SGLT2 INHIBITION FOR CARDIOVASCULAR ENDPOINT REDUCTION IN HYPERTENSION

The primary objective of this trial is to assess whether the addition of a sodium-glucose co-transporter 2 inhibitor (SGLT2i) to standard antihypertensive treatment confers a reduction in major adverse cardiovascular and renal events. This objective addresses the clinical need to determine if SGLT2 inhibition provides additional cardio-renal protection beyond conventional blood pressure management in patients with arterial hypertension. The trial evaluates dapagliflozin 10 mg administered orally compared to placebo, with treatment duration extending up to 78 months. The clinical relevance lies in potentially establishing a novel therapeutic strategy for reducing cardiovascular and renal morbidity in the hypertensive population through dual mechanisms of blood pressure reduction and metabolic benefit.

This clinical trial enrolled a total of **50 participants** diagnosed with **arterial hypertension**. The study population consisted of both **male and female subjects** aged **60 years and older**, including individuals in the **adult** and **elderly** age categories. Participants were selected based on specific blood pressure criteria, requiring either newly diagnosed hypertension with systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg measured on different days, or existing hypertension diagnosis confirmed at screening. Eligible participants were required to have either a documented history of at least one **cardiovascular event** such as **myocardial infarction**, **stroke**, stable angina, clinical evidence of **coronary heart disease**, **peripheral arterial disease**, or **transient ischemic attack**, with the exclusion of recent myocardial infarction or stroke within the preceding three months. Alternatively, participants could qualify through the presence of at least one **cardiovascular risk factor**, including current smoking of more than one cigarette per day for at least one year, elevated **LDL-cholesterol** levels ≥4.0 mmol/L, age ≥75 years, **ESC HeartScore** ≥15%, **BMI** ≥32 kg/m², or reduced **eGFR** ≤60 mL/min/1.73m² as estimated by the CKD-EPICr 2021 formula. The trial population represented patients with hypertension and established cardiovascular disease or significant cardiovascular risk factors.

This clinical trial investigates the addition of a sodium-glucose co-transporter 2 inhibitor (SGLT2i) to standard antihypertensive treatment for the reduction of major adverse cardiovascular and renal events in patients with arterial hypertension. The study is designed as a randomized, double-blind, placebo-controlled Phase 3 trial. The investigational medicinal product is dapagliflozin administered as a 10 mg film-coated tablet via the oral route, with a maximum daily dose of 10 mg. The control group receives a matching placebo. The maximum treatment period is 78 weeks. The overall trial duration extends from the estimated recruitment start date in December 2025 to the estimated end date in December 2033.

Eligible participants must be at least 60 years of age with documented hypertension, defined as systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg. Participants must have either a history of at least one cardiovascular event (excluding myocardial infarction or stroke within the preceding 3 months) such as myocardial infarction, stroke, stable angina, clinical evidence of coronary heart disease, peripheral arterial disease, or transient ischemic attack, or the presence of at least one cardiovascular risk factor including current smoking, elevated LDL-cholesterol ≥4.0 mmol/L, age ≥75 years, ESC HeartScore ≥15%, body mass index (BMI) ≥32 kg/m², or estimated glomerular filtration rate (eGFR) ≤60 mL/min/1.73m² as estimated by the CKD-EPICr 2021 formula.

The primary endpoint is the time until first occurrence of a composite outcome comprising non-fatal stroke, non-fatal myocardial infarction, revascularisation procedures for atherosclerotic disease, hospitalisation or emergency department visit for heart failure (HF), unplanned hospitalisation for new-onset atrial fibrillation (AF), new-onset atrial flutter (AFL) or ventricular arrhythmia, sustained decline in eGFR of at least 50%, end-stage kidney disease defined as eGFR <15 mL/min/1.73m² or requiring chronic dialysis or renal transplantation, and death from renal or cardiovascular causes. Secondary endpoints include individual components of the primary composite outcome, all-cause mortality, rate of decline in eGFR at 8 weeks and 48 months, changes in systolic and diastolic blood pressure at 8 weeks, 12 months and 48 months, composite of primary endpoint or death from any cause, development of type 2 diabetes, time to coronary revascularization procedure, improvement in quality of life assessed by EQ VAS Score and HeartQoL Global Score, decline of cognition measured by MoCA Test Score, increase of blood markers of neurodegeneration (Ptau 217, Nfl), and frailty assessment at baseline, 12 months, 24 months, and 48 months.

