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.
The DECLARE-TIMI 58 trial showed that the SGLT-2 inhibitor dapagliflozin reduced the rate
of cardiovascular death or hospitalization for heart failure in a manner consistent with
the findings observed in the EMPA-REG trial. Dapagliflozin was also associated with a
large reduction in the rate of progression to end-stage renal failure. In consistence
with the data on empagliflozin, 6 months after randomization, the mean decrease in the
estimated GFR was larger in the dapagliflozin group than in the placebo group. However,
the mean change equalized by 2 years, and at 3 and 4 years the mean decrease in eGFR was
less with dapagliflozin than with placebo. The absolute difference in eGFR was smaller
than that observed in the EMPA-REG OUTCOMES trial; however, the inclusion criteria in the
DECLARE-TIMI 58 trial ensured that most of the participants had normal kidney function at
the start of the treatment period. In the CREDENCE trial, canagliflozin had a similar
effect on the glomerular filtration rate with the curves crossing at approximately one
year. The effect on proteinuria, on the other hand, was substantial, occurred soon after
the start of treatment, and was sustained for the entire study period. In the randomized,
double-blind DELIGHT trial, dapagliflozin reduced the urine albumin-to-creatinine ratio
in type 2 diabetics with 21.0 % (95 % confidence interval -34.1 to -5.2; p=0.01) after 24
weeks of treatment. The effect was almost immediate and was sustained from 4-24 weeks.
Several facts suggest that the cardioprotective and renoprotective effects of SGLT-2
inhibitors are to some extent independent of their glucose-lowering effect. First, the
reductions in the levels of HbA1c in the EMPA-REG OUTCOMES and DECLARE TIMI 58 trials
were modest compared with the pronounced effects on cardiovascular and renal outcomes.
Second, the effect on renal outcomes seems to be independent of the effect on HbA1c.
Third, the DAPA-HF trial in patients with and without diabetes recently demonstrated that
the effect on cardiovascular outcomes was as large in non-diabetics as in patients with
diabetes. Finally, in the DAPA-CKD trial, 4304 patients with a baseline eGFR between 25
and 75 ml/min/1.73m2 with or without diabetes were randomized to treatment with
dapagliflozin 10 mg or placebo once daily. The primary endpoint was a sustained decline
in eGFR ≥ 50 %, end-stage kidney disease, or renal or cardiovascular death. There was a
substantial reduction in the hazard of reaching the primary endpoint in the dapagliflozin
arm (hazard ratio 0.61, p < 0.001) irrespective of whether the patients had diabetes or
not.
One of the major mechanisms of action of the SGLT-2 inhibitors is to decrease proximal
tubular sodium and chloride reabsorption in the kidneys, leading to a reset of the
tubuloglomerular feedback. This induces plasma volume contraction without activation of
the sympathetic nerve system, decreases harmful glomerular hyper-filtration leading to
better long-term renal preservation, and improves the diuretic and natriuretic responses
to other diuretic agents. How this translates into a beneficial effect on the
cardiovascular system is at present unclear. Heart transplant recipients have many common
features with the heart failure population with metabolic disturbances, a propensity for
coronary disease (allograft vasculopathy), and progressive nephropathy. Based on these
premises, DAPARHT trial is designed to assess the hypothesis that treatment with
dapagliflozin for one year ameliorates the decline in kidney function that often occurs
in heart transplant recipients.