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

Study Overview
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Brief Summary
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The goal of this study is to better understand the effects of a sodium-glucose transport protein 2 inhibitor, dapagliflozin, added on to standard of care on heart and lung function and circulating metabolites (substances created when our bodies break down food, drugs, or its own tissues) in patients with chronic kidney disease.

Detailed Description
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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% on 2D-speckle tracking echocardiography or meeting any 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). 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.

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

Conditions
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Chronic Kidney Diseases, Heart Failure With Preserved Ejection Fraction, Kidney Diseases, Heart Failure

Intervention / Treatment
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* Drug: Dapagliflozin 10 MG [Farxiga]


Participation Criteria
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Eligibility Criteria
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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 any 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%) 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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
Interventional Model Description: 30 subjects will be randomized to intervention. 30 subjects will be randomized to standard of care.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention group<br>Thirty individuals will be randomized to dapagliflozin 10mg to be taken daily for six months. | Drug: Dapagliflozin 10 MG [Farxiga]<br>* 10mg (milligram) tablet to be taken orally once daily for 6 months. Manufacturer: Astrazeneca. Study drug will be stored and dispensed by the Interventional Drug Service Pharmacy at Northwestern University.<br>|
| No Intervention: Standard of Care group<br>Thirty individuals will be randomized to standard of care treatment. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Left ventricular longitudinal strain (LVLS) | 2D-speckle tracking echocardiography | 6 months | 
| Peak VO2 (oxygen consumption) | Cardiopulmonary exercise stress test | 6 months | 
| Circulating plasma metabolite concentrations | Plasma | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Left Atrial Reservoir Strain (LARS) | 2D-STE | 6 months | 
| Right ventricular free wall strain | 2D-STE | 6 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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kidney, heart failure, kidney diseases