The study involves a screening visit for eligibility assessment and enrollment. Follow-up visits are scheduled at 8 weeks, 12 months, 24 months, and 48 months to evaluate efficacy and safety parameters, including blood pressure measurements, eGFR estimation, quality of life assessments, cognitive function testing, and biomarker analysis. An end-of-study visit is conducted at 48 months or upon early termination. The expected length of participant involvement is approximately 48 months from randomization to study completion. Early termination from the study may occur due to occurrence of primary endpoint events, development of unacceptable adverse events, withdrawal of consent, investigator decision, loss to follow-up, or protocol violations that compromise participant safety or data integrity.

The experimental medication utilized in this clinical trial is **dapagliflozin**, a **sodium-glucose co-transporter 2 inhibitor** (SGLT2i). The investigational medicinal product is supplied as Dapagliflozin Ascend 10 mg **film-coated tablets**, manufactured by Ascend GmbH. The active substance is dapagliflozin, which is of chemical origin. The pharmaceutical formulation is administered via the **oral route**. The dosage regimen consists of **10 mg** administered once daily, corresponding to a maximum daily dose of 10 mg and a maximum total dose of 10 mg per administration. The maximum treatment period for dapagliflozin administration is **78 weeks**. The medication is added to standard antihypertensive treatment as part of the therapeutic intervention being evaluated for its efficacy in reducing major adverse **cardiovascular** and **renal** events in participants with **hypertension**.

A matched **placebo** for dapagliflozin is employed as the comparator treatment in this clinical trial. The placebo is designed to be indistinguishable from the active dapagliflozin formulation to maintain blinding integrity throughout the study. The placebo does not contain any active pharmaceutical ingredients and serves as the control intervention against which the efficacy and safety of dapagliflozin are assessed. Participants randomized to the placebo group receive the comparator treatment in addition to their standard antihypertensive therapy, following the same administration schedule as those receiving the active investigational medicinal product.

Efficacy will be assessed through a primary composite endpoint measuring the time until first occurrence of several major adverse cardiovascular and renal events. These events include non-fatal stroke, non-fatal myocardial infarction, revascularisation procedures for atherosclerotic disease, hospitalisation or emergency department visit for heart failure, unplanned hospitalisation for new-onset atrial fibrillation, new-onset atrial flutter or ventricular arrhythmia, sustained decline in the estimated glomerular filtration rate of at least 50% (estimated by CKD-EPICr 2021 formula), end-stage kidney disease defined as eGFR less than 15 mL/min/1.73m2 or requiring chronic dialysis or renal transplantation, and death from renal or cardiovascular causes.

Secondary efficacy parameters include the individual components of the primary composite outcome, all-cause mortality, rate of decline in the eGFR estimated by CKD-EPICr 2021 formula at 8 weeks and 48 months, change in systolic blood pressure at 8 weeks, 12 months and 48 months, change in diastolic blood pressure at 8 weeks, 12 months and 48 months, composite of primary endpoint or death from any cause, development of type 2 diabetes, and time to coronary revascularization procedure. Additional secondary endpoints include improvement in quality of life assessed through the area-under-the-curve of EQ VAS Score and HeartQoL Global Score changes at baseline, 12 months, 24 months, and 48 months, decline of cognition measured by MoCA Test Score at baseline, 12 months, 24 months, and 48 months, increase of blood markers of neurodegeneration including Ptau 217 and Nfl at baseline, 12 months, 24 months, and 48 months, and frailty assessed at baseline, 12 months, 24 months, and 48 months.