Open-Label, Randomized, Controlled, Crossover Trial on the Effect of Dapagliflozin in Patients With ADPKD Receiving Tolvaptan

Abstract

Introduction: Although dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, delays the progression of chronic kidney disease (CKD), its effect on patients with autosomal dominant polycystic kidney disease (ADPKD) has not been established. We conducted an open-label, randomized controlled crossover trial to evaluate the additive effects of dapagliflozin in patients with ADPKD receiving tolvaptan.

Methods: A total of 27 patients were randomly counterbalanced to receive dapagliflozin 10 mg or usual care without dapagliflozin for 6 months. The primary endpoint was the slope of the estimated glomerular filtration rate (eGFR) determined by linear regression from 1 to 6 months, and the secondary endpoints included changes in total kidney volume (TKV). eGFR was calculated based on creatinine levels (eGFR_cr), cystatin C levels (eGFR_cys), and the mean of eGFR_cr and eGFR_cys (eGFR_cr-cys).

Results: There were significant attenuations in the eGFR_cr-cys and eGFR_cys slopes during the dapagliflozin trial compared with the one without dapagliflozin (2.57 ± 7.88 vs. -5.65 ± 9.57 ml/min per 1.73 m² per year, P = 0.002; 3.91 ± 11.40 vs. -8.43 ± 13.44 ml/min per 1.73 m² per year, P = 0.003, respectively). Meanwhile, the eGFR_cr slope was potentially moderate during the trial with dapagliflozin (1.03 ± 10.78 vs. -3.66 ± 8.88 ml/min per 1.73 m² per year, P = 0.06). The 6-month change in TKV was significantly attenuated during the trial with dapagliflozin compared with the one without dapagliflozin (-0.44 ± 4.91% vs. 5.04 ± 8.09%, P = 0.01).

Conclusion: In patients with ADPKD treated with tolvaptan, dapagliflozin may have an additive effect in slowing ADPKD progression.

Keywords: autosomal dominant polycystic kidney disease; dapagliflozin; estimated glomerular filtration rate; sodium–glucose cotransporter 2 inhibitor; tolvaptan; total kidney volume.

Graphical abstract

Figure 1

Crossover flow chart of the trial process.

Figure 2

CONSORT flow diagram of patients through the various phases of the clinical trial.

Figure 3

Mean change in the values of (a) eGFR_cr-cys, (b) eGFR_cys, and (c) eGFR_cr during the whole study period in groups 1 and 2 from 0 to 12 months using linear mixed models. The model included fixed effects such as group (1 or 2), period (0–12 months), and 0-month eGFR, as well as an interaction term (period × group). Cr, creatinine; Cys, cystatin C; DAPA, dapagliflozin; eGFR, estimated glomerular filtration rate.

Figure 4

Mean change in the values of (a) eGFR_cr-cys, (b) eGFR_cys, and (c) eGFR_cr during trials with and without dapagliflozin from 1 month to 6 months using linear mixed models. The model included fixed effects such as trial (with or without dapagliflozin), period (1–6 months), and 1-month eGFR, as well as an interaction term (period × trial). ∗P< 0.05; ∗∗P< 0.01 versus the trial without dapagliflozin. Bar represents mean ± SEM. cr, creatinine; cys, cystatin C, eGFR, estimated glomerular filtration rate.

Figure 5

Mean change in the values of (a) eGFR_cr-cys, (b) eGFR_cys, and (c) eGFR_cr during trials with and without dapagliflozin from 0 to 6 months using linear mixed models. The model included fixed effects, such as trial (with or without dapagliflozin), period (0–6 months), and 0-month eGFR as well as an interaction term, period × trial. ∗∗P< 0.01; ∗∗∗P< 0.001 versus the trial without dapagliflozin. Bar represents mean ± SEM. Cr, creatinine; Cys, cystatin C, eGFR, estimated glomerular filtration rate.