DAPARHT: DAPAgliflozin for Renal Protection in Heart Transplant Recipients

Heart transplant is the treatment of choice for selected patients with end-stage heart failure. Worldwide, approximately 5000 procedures are performed annually. Whereas the first successful heart transplant led to a mere 18 days' prolongation of the recipient's life, the median survival after transplantation is now more than 11 years. Important surgical advances, as well as optimal medical therapy, are responsible for this improvement, but reducing morbidity and mortality further is a significant challenge. Beyond the first year, outcomes have not improved over the last decades. An important reason for this is the considerable burden of long-term side effects induced by immunosuppressive therapy. Chronic renal failure occurs in approximately 11 % of heart transplant recipients during the first five years after transplant and is associated with a large increase in mortality. A major cause of renal injury is a calcineurin inhibitor (CNI)-related nephrotoxicity. Calcineurin inhibitors revolutionized transplant medicine when introduced in the early 1980'ies and remain the mainstay of immunosuppressive therapy after a heart transplant. However, the therapy is an important contributor to post-transplant nephropathy. Furthermore, CNIs seem to contribute to metabolic disturbances including diabetes mellitus, hypertension, and oxidative stress after a heart transplant.

The deterioration of renal function after a heart transplant appears to be linear. In a Swedish material, the average yearly drop in the estimated glomerular filtration rate (eGFR) was 2.2 ± 14.6 ml/min/1.73 m2. In the NOCTET trial, which comprised 282 Scandinavian heart and lung transplant recipients who were randomized to treatment with a CNI or low-dose CNI and everolimus 1-10 years after surgery, the measured glomerular filtration rate (GFR) declined 7.2 ml/min/1.73m2 during a mean follow up of 5.6 years (i.e. 1.3 ml/min/1.73m2 per year) independently of the time since transplantation and baseline GFR.

Proteinuria is an important determinant of ensuing renal failure. Approximately 25 % of patients listed for heart transplant have at least trace proteinuria. Of the investigators' maintenance heart transplant recipients, 18 % have manifest proteinuria defined as urine protein/creatinine ratio ≥ 30 mg/g. The median ratio is 49.5 mg/g (interquartile range 37-84), consistent with a daily loss of approximately 500 mg of protein in the urine.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) inhibit glucose reuptake in the proximal tubules of the nephrons. They thereby cause loss of glucose in the urine and induce osmotic diuresis. SGLT2i have now been studied in several large placebo-controlled cardiovascular outcomes trials in patients with type 2 diabetes. These trials were performed to satisfy regulatory requirements, specifically to exclude the excess risk of cardiovascular death, myocardial infarction, or stroke, and to test for efficacy. Despite a modest reduction in glycated haemoglobin (HbA1c), all the trials so far have shown that SGLT2i robustly reduces the risk of hospitalization for heart failure and prevents the progression of kidney disease.

In the EMPA-REG OUTCOME trial, treatment with the SGLT-2 inhibitor empagliflozin resulted in a reduction of cardiovascular mortality of 38%. In addition, empagliflozin significantly reduced admissions for heart failure and the incidence of end-stage kidney disease. Among patients allocated to empagliflozin, the mean change in estimated GFR (eGFR) from baseline to follow-up after 3 years was 4.7 ml per minute per 1.73 m2 better than in patients allocated to placebo. However, immediately after starting the drug, the patients on active treatment experienced an apparent reduction in the eGFR. The curves did not cross until after the first year of treatment, where after a between-group difference was manifest in favor of empagliflozin. The event curves diverged right up to the end of the trial, and there was an additional increase in the difference in the eGFR between the active drug arm and the placebo arm after stopping the treatment, suggesting that while empagliflozin is indeed renoprotective in patients with type 2 diabetes, there is an on-treatment suppression of eGFR analogue to the effect produced by angiotensin-converting enzyme inhibitors/angiotensin II receptor antagonists.