The Role of GLP-1R and GIPR Agonism in Heart Failure

Phelopater Sedrak; Kim A. Connelly

doi:10.58931/cdet.2025.3138

Authors

Phelopater Sedrak, MD Department of Internal Medicine, University of Toronto, Toronto, Ontario, Canada
Kim A. Connelly, MBBS, PhD Keenan Research Centre for Biomedical Science, Unity Health, Keenan Chair in Research Leadership, University of Toronto

DOI:

https://doi.org/10.58931/cdet.2025.3138

Abstract

Heart failure (HF) is a clinical syndrome characterized by signs and symptoms of structural and functional cardiac abnormalities. It is corroborated by elevated N-terminal pro‑B‑type natriuretic peptide (NT-proBNP) levels and objective evidence of pulmonary or systemic congestion. More than 100,000 Canadians are diagnosed with HF annually. For years, HF has been classified based on left ventricular ejection fraction (LVEF). HF with reduced ejection fraction (HFrEF) refers to symptomatic HF with an LVEF <40%. However, if the LVEF is >50%, this is known as HF with preserved ejection fraction (HFpEF). In HFpEF, obesity is commonly implicated in the disease pathophysiology, and is present in up to 80% of people with this condition. Obesity contributes to concentric heart remodelling through mechanisms such as insulin resistance, diabetes, hyperlipidemia, visceral adipose tissue expansion, and myocardial steatosis. Additionally, obesity leads to a pro-inflammatory state which affects the vasculature and visceral organs.² Glucagon‑like peptide-1 receptor agonists (GLP‑1RAs), such as semaglutide, have shown promise in weight reduction across multiple Phase 3 clinical trials. Agents combining GLP-1RA and glucose-dependent insulinotropic peptide receptor (GIPR) agonism, such as tirzepatide, have also contributed to clinically significant weight loss. As such, their impact in addressing obesity‑related HFpEF is under investigation. This paper reviews the data on GLP-1RAs and tirzepatide in patients with HF across the LVEF spectrum, with a particular focus on those with HFpEF.

Author Biographies

Phelopater Sedrak, MD, Department of Internal Medicine, University of Toronto, Toronto, Ontario, Canada

Dr. Phelopater Sedrak is an internal medicine resident at the University of Toronto, where he also completed his medical school education. His academic interests are in novel therapies for heart failure and the promotion of health equity in inpatient practices. Dr. Sedrak is actively involved in teaching and mentoring medical students across various stages of their training. He also has an interest in advancing the point of care ultrasound curriculum. He has received multiple awards for clinical excellence in patient care at the undergraduate medical level.

Kim A. Connelly, MBBS, PhD, Keenan Research Centre for Biomedical Science, Unity Health, Keenan Chair in Research Leadership, University of Toronto

Dr. Kim Connelly is a Cardiologist and Scientist who is both nationally recognized as an expert in echocardiography, cardiovascular MRI and the impact of diabetes upon cardiac function and ventricular remodeling. Dr. Connelly runs a basic research laboratory at the Keenan Research Centre at St. Michael’s Hospital where he focuses upon basic mechanisms of disease – primarily around the role of pathological extracellular matrix accumulation with a focus upon integrin biology and translating discoveries into therapies in humans. He is a member of the editorial board of various journals such as The Canadian Journal of Cardiology and Cardiovascular Diabetology. He has received funding from the Heart and Stroke Foundation Canada, CIHR, Canadian Foundation of Innovation, Ministry of Ontario and industry sources, totally >$5 million as principal investigator. As a co-investigator, he has been part of >$20 million in funding, from the Ministry of Ontario, HSF, CIHR, CFI and industry sources. Dr. Connelly has been recognized for his contributions to science by being awarded a HSF clinician scientist award, a CIHR New Investigator Award, an Early Researcher Award from the Ministry of Ontario, the SC Verma award and the Insulin 100 emerging leader award to celebrate 100 years since the discovery of insulin at University of Toronto, as well as Canadian Cardiovascular Congress YIA 2012. He is past chair of the Canadian Cardiovascular guideline and was chair of the macrovascular complication section for Diabetes Canada CPG 2018. Dr. Kim Connelly is the executive director of the Keenan Research Centre for Biomedical Science and holds the Keenan Chair in Research Leadership, and is the head of the Division of Cardiology, St. Michael’s hospital, Toronto.

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The Role of GLP-1R and GIPR Agonism in Heart Failure

Authors

DOI:

Abstract

Author Biographies

Phelopater Sedrak, MD, Department of Internal Medicine, University of Toronto, Toronto, Ontario, Canada

Kim A. Connelly, MBBS, PhD, Keenan Research Centre for Biomedical Science, Unity Health, Keenan Chair in Research Leadership, University of Toronto

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