Investigation of Dapagliflozin on Pathophysiological Mechanisms in Heart Failure with Preserved Ejection Fraction

The primary objective of this study is to identify the underlying **biological** and **biomechanical** mechanisms responsible for the cardiovascular benefit demonstrated by sodium-glucose cotransporter 2 (iSGLT2) inhibitors in patients with heart failure with preserved ejection fraction (HFpEF). Understanding these mechanisms is clinically relevant as it may provide insights into the therapeutic effects of iSGLT2 inhibitors, potentially leading to improved management strategies for HFpEF.

Secondary objectives include:

• Evaluating the effect of iSGLT2 treatment on left ventricular (LV) systolic and diastolic properties in HFpEF patients.
• Quantifying the relative contribution of intrinsic diastolic properties and flow patterns on filling pressures in diabetic patients with HFpEF under SGLT2 treatment.
• Investigating the association between geometric remodeling and intraventricular flow changes, and their impact on diastolic function and functional limitation in HFpEF patients.
• Studying structural and biomechanical alterations characterizing HFpEF, including changes in cardiomyocytes, fibrosis, collagen cross-linking, microvascular abnormalities, and inflammation.
• Assessing the effect of dapagliflozin on myocardial remodeling patterns in endomyocardial biopsies from HFpEF patients.
• Investigating the effect of dapagliflozin on molecules involved in cardiomyocyte stiffness and extracellular matrix remodeling.
• Quantifying circulating biochemical markers of myocardial remodeling in HFpEF patients, reflecting alterations in myocardial components.
• Correlating histological and biochemical findings with cardiac biomechanics and functional parameters to enhance patient phenotyping and understand dapagliflozin's mechanism of action.
• Evaluating the impact of dapagliflozin treatment on circulating biomarkers of myocardial remodeling.

The clinical trial focuses on individuals diagnosed with **heart failure with preserved ejection fraction** (HFpEF). The study population includes adults of both genders aged 18 years and older, with a left ventricular ejection fraction (LVEF) of 50% or greater. Participants must have a clinical diagnosis of HFpEF, evidenced by a history of hospitalization or the need for intravenous diuretic treatment within the previous six months, along with echocardiographic evidence of diastolic dysfunction. The trial includes patients with or without Type II Diabetes Mellitus, provided they are in a clinically stable condition, defined as more than one month post-hospitalization for heart failure decompensation or since the last intravenous diuretic treatment. Participants must have a clinical indication for cardiac catheterization and a clinical indication to receive de novo treatment with SGLT2 inhibitors. Both male and female subjects are included, and the trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Key lifestyle considerations such as diet and physical activity are not specified. The selection process requires signed informed consent from all participants.

The clinical trial is designed to evaluate the effects of sodium-glucose cotransporter 2 inhibition on the mechanisms of **heart failure with preserved ejection fraction** (HFpEF). This is a Phase IV, randomized, double-blind, controlled study. The trial will involve the administration of **dapagliflozin** in the form of Forxiga 10 mg film-coated tablets, taken orally. The study is expected to commence recruitment on June 1, 2023, and conclude by June 1, 2026, with a maximum treatment period of 12 months for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age (≥18 years), left ventricular ejection fraction (LVEF ≥ 50%), and a clinical diagnosis of HFpEF. The screening will also confirm a history of hospitalization or intravenous diuretic treatment within the past six months, along with evidence of diastolic dysfunction. Following successful screening, participants will be randomized to receive either the active treatment or a placebo.

Subsequent follow-up visits will be scheduled at regular intervals to monitor the primary endpoints, which include systolic and diastolic properties derived from pressure-volume curve analysis. Secondary endpoints will assess reverse geometric remodeling of the left ventricle, intraventricular flow patterns, cardiomyocyte alterations, and other cardiovascular parameters. The end-of-study visit will occur at the conclusion of the 12-month treatment period, where final assessments will be conducted to evaluate the long-term effects of the treatment.

Participant involvement is expected to last for the entire duration of the treatment period, approximately 12 months, unless early termination is warranted. Conditions that may lead to early withdrawal from the study include adverse events, non-compliance with the study protocol, or withdrawal of consent. The trial aims to provide insights into the biological and biomechanical mechanisms responsible for the cardiovascular benefits observed with SGLT2 inhibitors in patients with HFpEF.

The clinical trial involves the administration of **Forxiga 10 mg film-coated tablets**, which contain the active substance **dapagliflozin**. Dapagliflozin is a chemical compound classified under the ATC code A10BK01. The pharmaceutical form of the medication is a film-coated tablet, designed for oral administration. The dosage regimen for the trial specifies a maximum daily dose of 10 mg, with the treatment period extending up to 12 weeks. The tablets are manufactured by AstraZeneca AB and are not formulated for pediatric use. The administration of the medication is strictly oral, and participant compliance will be monitored throughout the study to ensure adherence to the dosing schedule.

In this clinical trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on evaluating the effects of the experimental medication, Forxiga, in the context of the study's objectives. The trial aims to investigate the biological and biomechanical mechanisms responsible for the cardiovascular benefits observed with sodium-glucose cotransporter 2 inhibition in patients with heart failure with preserved ejection fraction. Compliance monitoring will be conducted to ensure that participants adhere to the prescribed dosing regimen, thereby maintaining the integrity of the trial data.

Efficacy in the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoints focus on the **systolic** and **diastolic** properties derived from pressure-volume (PV) curve analysis, specifically measuring maximum elastance, relaxation, stiffness, equilibrium volume, and elastic recoil. These parameters will provide insights into the cardiovascular benefits of sodium-glucose cotransporter 2 inhibition in patients with heart failure with preserved ejection fraction (HFpEF).

Secondary endpoints include a comprehensive evaluation of reverse geometric remodeling variables of the left ventricle (LV) using cardiac magnetic resonance imaging (MRI) to measure ventricular volumes and mass. Intraventricular flow patterns will be assessed through Doppler echocardiography and phase-contrast MRI, focusing on vorticity parameters and blood transport into the LV, as well as energy exchange between the myocardium and blood. Additional assessments will cover cardiomyocyte alterations, including the grade of hypertrophy and expression of pro-hypertrophic genes, interstitial and perivascular fibrosis, degree of collagen crosslinking, microvascular alterations, cardiomyocyte stiffness, and extracellular matrix components. Biomarkers such as NT-proBNP and high-sensitivity troponin T (TnT) will also be evaluated.