Effect of Dapagliflozin on Metabolomics and Cardiac Mechanics in Chronic Kidney Disease

This is a 6-month interventional patient-oriented research study of sixty patients with chronic kidney disease (CKD) and evidence of subclinical heart failure with preserved ejection fraction (HFpEF) (estimated glomerular filtration rate [eGFR] 25-60 ml/min/1.73m2, absolute left ventricular longitudinal strain [LVGLS] <18% or left atrial reservoir strain (LARS) < 25% on 2D-speckle tracking echocardiography or meeting 3/5 of the American Society of Echocardiography criteria for diastolic dysfunction: septal e' <7 cm/sec, lateral e'<10 cm/sec, average E/e' ratio>14, left atrial volume index >34 mL/m2, or peak tricuspid regurgitation velocity >2.8 m/sec), or peak VO2 Females: ≤ 18 mL/kg/min, peak VO2 Males: ≤ 20 mL/kg/min on cardiopulmonary exercise testing, or lack of augmentation of LVLS or LARS during exercise. Half of the patients will be randomized to receive dapagliflozin for six months as an add-on to standard of care (SOC). Metabolomic testing and cardiac and functional exercise testing will be done at baseline and at six months. The aim of the current study is to investigate whether SGLT2i-induced metabolomic changes are associated with improved cardiac and functional testing ascertained on 2D-speckle tracking echocardiography or cardiopulmonary functional testing at six months.

Inclusion criteria

• >18 years of age
• eGFR 25-60 ml/min/1,73m2 (eGFR = estimated glomerular filtration rate)
• On stable doses of diuretics and/or angiotensin converting enzyme inhibitor or angiotensin receptor blocker
• Evidence of subclinical heart failure with preserved ejection fraction at their pre-exercise echocardiogram (defined as meeting 3/5 of the American Society of Echocardiography (ASE) criteria for diastolic dysfunction [septal e'<7 cm/wc, average E/e' ratio>14, left atrial volume index >34 mL/m2, and peak TR velocity >2.8 m/sec] or absolute left ventricular longitudinal strain < 18%, left atrial reservoir strain (LARS) < 25% on 2d speckle tracking echocardiography), lack of augmentation of LVLS or LARS during exercise, or peak VO2 Females: ≤ 18 mL/kg/min, peak VO2 Males: ≤ 20 mL/kg/min on cardiopulmonary exercise testing.

Exclusion criteria

• presence or history of diabetes
• coronary revascularization within the last 6 months
• hemodynamically significant valvular disease
• significant lung disease requiring home oxygen
• angina (chest pain)
• non-revascularized myocardial ischemia
• systolic BP <100 or >180 mmHg
• pregnancy
• clinical heart failure symptoms
• history of systemic disease processes that can cause HFpEF such as amyloidosis or sarcoidosis
• any musculoskeletal or chronic condition that will interfere with completion of cardiac testing
• active cancer
• immunosuppressive therapy
• baseline or pre-exercise echocardiogram demonstrates a reduced ejection fraction < 50%
• currently on sodium glucose cotransporter 2 inhibitor (SGLT2i) therapy
• Hypersensitivity to a SGLT2i
• Pre-existing liver disease
• ALT/AST> 3x normal (ALT = alanine aminotransferase AST = aspartate aminotransferase)
• history of recurrent urinary tract infections (in the opinion of the investigator) or a urinary tract infection in the last 3 months