehensive Review of Cardiovascular Disease Management: Cardiac Biomarkers, Imaging Modalities, Pharmacotherapy, Surgical Interventions, and Herbal Remedies. Cells. 2024;13(17):1471. Published 2024 Sep 1. doi:10.3390/cells13171471
5. Ferhatbegović L, Mršić D, Macić-Džanković A. The benefits of GLP1 receptors in cardiovascular diseases. Front Clin Diabetes Healthc. 2023;4:1293926. Published 2023 Dec 8. doi:10.3389/fcdhc.2023.1293926
6. Park B, Dennis F, He AZ, et al. Semaglutide promotes bone marrow-derived progenitor cell flux toward an anti-inflammatory and pro-regenerative profile in high-risk patients: the SEMA-VR CardioLink-15 trial. Eur Heart J. 2025. https://doi.org/10.1093/eurheartj/ehaf690
7. Pahwa R, Jialal I. Atherosclerosis. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK507799/
8. Verma S, Leiter LA, Mangla KK, et al. Epidemiology and Burden of Peripheral Artery Disease in People With Type 2 Diabetes: A Systematic Literature Review. Diabetes Ther. 2024;15(9):1893-1961. doi:10.1007/s13300-024-01606-6
9. Bonaca MP, Catarig AM, Houlind K, et al. Semaglutide and walking capacity in people with symptomatic peripheral artery disease and type 2 diabetes (STRIDE): a phase 3b, double-blind, randomised, placebo-controlled trial. Lancet. 2025;405(10489):1580-1593. doi:10.1016/S0140-6736(25)00509-4
10. Verma S, Catarig AM, Houlind K, et al. Sex Differences in Effectiveness of Semaglutide in Patients With Peripheral Artery Disease: The STRIDE Trial. J Am Coll Cardiol. 2025;86(20):1843-1857. doi:10.1016/j.jacc.2025.08.046