Randomized Trial of Sodium-glucose cotransporter-2 Inhibition(SGLT2i) in Heart Transplant Recipients

/Abstract 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, yet we believe these patients may derive multiple benefits from SGLT2i based on the mechanisms of action. We are proposing a multicenter randomized controlled trial of empagliflozin 10mg daily versus placebo for one year in Veterans with HTx enrolled at all six VA HTx national referral centers at Salt Lake City, Nashville, Richmond, Madison, Palo Alto and Houston. Kidney dysfunction is highly prevalent after heart HTx and is associated with a significant increase in mortality. Albuminuria is present in approximately 50% of Veterans after HTx, and estimated glomerular filtration rate (eGFR) begins to decrease linearly starting at the time of transplant. SGLT2i have been shown repeatedly to decrease albuminuria and slow the rate of eGFR decline. We hypothesize that SGLT2i with empagliflozin will similarly improve albuminuria and eGFR slope in HTx recipients (Aim 1). We also hypothesize that treatment with empagliflozin in HTx recipients will be associated with favorable safety and tolerability. SGLT2i are overall well-tolerated with rare serious adverse events but transplant recipients have been excluded from clinical trials of SGLT2i. We will establish the safety and tolerability of SGLT2i therapy in HTx recipients (Aim 2). SGLT2i additionally have pleiotropic effects on metabolism, inflammation, vascular function and erythropoiesis. We will evaluate the effects of empagliflozin on markers of cardiometabolic risk (hemoglobin A1c, inflammation, blood pressure, body weight) in HTx recipients (Aim 3a). Anemia is also common after HTx and is associated with poor outcomes. We hypothesize that empagliflozin will increase markers of erythropoiesis (hemoglobin, hematocrit, erythropoietin) (Aim 3b). As a result of CV, metabolic and/or erythropoietic benefits, HTx recipients may experience an improvement in functional status and/or health-related quality of life, which we will evaluate with a six-minute walk test and health-related quality of life metrics (Aim 3c). Project Number: 1I01CX002816-01A1 | Fiscal Year: 2025 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Josef Stehlik | Institution: VA SALT LAKE CITY HEALTHCARE SYSTEM, SALT LAKE CITY, UT | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 NEPH-N (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11048998