Randomized Trial of SGLT2i in Heart Transplant Recipients

Randomized Trial of Sodium-glucose Cotransporter 2 Inhibition in Heart Transplant Recipients

Heart transplant (HTx) is an established therapy for advanced heart disease that restores quality of life and improves survival. However, due to preexisting comorbidities combined with the immunosuppressive therapies required after transplantation, HTx recipients remain at high risk for kidney, cardiovascular (CV), and metabolic disease. Large randomized clinical trials have recently shown that sodium-glucose cotransporter 2 inhibitors (SGLT2i) have potent kidney protective and CV benefits in many populations of patients with chronic kidney disease (CKD), CV disease and/or diabetes. SGLT2i have not been studied prospectively in HTx recipients, which represents a barrier to their use in this population.

In this multicenter randomized controlled trial in Veterans with HTx, investigators will evaluate the potential benefits of empagliflozin on kidney function, cardiometabolic risk, erythropoiesis, and functional status. A total of 200 Veterans will be randomly assigned to receive either empagliflozin 10 mg daily or a matching placebo for 12 months.

Study Overview

• Status: Recruiting
• Conditions: Cardiovascular Disease; Kidney Disease; Heart Transplant
• Intervention / Treatment: Drug: Empagliflozin; Drug: Placebo

Detailed Description

Heart transplant (HTx) markedly improves patient health-related quality of life (hrQoL) and survival in advanced heart failure (HF). However, HTx recipients remain at elevated risk for kidney and cardiovascular (CV) morbidity and mortality. Mitigating the negative effects of these morbidities on long-term survival and on patient hrQoL after HTx is a critical unmet need. Large clinical trials have recently shown that sodium glucose cotransporter 2 inhibitors (SGLT2i) have potent kidney protective and CV benefits. By preventing glucose reabsorption in the renal proximal tubule and promoting glycosuria, SGLT2i trigger multiple downstream effects, including improvement in insulin sensitivity and in mitochondrial efficiency in kidney and heart. SGLT2i also modulate sympathetic activity, improve endothelial function and reduce inflammation, with resultant improvement in myocardial and vascular function. SGLT2i increase erythropoietin levels and improve iron utilization. HTx is often complicated by development of chronic kidney disease (CKD), diabetes mellitus (T2D), anemia, and CV events, especially cardiac allograft vasculopathy (CAV). Although SGLT2i may significantly reduce development of these complications, prospective studies of SGLT2i did not include transplant recipients, leaving an important knowledge gap. HTx recipients could derive particularly significant benefits from SGLT2i therapy. The investigators hypothesize that SGLT2i with empagliflozin in HTx recipients will result in beneficial effects on kidney function, cardiometabolic risk, erythropoiesis and functional status, and that SGLT2i use in this population will be safe and well tolerated. The specific aims of this study are:

Specific Aim 1. Investigate the effects of SGLT2i with empagliflozin on kidney function in HTx recipients.

Kidney disease after HTx is a potent predictor of mortality. Investigators hypothesize that treatment with empagliflozin will preserve kidney function after HTx.

Aim 1a. Assess the effects of SGLT2i on urinary albumin-to-creatinine ratio (UACR). Albuminuria, represented by UACR and an independent predictor of kidney outcomes, was consistently reduced by SGLT2i in the landmark trials of SGLT2i. Approximately 50% of Veterans after HTx have at least moderate albuminuria. Investigators hypothesize that empagliflozin therapy will decrease albuminuria in HTx recipients.

Aim 1b. Assess the effect of SGLT2i on estimated glomerular filtration rate (eGFR).

SGLT2i therapy was associated with significantly slower decline of eGFR in all SGLT2i clinical trials of CKD. Investigators hypothesize that empagliflozin treatment will result in an improvement of eGFR slope in HTx recipients.

Specific Aim 2. Establish the safety and tolerability of SGLT2i therapy in HTx recipients.

SGLT2i have been tested prospectively in >75,000 patients and demonstrated a favorable safety profile. Exclusion of organ transplant recipients from these trials resulted in an important knowledge gap-the lack of safety and tolerability data in this population, which limits clinicians' use of SGLT2i in HTx recipients. Investigators hypothesize that treatment with empagliflozin in HTx recipients will be associated with favorable safety and tolerability.

