This is a 60-patient randomized, double-blind, placebo-controlled mechanistic study to understand the utility of empagliflozin in worsening heart failure (HF) patients with or without diabetes. Participants will be randomized to empagliflozin or placebo for 6 weeks, followed by a crossover of placebo patients to active therapy at 6 weeks-12 weeks.

This is a 60-patient randomized, double-blind, placebo-controlled mechanistic study to understand the utility of empagliflozin in worsening heart failure (HF) patients with or without diabetes.

The broad study design aims to evaluate change in gold standard determined body fluid spaces, sodium avidity, and cardio-renal biomarkers longitudinally in patients treated with placebo vs. empagliflozin over a 6 week period. Primary analysis of the randomized intervention will occur during the 6 week double blind period. Crossover of placebo patients to active therapy from 6-12 weeks will provide additional exploratory mechanistic data at low incremental cost and provide added benefit to enrollment of the study.

Inclusion Criteria:

• A clinical diagnosis of worsening heart failure (worsening of congestive symptoms with current therapies) in the opinion of the investigator.
• A planned outpatient diuretic intervention (either up-titration of loop or addition of thiazide diuretic) for worsening heart failure per treating clinician. Diuretic intervention can occur via an unplanned in person visit (e.g., outpatient ambulatory clinic, emergency department, same day access visit) or via a telephone encounter (e.g., patient calling the clinic with reported weight gain and SOB that is prescribed uptitration of diuretic therapy).
• Estimated or reported weight gain of at least 5 lbs.
• Chronic daily oral loop diuretic dose ≥ 20mg furosemide equivalents for at least one month prior to enrollment
• Estimated GFR (eGFR) ≥ 20 mL/min/1.73 m2
• Age ≥ 18 years old
• Signed informed consent
• English speaking participants only

Exclusion Criteria:

• Need for heart failure hospitalization at the time of randomization
• Current use or plan to initiate renal replacement therapy
• Significant bladder dysfunction or urinary incontinence
• Inability to comply with the serial urine collection procedures
• Chronic use of natriuretic doses of thiazide diuretics (≥50mg hydrochlorothiazide or equivalent)
• Critical stenotic valvular disease, complex congenital heart disease or prior heart transplant
• History of type 1 diabetes, diabetic ketoacidosis, "brittle" diabetes 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 or current urosepsis or frequent urinary tract infections
• Anemia with hemoglobin <8g/dL (due to required phlebotomy for the study) or active bleeding
• Pregnancy or breastfeeding
• Appears unlikely or unable to participate in the required study procedures, as assessed by the study PI, study coordinator, or designee (ex: clinically-significant psychiatric, addictive, or neurological disease)

Double-blind