Effects of Enavogliflozin on Coronary Microvascular and Cardiac Function in Obesity

In recent years, the prevalence of obesity has increased, which acts as a significant risk factor for cardiovascular diseases. Obesity is closely related to reduced microvascular function, increased insulin resistance, and elevated blood pressure, and it is particularly known to be a major cause of heart failure with preserved ejection fraction (HFpEF) and diastolic dysfunction. Coronary microvascular dysfunction (CMD) leads to angina, myocardial infarction, and heart failure, which are associated with increased mortality. CMD has recently gained more importance as one of the key mechanisms of HFpEF. However, CMD often shows poor response to standard treatments, and when not recognized by healthcare providers, it can result in poor outcomes due to a lack of appropriate treatment.

Sodium-Glucose Cotransporter 2 (SGLT2) inhibitors are drugs that inhibit glucose reabsorption by blocking SGLT2 in the proximal tubules of the kidneys, thereby lowering blood sugar. Initially developed as oral hypoglycemic agents, previous randomized controlled studies have shown that they also have significant beneficial effects on heart failure and cardiovascular diseases not only in diabetic patients but also in non-diabetic patients. Recent studies have also demonstrated the effectiveness of SGLT2 inhibitors in patients with HFpEF. SGLT2 inhibitors reduce excessive sodium excretion through urine, which reduces fluid volume, lowers blood pressure, and decreases body weight, but the exact mechanism of their significant effects in cardiovascular diseases is still not fully understood. In particular, research on the effects of SGLT2 inhibitors on microvascular function is still limited. Recently, a randomized controlled study involving 16 diabetic patients reported an increase in myocardial flow reserve after 4 weeks of dapagliflozin administration, while another study involving 90 high-risk cardiovascular diabetic patients showed no significant change in myocardial flow reserve at 13 weeks with empagliflozin. Regarding enavogliflozin, a recent animal study in pigs suggested that it could improve vascular function by intervening in coronary endothelial cell function.

This study hypothesized that enavogliflozin would improve microvascular abnormalities and enhance heart function and cardiopulmonary exercise capacity in obesity-related cardiovascular diseases. Therefore, the objective of this study is to analyze the effects of enavogliflozin on heart function and microvascular function in obese patients compared to a placebo, and to evaluate the improvement in cardiopulmonary exercise capacity in these patients.

Inclusion criteria

The following criteria must be met for inclusion in the study:

• Obesity or Abdominal Obesity:

Body Mass Index (BMI) ≥ 25 kg/m², or Waist circumference: Male ≥ 90 cm, Female ≥ 85 cm.

• Diabetes:

Hemoglobin A1c ≥ 6.5%, or Fasting blood glucose ≥ 126 mg/dL after 8 hours of fasting, or Currently on antidiabetic medication. Blood test results must be within 3 months prior to enrollment.

Other inclusion criteria:

Age between 20 and 79 years. Patients who have undergone coronary flow velocity reserve testing. For baseline echocardiography, left ventricular diastolic dysfunction will be evaluated structurally (LV dimension, LV mass index, LA size) and hemodynamically (Doppler data, left ventricular ejection fraction, strain data).

Exclusion criteria

• Left ventricular ejection fraction (LVEF) < 50%
• History of coronary artery disease, or patients who have undergone coronary artery intervention or coronary artery bypass grafting.
• Patients with suspected obstructive coronary artery disease, including those with chest pain and positive stress test results (e.g., exercise treadmill test, dobutamine stress echocardiography, myocardial perfusion imaging).
• Second-degree or higher atrioventricular block, symptomatic bradycardia, sick sinus syndrome, or Wolff-Parkinson-White syndrome.
• Chronic kidney disease (GFR < 30 mL/min/1.73 m²) or end-stage renal disease on hemodialysis or peritoneal dialysis.
• Asthma, chronic obstructive pulmonary disease, or primary pulmonary hypertension.
• Moderate or severe valvular heart disease or congenital heart disease, or patients with a history of open-heart surgery.
• Active cancer within the last 5 years, or patients currently receiving chemotherapy.
• Vasculitis associated with autoimmune diseases, such as systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA).
• Patients who cannot undergo exercise testing, such as treadmill or bicycle ergometer testing.
• Use of any other SGLT2 inhibitors (e.g., dapagliflozin, empagliflozin) within the past 6 months, or a known allergy to these drugs.
• Pregnant or breastfeeding women.
• Women planning pregnancy during the study period (or within 24 weeks from the start of the study, including the 12-week observation period).
• Acute urinary tract infection at the time of enrollment.