Researchers have found that inhibiting the hormone glucagon may offer a treatment option for a prevalent and challenging form of heart failure impacting millions around the globe.
Scientists from Duke-NUS and their partners have identified a promising approach for heart failure with preserved ejection fraction (HFpEF), a particularly difficult-to-treat heart condition. Their research revealed that heart cells affected by this disease show increased activity of glucagon, a hormone produced by the pancreas that elevates blood sugar (glucose) levels. With this new understanding, the team demonstrated that a medication capable of blocking glucagon’s effects can lead to notable improvements in heart function.
Heart failure is a critical global health issue where the heart struggles to pump blood effectively. In Singapore, it ranks as a leading cause of mortality, representing 17 percent of local cardiac hospital admissions[1]. Worldwide, around 64 million individuals are estimated to suffer from this condition[2], with HFpEF constituting nearly half of those cases[3].
In HFpEF, while the heart can pump blood normally, its muscles lack the flexibility to relax properly, preventing efficient blood refilling in the chambers. This condition is commonly observed in older individuals and those with multiple risk factors such as high blood pressure (hypertension), obesity, and diabetes. Patients typically experience symptoms like shortness of breath, fatigue, and decreased exercise tolerance. This differs from heart failure with reduced ejection fraction (HFrEF), where the heart muscle becomes weakened and is unable to pump blood forcefully, resulting in less blood being delivered throughout the body.
Previous research has examined how hypertension and metabolic diseases related to obesity, such as diabetes, stress the heart, but typically focused on each factor independently. The current study, published in Circulation Research, bridges this gap by simultaneously considering both factors and revealing, for the first time, the molecular pathways involved in the progression of HFpEF.
In their preclinical research, a multidisciplinary team from Duke-NUS, along with collaborators from the University of Cincinnati College of Medicine, UCLA, the University of Toronto, and UNC School of Medicine, explored the impact of hypertension-induced stress on lean heart models compared to those affected by diabetes or obesity. Their findings indicated that the lean models developed HFrEF, commonly seen in patients with hypertension, while the obese models progressed to HFpEF, suggesting that a combination of stressors leads to the disease and creating a solid foundation for further exploration.
Utilizing cutting-edge single-cell RNA sequencing technologies, the researchers meticulously examined the expression of every identified gene within individual heart cells. This technique allowed them to identify specific genetic variations linked to HFpEF. Notably, in the obese models, they discovered that the most active genes corresponded to those associated with glucagon activity.
Professor Wang Yibin, who directs the Cardiovascular & Metabolic Disorders Programme at Duke-NUS and leads the study, stated:
“We found that, under stress from conditions like high blood pressure and metabolic disorders such as obesity and diabetes, glucagon signaling becomes overly active in heart cells. This increased activity plays a crucial role in developing heart failure with preserved ejection fraction (HFpEF) by raising heart stiffness and hindering its ability to relax and fill with blood.”
The researchers subsequently tested a drug that blocks the glucagon receptor in preclinical HFpEF models, resulting in significant enhancements in heart function, including reduced stiffness, improved relaxation, a better capacity for blood filling, and overall enhanced heart performance.
Assistant Professor Chen Gao from the University of Cincinnati College of Medicine; the study’s lead author, noted:
“Our findings provide compelling support that a glucagon receptor blocker could effectively treat HFpEF. Repurposing this medication, already under evaluation in diabetes clinical trials, could streamline the process, offering faster and more effective relief to millions of heart patients.”
Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS, added:
“As our population ages, an increase in patients with multiple health issues, including heart failure, diabetes, and hypertension, is expected, posing a significant challenge to healthcare systems. Understanding how these diseases interact and elucidating their underlying mechanisms is vital to advancing knowledge of heart failure and developing effective treatments.”
The research team aims to collaborate with clinical partners to launch trials assessing the glucagon receptor blocker in humans with HFpEF. Success in these trials could result in one of the first effective therapies for this challenging condition, greatly enhancing the quality of life for millions around the world.
Duke-NUS is recognized as a leader in medical education and a key player in biomedical research, integrating fundamental scientific inquiry with practical applications to deepen the understanding of prevalent diseases, such as heart failure, and to develop innovative treatment solutions for individuals in Singapore and beyond.
[1] Chan WX, Lin W, and Wong RCC. Transitional care to reduce heart failure readmission rates in South East Asia. Cardiac Failure Review 2016; 2: 85-9.
[2] Savarese G, Becher PM, Lund LH, Seferovic P, Rosano GM, Coats AJ. Global burden of heart failure: a comprehensive and updated review of epidemiology. Cardiovascular Research. 2022 Dec 1;118(17):3272-87.
[3] Epidemiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 2017; 14:591-602.
