Randomized Trial of SGLT2i in Heart Transplant Recipients
- Conditions
- Heart TransplantCardiovascular DiseaseKidney Disease
- Interventions
- Drug: Placebo
- Registration Number
- NCT06625073
- Lead Sponsor
- VA Office of Research and Development
- Brief Summary
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.
- 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.
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 200
- Age 18 years or older
- Heart transplant recipient, 3 months after transplant
- eGFR <20 mL/min/1.73m2
- Type 1 diabetes mellitus
- HbA1C >10%
- Baseline UACR <30 mg/g in patients without T2D
- Known allergy or intolerance to SGLT2i
- Active uncontrolled infection
- Multiorgan transplant
- SGLT2i treatment in the last 30 days
- Pregnancy, breast-feeding or woman of child-bearing age not on birth control
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Empagliflozin 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. Placebo 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.
- Primary Outcome Measures
Name Time Method Urinary albumin-to-creatinine ratio (UACR) 12 months UACR difference (mg/g) in subjects in active arm vs control arm
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] 12 months Adverse and serious adverse events difference in active arm vs control arm
- Secondary Outcome Measures
Name Time Method Estimated Glomerular Filtration Rate (eGFR) 12 months eGFR difference (mL/min/1.73m2) in subjects in active arm vs control arm
Hemoglobin A1c (HbA1c) 12 months HbA1c difference (%) in subjects in active arm vs control arm
Fasting blood glucose 12 months Fasting blood glucose difference (mg/dL) in subjects in active arm vs control arm
Body weight 12 months Body weight difference (kg) in subjects in active arm vs control arm
Systolic and diastolic blood pressure 12 months Systolic and diastolic blood pressure difference (mmHg) in subjects in active arm vs control arm
Serum high sensitivity C-reactive protein (hsCRP) 12 months Serum hsCRP difference (mg/L) in subjects in active arm vs control arm
Serum N-Terminal Pro-B-Type Natriuretic Peptide (NTproBNP) 12 months Serum NTproBNP difference (pg/mL) in subjects in active arm vs control arm
Hemoglobin 12 months Hemoglobin difference (g/dl) in subjects in active arm vs control arm
Serum erythropoietin 12 months Serum erythropoietin difference (mU/mL) in active arm vs control arm
Hematocrit 12 months Hematocrit difference (%) in active arm vs control arm
Serum transferrin saturation 12 months Serum transferrin saturation difference (%) in active arm vs control arm
Six Minute Walk Test 12 months Difference in distance (m) covered in the 6 minute walk test in active arm vs control arm
Serum high sensitivity Troponin 12 months Serum high sensitivity Troponin difference (pg/mL) in subjects in active arm vs control arm
Kansas City Cardiomyopathy Questionnaire-12 12 months Kansas City Cardiomyopathy Questionnaire-12 overall summary score difference in active arm vs control arm. Scale range 0-100. Higher result is better.
Serum tumor necrosis factor -a (TNF-a) 12 months TNF-a difference (pg/mL) in subjects in active arm vs control arm
Serum interleukin 6 (IL-6) 12 months IL-6 difference (pg/mL) in subjects in active arm vs control arm
Serum interleukin 1b(IL-1b) 12 months IL-1b difference (pg/mL) in subjects in active arm vs control arm
Trial Locations
- Locations (6)
VA Palo Alto Health Care System, Palo Alto, CA
🇺🇸Palo Alto, California, United States
Tennessee Valley Healthcare System Nashville Campus, Nashville, TN
🇺🇸Nashville, Tennessee, United States
Michael E. DeBakey VA Medical Center, Houston, TX
🇺🇸Houston, Texas, United States
VA Salt Lake City Health Care System, Salt Lake City, UT
🇺🇸Salt Lake City, Utah, United States
Hunter Holmes McGuire VA Medical Center, Richmond, VA
🇺🇸Richmond, Virginia, United States
William S. Middleton Memorial Veterans Hospital, Madison, WI
🇺🇸Madison, Wisconsin, United States