The Effects and Mechanism of SGLT2 Inhibitors in Stage B of Heart Failure With Hypertension

Study Overview
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Brief Summary
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This study is a multicenter randomized controlled trial designed to recruit individuals in the pre-heart failure stage who have hypertension without concurrent diabetes. Participants will be randomly allocated in a 1:1 ratio into the empagliflozin group (10 mg daily) or the placebo group, and they will undergo a follow-up period of 6 months. The primary endpoint for evaluation will be the left atrial volume index. The secondary endpoints will encompass cardiac structure and function parameters, as well as biomarkers obtained from blood samples. These biomarkers will include indicators of fibrosis, inflammation, cardiac function, and routine blood parameters. The overarching goal of the research is to comprehensively assess the impact of empagliflozin on the cardiac structure and function of pre-heart failure patients with hypertension while delving deeply into the mechanisms through which it exerts its effects.

Detailed Description
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As a critical risk factor for heart failure, hypertension can induce left ventricular hypertrophy, decrease cardiac function, and ultimately lead to the development of heart failure. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been confirmed to reduce cardiovascular events and the risk of heart failure hospitalization in patients with diabetes and heart failure. They also exhibit beneficial effects, such as improving left ventricular structure, inhibiting myocardial fibrosis, anti-inflammatory properties, and promoting microcirculation improvement. However, whether SGLT2 inhibitors could provide myocardial protection in non-diabetic patients who have not yet developed heart failure remains uncertain. This study is a multicenter randomized controlled trial aiming to recruit pre-heart failure patients with hypertension without diabetes. These patients will be randomly allocated in a 1:1 ratio into the empagliflozin group (10 mg daily) or the placebo group, followed by a 6-month follow-up period. The study aims to investigate whether empagliflozin, under the precondition of well-controlled hypertension, could improve the cardiac structure and function of pre-heart failure patients, and explore the associated mechanisms based on the changes in biomarkers. The primary endpoint assessment will focus on the left atrial volume index, while the secondary endpoints will include parameters related to cardiac structure and function, as well as biomarkers detected from blood samples. These biomarkers encompass fibrosis indicators, inflammation markers, cardiac function indicators, and routine blood parameters. The objective of this study is to comprehensively evaluate the impact of empagliflozin on the cardiac structure and function of pre-heart failure patients with hypertension and delve into the underlying mechanisms of its function.

Official Title
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The Effects and Mechanism of SGLT2 Inhibitors in Stage B of Heart Failure With Hypertension

Conditions
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Heart Failure, Hypertension, Left Ventricle Remodeling, Left Atrial Dilatation

Intervention / Treatment
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* Drug: Empagliflozin 10 MG
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: • Meeting all the following criteria: Aged 40 and above. Hypertensive patients currently taking at least one antihypertensive medication as recommended by guidelines, and blood pressure is within the target range (<140/90 mmHg). B-type natriuretic peptide (BNP) levels between 35-280 pg/mL or N- terminal pro-B-type natriuretic peptide (NT-pro BNP) levels between 125-1000 pg/mL in the past 6 months. Left atrial volume index measured by echocardiography exceeding 34 mL/m² in the past 6 months. Signing an informed consent form. Exclusion Criteria: • Exclusion criteria include any of the following conditions: History of diabetes. History of heart failure. History of coronary artery disease. Left ventricular systolic dysfunction, defined as LVEF < 50%. Systolic blood pressure < 100 mmHg. Persistent atrial fibrillation. Severe valvular heart disease. Severe obstructive disease of the left ventricular outflow tract, including aortic valve stenosis. Genitourinary tract infection. Chronic kidney disease or estimated Glomerular Filtration Rate (eGFR) < 45 ml/min/1.73m². Alanine aminotransferase or aspartate aminotransferase levels > 3 times the upper limit of normal. Contraindications to taking SGLT2 inhibitors. Currently taking SGLT2 inhibitors, SGLT-1/2 inhibitors, or other antihyperglycemic medications (including metformin, glucagon-like peptide-1 receptor agonists, etc.). Pregnancy or planning pregnant, or currently breastfeeding. Malignant tumors or other severe illnesses with a life expectancy of less than 3 years. History of alcohol abuse or substance abuse within the past year. Mental disorders or communication barriers, cognitive impairments, or other severe illnesses that may affect participation in the study. Participation in or currently participating in other clinical trials within the last 3 months. Known poor compliance with study follow-up or study drug. Any condition or contraindication that makes a person intolerant to magnetic resonance imaging (MRI) or contraindicates MRI examination, such as the presence of implanted intracranial aneurysm clips, cardiac pacemakers or defibrillators, insulin pumps, etc.

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Empagliflozin<br> | Drug: Empagliflozin 10 MG<br>* Each participant in the empagliflozin treatment group takes a daily dose of 10mg.<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Each participant in the placebo group takes a daily dose of placebo 10mg.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of left atrial volume index | The change of left atrial volume index after 6 months treatment | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of cardiac structure and functional | Left ventricular functional parameters, such as Left Ventricular Ejection Fraction (%), and the ratio of early diastolic mitral valve flow velocity to mitral annular motion velocity (E/e' ratio in cm/s), were assessed. Global Longitudinal Strain (%) was calculated as (length of the myocardium at end-systole - length of the myocardium at end-diastole) / length of the myocardium at end-diastole) × 100. Left ventricular structural parameters, including Left Ventricular Mass (g) and Body Surface Area (m²), were combined to calculate the Left Ventricular Mass Index in g/m². Left atrial functional parameters, including Left Atrial Ejection Fraction (%), Left Atrial Volume (mL), and Body Surface Area (m²), were assessed using transthoracic echocardiography. The Left Atrial Volume Index was reported in mL/m². | 6 months | 
| Biomarkers | Biomarker concentrations were measured as follows: NT-pro BNP in picograms per milliliter (pg/mL). Cardiac Troponin I in nanograms per milliliter (ng/mL). Cardiac Fibrosis Biomarkers, including Matrix Metalloproteinases (MMP-2, MMP-3, MMP-4) in picograms per milliliter (pg/mL) and soluble ST2 protein (sST-2) in nanograms per milliliter (ng/mL). Inflammation Biomarkers, including High-sensitivity C-reactive protein (hs-CRP) in milligrams per liter (mg/L) and Interleukin-6 (IL-6), Interleukin-1β (IL-1β), and Galectin-3 (Gal-3) in picograms per milliliter (pg/mL). | 6 months | 
| Vascular Compliance | 24-hour ambulatory blood pressure monitoring. | 6 months | 
| Estimated Glomerular Filtration Rate (eGFR) | Change of eGFR | 6 months |