Explore the latest ISN Global Trials Focus selections featuring a “Trial of the month” on the effect of dapagliflozin in patients with ADPKD receiving tolvaptan
ISN-ACT Global Trials Focus editorial team member Michele Provenzano summarizes the design and outcomes of the latest “Trial of the month” featured in ISN-ACT Global Trials Focus.
Trial of the month:
DAPA-tolvaptan: First trial of SGLT2 inhibition in ADPKD with background tolvaptan therapy
Open-label, randomized, controlled, crossover trial on the effect of dapagliflozin in patients with ADPKD receiving tolvaptan
Uchiyama et al., KI Reports 2025
Summary
In this open-label, crossover trial, 27 autosomal dominant polycystic kidney disease (ADPKD) participants on stable high-dose tolvaptan (>60mg/day, >3 months, with eGFR >25 ml/min/1.73 m2) were randomized to receive dapagliflozin 10mg daily or usual care for 6-months, then crossed to the alternate arm for another 6 months, without a washout period.
Participants with diabetes were excluded. The primary endpoint was the eGFR slope from months 1 to 6, based on creatinine levels (eGFRcr), cystatin C levels (eGFRcys), and combined estimates (eGFRcr-cys). Participants had a mean age of 49.7 years; 52% were male, and 15% had a family history of ADPKD.
Significant attenuations in the eGFRcr-cys and eGFRcys slopes were observed during the dapagliflozin treatment period compared to the period without dapagliflozin (2.57 ± 7.88 vs. −5.65 ± 9.57 ml/min/1.73 m2 /year, P = 0.002; 3.91 ± 11.40 vs. −8.43 ± 13.44 ml/min/1.73 m2/year, P = 0.003, respectively).
The eGFRcr slope showed a moderate improvement during dapagliflozin treatment, though this did not reach statistical significance (1.03 ± 10.78 vs. −3.66 ± 8.88 ml/min per 1.73 m2 per year, P = 0.06). An initial dip in eGFR was observed in the first month of dapagliflozin use, followed by a slight increase during the period without dapagliflozin.
During dapagliflozin treatment, total kidney volume (TKV) growth was significantly attenuated compared to the period without dapagliflozin (−0.44 ± 4.91 vs. 5.04% ± 8.09%, P = 0.01). Additionally, body weight gain was smaller (P = 0.01), plasma vasopressin levels were higher (P = 0.002), and systolic blood pressure was lower (P = 0.04) during the dapagliflozin treatment period compared with the period without dapagliflozin.
Commentary
SGLT2 inhibitors (SGLT2i) are now widely used for chronic kidney diseases of varying etiologies, demonstrating proven benefits for patients with and without diabetes, and across various levels of albuminuria and stages of kidney disease.
However, most SGLT2i trials have excluded patients with ADPKD, making this trial a unique contribution to the field. A major concern is that SGLT2i may increase vasopressin levels, which could potentially stimulate cyst growth. However, the concurrent use of tolvaptan, a vasopressin V2 receptor antagonist, may mitigate this effect and enhance overall kidney protection.
This open-label crossover trial assessed the combination of dapagliflozin and tolvaptan in patients with ADPKD. The trial demonstrated the additive benefits of dapagliflozin, including a slower decline in kidney function and reduced kidney volume growth, without significant safety concerns. In addition to kidney-specific effects, dapagliflozin improved other parameters, such as decreased body weight, lower systolic blood pressure, and increased hemoglobin levels. These effects may work synergistically to slow disease progression and enhance patient outcomes, including delaying time to dialysis and reducing symptom burden, such as pain related to kidney size.
This study has several limitations. As a small, short-duration pilot trial with an open-label, crossover design and no washout period, the risk of carryover effects and potential bias from lack of blinding cannot be excluded. However, key outcomes (eGFR and TKV) were objectively assessed by third-party reviewers.
Imbalances in TKV between treatment periods could have influenced results, although this was minimized by the crossover design and consistent Mayo imaging classification across the groups.
The lack of PRO-PKD scores limited stratification by disease progression risk, as genetic testing is not routinely performed in Japanese clinical practice.
Nonetheless, these promising findings support the need for larger, longer-term parallel-group randomized controlled trials to confirm dapagliflozin’s role as an adjunctive therapy and potentially expand treatment options for patients with ADPKD.
Read all global trials selections from the ISN-ACT initiative available in several languages.