Specific Aim 3. Evaluate the cardiometabolic, erythropoietic and functional effects of SGLT2i after HTx.

Cardiometabolic risks in HTx recipients contribute to CAV, graft failure, functional limitations and mortality. Investigators hypothesize that empagliflozin therapy will result in favorable cardiometabolic, erythropoietic and functional effects.

Aim 3a. Assess the effects of SGLT2i on markers of cardiometabolic risk.

Investigators will examine the effect of empagliflozin on hemoglobin A1c (HbA1c), body weight and blood pressure (BP), inflammation and on cardiac allograft health assessed through cardiac imaging and cardiac biomarkers. Investigators hypothesize that empagliflozin therapy will result in favorable cardiometabolic effects.

Aim 3b. Assess the effects of SGLT2i on erythropoiesis.

SGLT2i stimulates erythropoiesis, but the exact mechanisms are not well understood. Investigators hypothesize that empagliflozin will result in an increase in serum erythropoietin and amelioration of anemia in HTx recipients.

Aim 3c. Assess the effects of SGLT2i on functional status and health-related quality of life.

SGLT2i have improved functional status and hrQoL in non-transplant populations. Investigators hypothesize that the favorable kidney, cardiometabolic and erythropoietic effects of empagliflozin after HTx will result in a corresponding increase in six-minute walk test (6MWT) and hrQoL after transplant.

• Study Type: Interventional
• Enrollment (Estimated): 200
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Heather Hanson, AAS BS; Phone Number: 4543 (801) 582-1565; Email: Heather.Hanson@va.gov
• Study Contact Backup: Name: Josef Stehlik, MD MPH; Phone Number: 4543 (801) 582-1565; Email: josef.stehlik@va.gov

Study Locations

• United States
  • California
    • Palo Alto, California, United States, 94304-1207
      • Not yet recruiting
      • VA Palo Alto Health Care System, Palo Alto, CA
      • Contact: Karim Sallam, MD; Phone Number: 61848 650-493-5000; Email: Karim.Sallam@va.gov
  • Tennessee
    • Nashville, Tennessee, United States, 37212-2637
      • Not yet recruiting
      • Tennessee Valley Healthcare System Nashville Campus, Nashville, TN
      • Contact: Henry Ooi, MD; Phone Number: 615-327-4751; Email: henry.ooi@va.gov
  • Texas
    • Houston, Texas, United States, 77030-4211
      • Not yet recruiting
      • Michael E. DeBakey VA Medical Center, Houston, TX
      • Contact: Savitri E Fedson, MD; Phone Number: 713-791-1414; Email: savitri.fedson@va.gov
  • Utah
    • Salt Lake City, Utah, United States, 84148-0001
      • Recruiting
      • VA Salt Lake City Health Care System, Salt Lake City, UT
      • Principal Investigator: Josef Stehlik, MD MPH
      • Contact: Heather Hanson, AAS BS; Phone Number: 4543 801-582-1565; Email: Heather.Hanson@va.gov
  • Virginia
    • Richmond, Virginia, United States, 23249-0001
      • Not yet recruiting
      • Hunter Holmes McGuire VA Medical Center, Richmond, VA
      • Contact: Neil Lewis, MD; Phone Number: 804-675-5000; Email: neil.lewis@va.gov
  • Wisconsin
    • Madison, Wisconsin, United States, 53705-2254
      • Not yet recruiting
      • William S. Middleton Memorial Veterans Hospital, Madison, WI
      • Contact: David R Murray, MD; Phone Number: 608-256-1901; Email: david.murray@va.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age 18 years or older
2. Heart transplant recipient, 3 months after transplant

Exclusion Criteria:

1. eGFR <20 mL/min/1.73m2
2. Type 1 diabetes mellitus
3. HbA1C >10%
4. Baseline UACR <30 mg/g in patients without T2D
5. Known allergy or intolerance to SGLT2i
6. Active uncontrolled infection
7. Multiorgan transplant
8. SGLT2i treatment in the last 30 days
9. Pregnancy, breast-feeding or woman of child-bearing age not on birth control

