Ertugliflozin in Chronic Heart Failure

This is a randomized placebo controlled mechanistic study to understand the utility of ertugliflozin in heart failure patients with or without diabetes, compared to both placebo and the active control metolazone. The broad study design will be designed around evaluation of change in gold standard determined body fluid spaces (blood volume, extracellular fluid, total body water), administering a sodium chloride challenge, and collecting the necessary biospecimens to test our hypotheses. The general study design will randomize to ertugliflozin vs. placebo for a total therapy of 6 weeks.

• Ertugliflozin (Drug): Participants will be randomized to six weeks of treatment with either ertugliflozin, metolazone, or a placebo
• Metolazone (Drug): Participants will be randomized to six weeks of treatment with either ertugliflozin, metolazone, or a placebo
• Placebo (Drug): Participants will be randomized to six weeks of treatment with either ertugliflozin, metolazone, or a placebo

Primary outcomes

• Change from baseline to day 7 of plasma volume by add-on to loop diuretic therapy [7 days]: The primary outcome of the chronic effects of add-on placebo, thiazide-like diuretic, or SGLT2 inhibitor is to determine the change in plasma volume from baseline to day 7
• Change from baseline to 6 weeks of plasma volume by add-on to loop diuretic therapy [6 weeks]: The primary outcome of the chronic effects of add-on placebo, thiazide-like diuretic, or SGLT2 inhibitor is to determine the change in plasma volume from baseline to 6 weeks
• Natriuretic effect of adjuvant to loop diuretic therapy [1 day]: The natriuretic effect of each arm with loop diuretic therapy will be measured by the urine sodium output and FeNa.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. A clinical diagnosis of chronic heart failure (either systolic or diastolic)
2. Chronic daily oral loop diuretic dose use
3. eGFR ≥20 mL/min/1.73 m2
4. English speaking participants only
5. Signed informed consent

Exclusion Criteria:

1. Current use or plan to initiate renal replacement therapy or ultrafiltration
2. Significant bladder dysfunction or urinary incontinence
3. Inability to comply with the serial urine collection procedures
4. Current use of a thiazide or thiazide like diuretics or use within 5 half-lives of the drug, including metolazone
5. Current use of a SGLT-2 inhibitor, or in the treating provider's judgement, contraindication to be withdrawn from current use of an SGLT-2 inhibitor
6. Prior heart transplant, critical stenotic valvular disease or complex congenital heart
7. 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 3 months
8. History of or current urosepsis or frequent urinary tract infections
9. Anemia with hemoglobin <8g/dL (due to required phlebotomy for the study)
10. Pregnancy or breastfeeding
11. 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)
12. Inability to give written informed consent or follow study protocol
13. Severe peripheral artery disease, previous amputation, or threatened amputation
14. Life expectancy < 3 months

• Jeffrey Testani, MD, Principal investigator, Yale University