Researchers identify glucagon blocker as promising therapy for heart failure
Pre-clinical studies demonstrated that blocking glucagon activity can improve heart function in heart failure with preserved ejection fraction (HFpEF), a type of heart disease that is notoriously difficult to treat.
Researchers at Duke-NUS Medical School (Singapore) and their collaborators have utilized single-cell RNA-sequencing methods to discover that HFpEF heart cells have high levels of glucagon activity. Glucagon is a pancreatic hormone that elevates blood glucose levels. Notably, testing a glucagon receptor blocker on a pre-clinical model of HFpEF resulted in significantly improved overall heart performance suggesting a potential new therapeutic approach.
Heart failure is considered a global pandemic, affecting 64 million people worldwide. HFpEF accounts for approximately half of those cases and is becoming an emerging unmet need as it is difficult to treat. In HFpEF the heart can pump normally but its muscles are too stiff to fill properly. This differs from heart failure with reduced ejection fraction (HFrEF), where the heart muscles are weakened and therefore can’t pump with enough force.
HFpEF is typically seen in older female adults, and people with comorbidities such as hypertension, obesity and diabetes. The two most prominent comorbidities observed with HFpEF, hypertension and metabolic disorders associated with obesity, have been well studied; however, these studies were conducted separately. The current study addresses this limitation by taking both stressors into account.
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To investigate how stress from hypertension affected lean hearts compared to diabetic/obese ones, the researchers used mice models. They found that the lean mice developed HFrEF, which is typically seen in people with hypertension, whereas the diabetic/obese mice developed HFpEF. This shows that a combination of stressors gives rise to HFpEF.
Following this finding, researchers used single-cell RNA sequencing to study the expression of every detected gene in every heart cell, revealing the specific genetic variations associated with HFpEF.
Senior author, Wang Yibin, commented on the findings: “Under stress conditions such as high blood pressure and metabolic disorders like obesity and diabetes, we found that glucagon signaling becomes excessively active in heart cells. This heightened activity contributes to the development of HFpEF by increasing heart stiffness and impairing its ability to relax and fill with blood.”
To confirm the impact of their findings, the team tested a glucagon receptor blocker in a pre-clinical model of HFpEF. They found significant improvements in heart function, including reduced heart stiffness, improved blood-filling capacity and overall better heart performance.
The study’s first author, Chen Gao, added, “Our study shows strong evidence that a glucagon receptor blocker could work well to treat HFpEF. Repurposing this drug, which is already being tested in clinical trials for diabetes, could bypass the lengthy drug development process and provide quicker and more effective relief to millions of heart patients.”
The researchers hope to conduct clinical trials to test the glucagon receptor blocker in humans with HFpEF. If it is found to be successful it could become one of the first effective treatments for HFpEF.