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Empagliflozin; A starting dose of empagliflozin 10 mg or matching placebo will be initiated after randomization and completion of the baseline testing. Participating subjects will remain at this dose for the whole study duration of 12 months.	Drug: Empagliflozin; A starting dose of empagliflozin 10 mg or matching placebo will be initiated after randomization and completion of the baseline testing. Participating subjects will remain at this dose for the whole study duration of 12 months.; Other Names: Jardiance
Placebo Comparator: Placebo; A starting dose of empagliflozin 10 mg or matching placebo will be initiated after randomization and completion of the baseline testing. Participating subjects will remain at this dose for the whole study duration of 12 months.	Drug: Placebo; A starting dose of empagliflozin 10 mg or matching placebo will be initiated after randomization and completion of the baseline testing. Participating subjects will remain at this dose for the whole study duration of 12 months.; Other Names: Control Group

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Urinary albumin-to-creatinine ratio (UACR)	UACR difference (mg/g) in subjects in active arm vs control arm	12 months
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]	Adverse and serious adverse events difference in active arm vs control arm	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Estimated Glomerular Filtration Rate (eGFR)	eGFR difference (mL/min/1.73m2) in subjects in active arm vs control arm	12 months
Hemoglobin A1c (HbA1c)	HbA1c difference (%) in subjects in active arm vs control arm	12 months
Fasting blood glucose	Fasting blood glucose difference (mg/dL) in subjects in active arm vs control arm	12 months
Body weight	Body weight difference (kg) in subjects in active arm vs control arm	12 months
Systolic and diastolic blood pressure	Systolic and diastolic blood pressure difference (mmHg) in subjects in active arm vs control arm	12 months
Serum high sensitivity C-reactive protein (hsCRP)	Serum hsCRP difference (mg/L) in subjects in active arm vs control arm	12 months
Serum N-Terminal Pro-B-Type Natriuretic Peptide (NTproBNP)	Serum NTproBNP difference (pg/mL) in subjects in active arm vs control arm	12 months
Hemoglobin	Hemoglobin difference (g/dl) in subjects in active arm vs control arm	12 months
Serum erythropoietin	Serum erythropoietin difference (mU/mL) in active arm vs control arm	12 months
Hematocrit	Hematocrit difference (%) in active arm vs control arm	12 months
Serum transferrin saturation	Serum transferrin saturation difference (%) in active arm vs control arm	12 months
Six Minute Walk Test	Difference in distance (m) covered in the 6 minute walk test in active arm vs control arm	12 months
Serum high sensitivity Troponin	Serum high sensitivity Troponin difference (pg/mL) in subjects in active arm vs control arm	12 months
Kansas City Cardiomyopathy Questionnaire-12	Kansas City Cardiomyopathy Questionnaire-12 overall summary score difference in active arm vs control arm. Scale range 0-100. Higher result is better.	12 months
Serum tumor necrosis factor -a (TNF-a)	TNF-a difference (pg/mL) in subjects in active arm vs control arm	12 months
Serum interleukin 6 (IL-6)	IL-6 difference (pg/mL) in subjects in active arm vs control arm	12 months
Serum interleukin 1b(IL-1b)	IL-1b difference (pg/mL) in subjects in active arm vs control arm	12 months

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Investigators: Principal Investigator: Josef Stehlik, MD MPH, VA Salt Lake City Health Care System, Salt Lake City, UT

Study record dates

Study Major Dates

• Study Start (Actual): January 20, 2026
• Primary Completion (Estimated): August 31, 2029
• Study Completion (Estimated): February 28, 2030

Study Registration Dates

• First Submitted: September 23, 2024
• First Submitted That Met QC Criteria: September 30, 2024
• First Posted (Actual): October 3, 2024

Study Record Updates

• Last Update Posted (Actual): January 22, 2026
• Last Update Submitted That Met QC Criteria: January 21, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Quality of Life; Empagliflozin; Safety and Tolerability; Heart Transplant; Functional Status; Erythropoiesis; Cardiometabolic Outcomes; Kidney Outcomes
• Additional Relevant MeSH Terms: Urogenital Diseases; Male Urogenital Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Cardiovascular Diseases; Kidney Diseases; Investigative Techniques; Epidemiologic Research Design; Epidemiologic Methods; Research Design; Methods; Control Groups; empagliflozin
• Other Study ID Numbers: NEPH-004-24S

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