Empagliflozin in Heart Failure: Diuretic and Cardio-Renal Effects

Study Overview
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Brief Summary
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The investigators propose a small pilot proof of concept study to not only prove the existence of, but also probe the mechanisms underlying cardio-renal effects of empagliflozin in patients with heart failure. The investigators propose a 50 patient randomized, double-blind, placebo-controlled crossover study with patients with stable HF, type II diabetes and an eGFR >45ml/min/1.73 m2 who are chronically receiving loop diuretics.

Detailed Description
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Study Objectives Study the acute/short term effect and cardio-renal mechanisms of sodium-glucose cotransporter 2 (SGLT2) inhibition in patients with heart failure. Determine the effect of chronic combined SLLGT2 and loop diuretic exposure in patients with heart failure. Primary Outcomes Aim 1 (Acute): Determine if acute SGLT2 inhibition will improve the natriuretic effect of a loop diuretic compared to placebo. Aim 2 (Chronic): Determine the effect of 14 days of SGLT2 inhibition on blood volume.

Official Title
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Empagliflozin in Heart Failure: Diuretic and Cardio-Renal Effects

Conditions
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Heart Failure, Type II; Diabetes

Intervention / Treatment
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* Drug: Empagliflozin
* Drug: Placebo Oral Capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Stable HF as defined by: No hospitalization for >60 days Stable HF medications for >=2 weeks, and stable diuretics for 4 weeks Opinion of HF cardiologist that the patient is at their optimal volume status Chronic daily oral loop diuretic dose >=20mg furosemide equivalents Diagnosis of type II diabetes Patient monitors blood glucose regularly at home eGFR >=45 mL/min/1.73 m2 >=18 years old Exclusion Criteria: Active titration of chronic HF medications expected during the study period Use of a non-loop diuretic, aside from an aldosterone antagonist (<=25mg spironolactone or <=50mg eplerenone) Critical stenotic valvular disease, complex congenital heart disease, or prior heart transplant History of diabetic ketoacidosis, brittle diabetes, and/or frequent hypoglycemia or severe hypoglycemic episodes requiring emergent intervention (ER visit or EMS response, glucagon administration or forced oral carbs) in the last 6 months History of bladder dysfunction, incontinence, pyelonephritis, urosepsis, or frequent urinary tract infections Anemia (defined as hemoglobin <8g/dL) Pregnancy or breastfeeding History of serious hypersensitivity Participation in another trial with an investigational drug within the 30 days prior to informed consent Use of another SGLT-2 inhibitor Appears unlikely, or unable to participate in the required study procedures, as assessed by the study PI or research RN (ex: clinically-significant psychiatric, addictive, or neurological disease) Inability to give written informed consent or follow study protocol

Ages Eligible for Study
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Minimum Age: 18 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: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Placebo, then empagliflozin<br>Patients are randomized upon enrollment to determine whether they take empagliflozin or the matched placebo during the first 2-week treatment phase of the study. All patients then undergo a 2-week washout period before crossing over to the alternate therapy. | Drug: Empagliflozin<br>* 10mg empagliflozin for a 2-week period<br>Drug: Placebo Oral Capsule<br>* 10 mg placebo for a 2-week period<br>|
| Experimental: Empagliflozin, then Placebo<br>Patients are randomized upon enrollment to determine whether they take empagliflozin or the matched placebo during the first 2-week treatment phase of the study. All patients then undergo a 2-week washout period before crossing over to the alternate therapy. | Drug: Empagliflozin<br>* 10mg empagliflozin for a 2-week period<br>Drug: Placebo Oral Capsule<br>* 10 mg placebo for a 2-week period<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| urine sodium concentrations via ion selective electrodes | Determine if acute SGLT2 inhibition will improve the natriuretic effect of a loop diuretic compared to placebo. Measuring the natriuretic effect of a loop diuretic (placebo v acute SGLT2 inhibition) via urine sodium output. | 36 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| blood volume | Determine the effect of 14 days of SGLT2 inhibition on blood volume. Daxor Blood Volume Sample Collection Volumex Injection: The Volumex tracer (radiolabeled albumin) is injected as an intravenous bolus (IV-push). (As soon as the tracer injection begins, a stopwatch is started and never zeroed out. Running times are used for the entire procedure). Serial Blood Collection A series of 5 post-Volumex blood samples is collected, after tracer injection, allowing for complete mixing in the bloodstream. Sample Timing: Samples are ideally spaced  6 minutes apart, and are collected approximately 12, 18, 24, 30 and 36 minutes after Volumex administration. | 14 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cardio-renal