Empagliflozin in Heart Failure: Diuretic and Cardio-Renal Effects (EMPA)

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.

Study Overview

• Status: Completed
• Conditions: Heart Failure; Type II; Diabetes
• Intervention / Treatment: Drug: Empagliflozin; Drug: Placebo Oral Capsule

Detailed Description

Study Objectives

1. Study the acute/short term effect and cardio-renal mechanisms of sodium-glucose cotransporter 2 (SGLT2) inhibition in patients with heart failure.
2. Determine the effect of chronic combined SLLGT2 and loop diuretic exposure in patients with heart failure.

Primary Outcomes

1. Aim 1 (Acute): Determine if acute SGLT2 inhibition will improve the natriuretic effect of a loop diuretic compared to placebo.
2. Aim 2 (Chronic): Determine the effect of 14 days of SGLT2 inhibition on blood volume.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06511
      • Yale New Haven Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Placebo, then empagliflozin; 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; 10mg empagliflozin for a 2-week period; Drug: Placebo Oral Capsule; 10 mg placebo for a 2-week period
EXPERIMENTAL: Empagliflozin, then Placebo; 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; 10mg empagliflozin for a 2-week period; Drug: Placebo Oral Capsule; 10 mg placebo for a 2-week period

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: Boehringer Ingelheim

Publications and helpful links

General Publications

• Griffin M, Rao VS, Ivey-Miranda J, Fleming J, Mahoney D, Maulion C, Suda N, Siwakoti K, Ahmad T, Jacoby D, Riello R, Bellumkonda L, Cox Z, Collins S, Jeon S, Turner JM, Wilson FP, Butler J, Inzucchi SE, Testani JM. Empagliflozin in Heart Failure: Diuretic and Cardiorenal Effects. Circulation. 2020 Sep 15;142(11):1028-1039. doi: 10.1161/CIRCULATIONAHA.120.045691. Epub 2020 May 15.

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 27, 2017
• Primary Completion (ACTUAL): May 14, 2019
• Study Completion (ACTUAL): June 1, 2019

Study Registration Dates

• First Submitted: January 17, 2017
• First Submitted That Met QC Criteria: January 17, 2017
• First Posted (ESTIMATE): January 23, 2017

Study Record Updates

• Last Update Posted (ACTUAL): June 26, 2020
• Last Update Submitted That Met QC Criteria: June 24, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: cardio-renal
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Heart Failure; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Empagliflozin
• Other Study ID Numbers: 2000020019

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No