by Gillian Rutherford, University of Alberta

Graphical abstract. Credit: Cell Reports (2024). DOI: 10.1016/j.celrep.2024.114573

A University of Alberta pharmacology researcher has discovered that a new experimental anti-obesity drug improves diastolic heart function in mice with type 2 diabetes independent of its weight loss effects, suggesting the drug may work as a treatment to prevent the most prevalent form of heart failure in people with diabetes.

The study is published in the Cell Reports.

John Ussher is a professor in the Faculty of Pharmacy and Pharmaceutical Sciences, Canada Research Chair in Pharmacotherapy of Energy Metabolism in Obesity and a member of both the Alberta Diabetes Institute and the Cardiovascular Research Institute.

"I believe that if we manage this type of heart disease for the 400-million-plus people who have been diagnosed with type 2 diabetes worldwide—if we get on top of it for someone diagnosed in their 40s or 50s—then they won't have this type of heart failure in their 60s and 70s," Ussher says.

"It's debilitating for the patient because they get out of breath from just walking up one flight of stairs, and it's also a huge burden on the health care system."

Ussher's lab tested the new anti-obesity drug Growth Differentiation Factor 15 (GDF15), which acts on the brain to decrease appetite and promote weight loss. It is currently in early clinical trials for use in humans. Obesity is a risk factor for both type 2 diabetes and cardiovascular disease.

The team gave GDF15 to mice with type 2 diabetes, while a control group lost weight through diet alone. The team found an improvement in diastolic heart function in both groups, but it was better in the mice that had received the drug. The research team determined that the drug caused this improvement because of its anti-inflammatory effects on the heart.

"One of the cell types that causes an inflammatory response in the heart is known as macrophages, and we saw fewer macrophages recruited to the heart," Ussher explains. "Several biomarkers of elevations in inflammation were decreased in the heart with GDF15 treatment "

Health Canada reports that more than three million Canadians live with diabetes, representing 8.9% of the population, and another 6.1% have prediabetes. About 80% of people with diabetes will die as a result of heart disease or stroke, according to the Canadian Diabetes Association.

The most common type of heart problem in type 2 diabetes is diastolic or "left-side" dysfunction, in which the heart does not relax properly between pumps. Symptoms include fatigue and shortness of breath.

The problem, says Ussher, is that patients who are newly diagnosed with type 2 diabetes do not often have their heart function tested because the focus of treatment is on blood sugar control through diet, weight loss and medication. This means patients with diabetes may live with diastolic dysfunction for many years without direct treatment. Later in life it can show up as an often fatal condition known as heart failure with preserved ejection fraction.

Ussher is devoting his research career to finding treatments for this hidden disease. He says the next step for his research will be to investigate the mechanism behind how GDF15 reduces inflammation in the heart.

The Ussher lab recently published another paper looking at an Ozempic-like drug called liraglutide, also known as Victoza, which they found also promotes weight loss and improves the heart's ability to relax.

Ussher notes that the weight loss impact of glucagon-like peptide-1 based drugs like Ozempic or Victoza is better than with GDF15, and studies suggest that the two drugs have synergistic actions and could be used together as complementary treatments.

More information: Jordan S.F. Chan et al, Growth differentiation factor 15 alleviates diastolic dysfunction in mice with experimental diabetic cardiomyopathy, Cell Reports (2024). DOI: 10.1016/j.celrep.2024.114573

Journal information: Cell Reports 

Provided by University of Alberta