Incretin Therapies in Obesity-related HFpEF

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

The central hypothesis to be tested is that patients with obesity and heart failure with preserved ejection fraction (HFpEF) prescribed tirzepatide will demonstrate reductions in measured plasma volume. In conjunction with state-of-the-art body composition analysis and measures of adipokines, this will establish an important mechanism of clinical benefit and inform disease pathophysiology. To accomplish this, this study will perform a 15-month prospective cohort study in 50 patients with obesity and HFpEF who clinically qualify for treatment with tirzepatide. The investigators will serially measure plasma volume and body composition with quantitative magnetic resonance to determine changes over time with tirzepatide treatment.

Study Overview

• Status: Not yet recruiting
• Conditions: Obesity; Heart Failure, Diastolic; Heart Failure With Preserved Ejection Fraction
• Intervention / Treatment: Drug: Tirzepatide

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Jessica Idumonyi; Phone Number: 212-305-1429; Email: joi2102@cumc.columbia.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Tirzepatide; After a 3-month control period, participants will be prescribed tirzepatide and undergo serial plasma volume measurement and body composition analysis. Participants will be prescribed tirzepatide under the brand name Monjauro if they have diabetes, and under the brand name Zepbound if they do not have diabetes. All participants will be initiated on an initial dose of 2.5 mg injected subcutaneously in the thigh or abdomen every week on same day and at the same time.

Drug: Tirzepatide; Glucagon-like 1 receptor agonist/glucose-dependent insulinotropic polypeptide receptor agonist; Other Names: Mounjaro

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma volume	Plasma volume is measured using 131-iodine labeled serum albumin. The isotope is injected via an intravenous line and serial blood samples are taken and analyzed using the Blood Volume Analyzer-100 to derive the participant's blood volume and plasma volume. This will be performed at serial visits to determine the effect of tirzepatide therapy on measured plasma volume over time.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fat mass	Body composition analysis will be performed with quantitative magnetic resonance (QMR). QMR will be performed early morning in a fasting state with participants in uniform hospital gowns and socks. Briefly, the QMR system generates a signal that modifies the spin of hydrogen atoms and uses an algorithm to evaluate the resulting T1 and T2 relaxation curves specific to one of the components of body composition: fat mass, fat-free mass, total body water. This will be performed at serial visits to determine the effect of tirzepatide therapy on fat mass over time.	12 months
Lean mass	Body composition analysis will be performed with QMR. QMR will be performed early morning in a fasting state with participants in uniform hospital gowns and socks. Briefly, the QMR system generates a signal that modifies the spin of hydrogen atoms and uses an algorithm to evaluate the resulting T1 and T2 relaxation curves specific to one of the components of body composition: fat mass, fat-free mass, total body water. This will be performed at serial visits to determine the effect of tirzepatide therapy on lean mass over time.	12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in serum leptin	Leptin is a hormone associated with fat mass. Serum leptin will be measured serially on tirzepatide therapy to determine if reductions in serum leptin are associated with reduced plasma volume.	12 months
Change in serum adiponectin	Adiponectin is an adipokine that is inversely associated with fat mass. Serum adiponectin will be measured serially on tirzepatide therapy to determine if increases in serum adiponectin are associated with reduced plasma volume.	12 months
Change in KCCQ clinical summary score	The Kansas City Cardiomyopathy Questionnaire (KCCQ) evaluates health status from several principal domains including physical function, social function, symptoms and quality of life. Higher scores indicate better health status, ranging from 0 to 100 points. The clinical summary score will be the exploratory endpoint of interest.	12 months
Change in left atrial volume	Transthoracic echocardiograms will be performed at the baseline and final study visits. Change in left atrial volume will be exploratory end point of interest.	12 months
Change in total body water	Body composition analysis will be performed with QMR. QMR will be performed early morning in a fasting state with participants in uniform hospital gowns and socks. Briefly, the QMR system generates a signal that modifies the spin of hydrogen atoms and uses an algorithm to evaluate the resulting T1 and T2 relaxation curves specific to one of the components of body composition: fat mass, fat-free mass, total body water. This will be performed at serial visits to determine the effect of tirzepatide therapy on total body water over time.	12 months

Collaborators and Investigators

• Sponsor: Columbia University

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): April 1, 2029
• Study Completion (Estimated): April 1, 2030

Study Registration Dates

• First Submitted: April 21, 2026
• First Submitted That Met QC Criteria: April 21, 2026
• First Posted (Actual): April 28, 2026

Study Record Updates

• Last Update Posted (Actual): May 4, 2026
• Last Update Submitted That Met QC Criteria: April 28, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Nutrition Disorders; Heart Diseases; Overnutrition; Body Weight; Overweight; Heart Failure; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Obesity; Heart Failure, Diastolic; Amino Acids, Peptides, and Proteins; Proteins; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptide Receptors; Receptors, G-Protein-Coupled; Receptors, Cell Surface; Membrane Proteins; Receptors, Gastrointestinal Hormone; Receptors, Peptide; Tirzepatide
• Other Study ID Numbers: AAAV9609

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes