Incretin Therapies in Obesity-related 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:

Specific Aim 1: To measure changes in PV in patients with obesity and HFpEF treated with tirzepatide. Hypothesis 1: Tirzepatide treatment will result in significant reduction in measured PV assessed using the gold standard indicator tracer dilution technique with 131-iodine-labeled albumin.

Specific Aim 2: To elucidate the relationship between changes in fat mass, serum adipokine profile, and PV in patients with obesity and HFpEF on tirzepatide treatment. Hypothesis 2: Reductions in QMR-estimated fat mass and reduction in serum leptin will be associated with significant reduction in measured PV.

Specific Aim 3: To quantify changes in lean mass in patients with obesity and HFpEF on tirzepatide treatment. Hypothesis 3: Treatment with tirzepatide will be associated with significant reduction in lean mass over time estimated with QMR.

Exploratory aim: To determine the impact of measured PV reduction on cardiac structure and quality of life in patients with obesity and HFpEF on tirzepatide therapy.

Inclusion criteria

• Diagnosis of heart failure (HF) per the ACC/AHA guidelines with NYHA class II-III symptoms
• Left ventricular ejection fraction >= 45% within 6 months of recruitment
• At least one of the following: elevated N-terminal pro- B-type natriuretic peptide (NT-proBNP) >=200 pg/ml (>=600 pg/ml with concurrent atrial fibrillation), evidence of structural heart disease (left atrial (LA) enlargement with LA volume index >29 mL/m2 or LA diameter >=40 mm in males/>38= mm in females), elevated filling pressures (resting wedge >15 mmHg or exercise wedge >25 mmHg, lateral E/e' ratio >12 or septal E/e' > 15)
• Body mass index (BMI) >30 kg/m2
• Stable doses of HF medications within 4 weeks of screening with optimal volume control in the opinion of the investigator.

Exclusion criteria

• Acute decompensated HF within 4 weeks of screening
• Major cardiovascular event within 90 days of screening (myocardial infarction, stroke)
• Alternate cause of HFpEF such as cardiac amyloidosis, infiltrative cardiomyopathy, hypertrophic cardiomyopathy, severe valvular disease
• Estimated glomerular fibrilation rate (EGFR) <15 ml/min/1.73m2 or dialysis dependence
• Poorly controlled diabetes (A1c > 9.5%) OR any type 1 diabetes mellitis
• History of acute or chronic pancreatitis
• Personal or family history of multiple endocrine neoplasia (MEN) or medullary thyroid cancer
• Clinically significant gastric emptying abnormality
• Medical comorbidities that limit survival
• Inability to comply with the study protocol
• Pregnancy