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.

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.

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

All subjects will be randomized to either empagliflozin 10 mg daily for 12 months or matching placebo. The subjects and the investigators will not know whether subjects are randomized to active arm (empagliflozin) or to control arm (placebo).