Evaluation of the Cardiac and Metabolic Effects of Semaglutide in Heart Failure with Preserved Ejection Fraction

This proposal is responsive to the FY21 PRMRP Topic Area of Cardiomyopathy and specifically addresses two key Areas of Encouragement in this Area, specifically: (1) development of novel therapeutic approaches for primary and secondary cardiomyopathies and (2) research to improve the understanding of the pathophysiology of cardiomyopathies. The current application has the potential to shift paradigms in the way we understand and treat patients with obesity-related cardiomyopathy/obese heart failure (HF) with preserved ejection fraction (HFpEF). Over half of all people in the United States with HF have HFpEF. In these patients, the pumping function ability of the heart is normal, but because the heart muscle is stiff, this increases the pressure inside the heart and lungs, causing shortness of breath. Patients with HFpEF experience marked limitations in quality of life, with disabling symptoms such as shortness of breath and severe fatigue with even simple activities such as walking or bathing. Even as the pumping ability of the heart in HFpEF is preserved, clinical outcomes after hospitalization are just as poor as we see for patients with HF that is caused by a weak heart muscle (termed HF with reduced ejection fraction, or HFrEF). Five years after a hospitalization for either form of HF, over 75% of patients will have died, and over 80% will have to be readmitted to the hospital. There are over eight effective treatments available for patients with HFrEF that have been proven to reduce the risk of HF hospitalizations or cardiovascular death. In striking contrast, there are few effective therapies for patients with HFpEF, making treatment of this syndrome one of the largest unmet needs in all of cardiovascular medicine. Recent studies have demonstrated that obesity is among the strongest risk factors for HFpEF. Up to 80% of Americans with HFpEF are obese, and patients with this obese phenotype of HFpEF, which has also been traditionally referred to as obesity-related cardiomyopathy, display several features that are distinct from other forms of HFpEF. In particular, the abnormalities in the heart that cause symptoms of shortness of breath are directly correlated with the amount of excess body fat. Patients with obesity-related cardiomyopathy/HFpEF display greater increases in plasma volume, thicker hearts, and more fat tissue around the heart that increases heart pressures to worsen symptoms. This has led us to hypothesize that if we could reduce body fat in patients with obesity-related cardiomyopathy/HFpEF, this could help treat improve their heart function and therefore improve quality of life and enhance their ability to be active. While there is currently no clearly established effective treatment for HFpEF, there are treatments available for obesity. Recent trials have shown that semaglutide, a medicine given once weekly by injection, leads to a 15% reduction in body weight over 1 year. This degree of weight loss is associated with multiple health benefits, including reduction in diabetes, lowering of blood pressure, reduction in gastric reflux, and reduction in sleep apnea and arthritis. It may also be that weight loss associated with semaglutide (and other interventions) might be a treatment for the heart directly. While medicines and surgical procedures are available to all patients with obesity (including patients with obesity-related cardiomyopathy), they are very rarely used or even considered as treatments. In this clinical trial, we propose to test whether an aggressive weight loss intervention based upon the combination of healthy lifestyle intervention together with semaglutide treatment can improve heart function and reduce the pressures in the heart and lungs that lead to shortness of breath, along with other potential favorable effects on the heart and body, as compared to treatment with placebo. To test this idea, we will randomize patients with obesity-related cardiomyopathy/HFpEF in a double-b