Identifying Therapeutic Mechanisms for Incretin-Based Treatment in Obesity-Related Heart Failure With Preserved Ejection Fraction (HFpEF)

The prevalence of obesity among United States adults is over 40% and is projected to affect over half the population within the coming decade. Obesity is a strong independent risk factor for the development of heart failure (HF) and specifically the phenotype of heart failure with preserved ejection fraction (HFpEF) of whom 84% have obesity. Accordingly, anti-obesity medications are a major focus of recent clinical investigation in patients with obesity and HFpEF. Randomized controlled trials studying incretin mimetics, including glucagon-like peptide 1 (GLP1) receptor agonist (semaglutide) and GLP1/glucose-dependent insulinotropic (GIP) receptor co-agonists (tirzepatide), have improved clinical outcomes patients with obesity and HFpEF. The mechanisms underlying the clinical benefit remain incompletely understood.

Patients with obesity and HFpEF demonstrate distinct structural and hemodynamic features mediated in part by plasma volume (PV) expansion. A major mechanism responsible for PV expansion in obesity is elevated serum leptin, an adipokine with a concentration directly proportional to fat mass. In excess, leptin activates neurohormonal and sympathetic pathways that result in hyperaldosteronism, perpetuating sodium retention and PV expansion in HFpEF. This leads to distinct echocardiographic and hemodynamic changes reflecting increased cardiac volumes and pressures. Compared to those without obesity, patients with obesity and HFpEF have greater left atrial (LA) dilatation, greater concentric left ventricular (LV) remodeling, greater right ventricular (RV) dysfunction, and elevated resting and exercise intracardiac filling pressures.

Preliminary data from secondary analyses of randomized trial data have shown significant reductions in estimated PV in patients on treatment tirzepatide compared to placebo. These changes were associated with improvements in end organ function, functional capacity, and quality of life. Notably, prediction equations to estimate PV are inaccurate, demonstrating weak correlation with the gold standard dilution technique with radiolabeled iodinated serum albumin. Measuring changes in PV with this method would establish an important mechanism of clinical benefit in this population.

In addition, to further understand this mechanism and inform disease pathophysiology, it is also imperative to understand changes in body composition that occur with incretin-based therapies. Quantitative magnetic resonance (QMR) is a highly precise body composition assessment technique that can estimate fat mass, fat-free (lean) mass, free water and total body water (TBW) over time and has been utilized by the research team in other HFpEF cohorts. The investigators will leverage this technology to demonstrate the association between reductions in fat mass and serum leptin with PV reduction, representing a key pathway in the pathophysiology of obesity and HFpEF. In addition, the impact of incretin mimetics on lean mass in patients with obesity and HFpEF is important to establish given the association between lean mass reduction with sarcopenia and poor outcomes in HFpEF, especially in older adults. Due to biased assessment techniques, prior studies have demonstrated highly variable effects on lean mass.

The following are the Specific Aims of the study: