- Chronic kidney disease is a common complication following heart transplantation, driven by preexisting kidney dysfunction, perioperative injury, and long-term exposure to nephrotoxic immunosuppressive medications.
- The DAPARHT trial randomized 430 heart transplant recipients to dapagliflozin 10 mg daily or placebo for 12 months to evaluate its effects on kidney function and safety.
- Dapagliflozin significantly improved the chronic estimated glomerular filtration rate (eGFR) trajectory compared with placebo, with a between-group difference of 1.7 mL/min/1.73 m² (95% CI, 0.1–3.3; P=0.03) from two weeks to 12 months.
- Dapagliflozin was associated with modest weight reduction, without significant differences in albuminuria or glycated hemoglobin (HbA1c). Adverse events of special interest were comparable between groups, although three participants with allograft rejection occurred in the dapagliflozin group versus none with placebo.
- Longer-term follow-up is needed to determine whether improvements in eGFR trajectory translate into sustained kidney protection and improved clinical outcomes.
Dapagliflozin significantly improved the chronic trajectory of kidney function compared with placebo in heart transplant recipients, according to findings from the DAPARHT randomized clinical trial presented at the American Heart Association (AHA) Scientific Sessions on November 8, 2026. The findings were presented by Dr. Stine Holmen, MD (Oslo University Hospital, Norway), and simultaneously published in Circulation (Holmen et al., 2026).
Chronic kidney disease remains a major cause of morbidity and mortality following heart transplantation. Kidney dysfunction in this population is multifactorial, reflecting preexisting renal impairment, perioperative complications, and prolonged exposure to calcineurin inhibitors, which can contribute to nephrotoxicity, hypertension, and diabetes. Although sodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated substantial kidney-protective benefits in patients with chronic kidney disease, heart failure, and diabetes, heart transplant recipients have largely been excluded from pivotal randomized trials. Consequently, evidence supporting their efficacy and safety in this population has been limited to observational studies.
The DAPARHT trial (NCT05321706) was an investigator-initiated, multicenter, double-blind, placebo-controlled trial conducted at six heart transplant centers across Norway, Sweden, and the Netherlands. Between June 2022 and September 2025, investigators randomized 430 adults who were at least one year post-heart transplantation and had a baseline eGFR of at least 25 mL/min/1.73 m² to receive dapagliflozin 10 mg once daily (n=217) or matching placebo (n=213), in addition to standard care. Patients with type 1 diabetes, active malignancy or ongoing cancer treatment, and current SGLT2 inhibitor use without an adequate washout period were excluded.
The primary endpoint was the chronic slope of eGFR from two weeks after randomization to 12 months, assessed using a linear mixed-effects model. This approach accounted for the expected initial decline in eGFR following SGLT2 inhibitor initiation and focused on the subsequent kidney function trajectory. Secondary endpoints included changes in body weight, urinary albumin-to-creatinine ratio (UACR) among participants with baseline albuminuria, and HbA1c among those with type 2 diabetes. Safety assessments included adverse events, allograft rejection, infections, and potential interactions with immunosuppressive therapy.
Of the 430 randomized patients, 424 were included in the primary analysis (215 receiving dapagliflozin and 209 receiving placebo). The mean age was 53 years, 29% were women, and the median time since heart transplantation was approximately seven years. Baseline mean eGFR was 67 mL/min/1.73 m², and most participants had relatively low levels of albuminuria. Hypertension was present in approximately two-thirds of patients, while type 2 diabetes was more prevalent in the placebo group (19.6% versus 12.1%). Most participants were receiving calcineurin inhibitors as part of their maintenance immunosuppressive regimen.
At 12 months, dapagliflozin significantly improved the chronic eGFR trajectory compared with placebo. Following an initial decline in eGFR during the first two weeks, patients receiving dapagliflozin experienced an estimated increase of 2.0 mL/min/1.73 m² (95% CI, 1.0–3.1) between two weeks and 12 months, compared with 0.3 mL/min/1.73 m² (95% CI, −0.8 to 1.4) in the placebo group. The between-group difference was 1.7 mL/min/1.73 m² (95% CI, 0.1–3.3; p=0.03), meeting the trial’s primary endpoint. Results were consistent in a prespecified alternative analysis incorporating baseline eGFR. However, the overall change in eGFR from baseline to 12 months did not differ significantly between groups (between-group difference, −0.6 mL/min/1.73 m²; 95% CI, −2.1 to 1.0; p=0.46).
Prespecified subgroup analyses generally favored dapagliflozin, with a numerically greater treatment effect observed among patients with diabetes. However, these analyses were exploratory, were not adjusted for multiple comparisons, and were limited by small subgroup sizes.
Among secondary outcomes, dapagliflozin was associated with a modest reduction in body weight compared with placebo (between-group difference, −1.34 kg; 95% CI, −2.05 to −0.63). No clear between-group differences were observed in UACR among participants with baseline albuminuria (−1.39 mg/mmol; 95% CI, −13.1 to 10.3) or HbA1c among those with type 2 diabetes (−1.85 mmol/mol; 95% CI, −5.72 to 2.02). These analyses were limited by relatively small sample sizes and were not adjusted for multiplicity.
Safety outcomes were broadly comparable between groups, although several findings warrant attention. Serious adverse events occurred in 22.3% of dapagliflozin-treated patients compared with 18.0% receiving placebo (P=0.25). Adverse events of special interest occurred in 7.4% versus 6.6%, respectively (P=0.78). Urinary tract infections accounted for 21 events in the dapagliflozin group and 15 in the placebo group, while overall infection events were similar. No cases of ketoacidosis or documented interactions with immunosuppressive therapy were reported. Allograft rejection occurred in three patients (1.4%) receiving dapagliflozin compared with none receiving placebo (P=0.18). Two deaths occurred in the dapagliflozin group and one in the placebo group. The investigators also reported more cancer events in the dapagliflozin group, an observation requiring further evaluation during longer-term follow-up.
The findings provide the first randomized, placebo-controlled evidence supporting a favorable effect of SGLT2 inhibition on the chronic eGFR trajectory in heart transplant recipients. However, the relatively short 12-month follow-up, preserved baseline kidney function, and largely stable eGFR in the placebo group limit conclusions regarding long-term kidney protection. Importantly, the trial evaluated a surrogate endpoint and was not powered to detect differences in kidney failure, cardiovascular events, mortality, or uncommon adverse events. The modest treatment effect and confidence interval approaching the null also warrant cautious interpretation.
The ongoing 24-month open-label extension study will assess whether the observed improvement in kidney function trajectory persists and translates into meaningful clinical benefits. For now, DAPARHT suggests that dapagliflozin may offer a kidney-protective strategy for clinically stable heart transplant recipients, although longer-term evidence is needed before its routine use for renal protection can be established in this population.
The investigator-initiated DAPARHT trial was sponsored by Oslo University Hospital and supported by Oslo University Hospital, the Norwegian Health Association, the Kardimmun Foundation, and AstraZeneca. AstraZeneca also supplied dapagliflozin and matching placebo but had no role in trial design, conduct, analysis, interpretation, or manuscript preparation.