Randomized Trial of Dapagliflozin in Patients With Nondiabetic Stage 4 CKD

Abstract

Introduction: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are nephroprotective in patients with chronic kidney disease (CKD) and mild-to-moderate renal insufficiency.

Methods: This prospective, randomized, cross-over, placebo-controlled, double-blind study compared the effects of 6-week dapagliflozin (10 mg/d) with placebo treatment in 31 consenting nondiabetic Caucasian adults with stage 4 CKD and proteinuria > 0.5 g/24 h. Participants were identified at the Nephrology Unit of Papa Giovanni XXIII Hospital and treated at Mario Negri Institute (Bergamo, Italy) between December 2021 and December 2023. Normalized glomerular filtration rate (GFR) (using iohexol plasma clearance) and 24-hour proteinuria (median of 3 urinary measurements) were co-primary outcomes. Analyses were by modified intention-to-treat.

Results: At 6 weeks, dapagliflozin significantly decreased GFR by 1.88 ± 5.00 ml/min per 1.73 m² (P = 0.022) and proteinuria by 0.50 (-0.10 to 0.80) g/24 h (P = 0.026) versus placebo. The dapagliflozin-induced GFR (P < 0.001) and proteinuria (P = 0.003) reduction was already significant at 1 week. At 6 weeks, dapagliflozin reduced absolute GFR (P = 0.026), the CKD-Epidemiology Collaboration (CKD-Epi) equation-based estimated GFR (eGFR) (P = 0.003), the Modification of Diet in Renal Disease (MDRD) equation-based eGFR (P = 0.002), 24-hour albuminuria (P = 0.001), total protein (P = 0.057) and albumin (P = 0.009) fractional clearances, and fasting blood glucose (P < 0.001); and increased serum albumin (P = 0.001), renin activity (P = 0.020), glucosuria (P < 0.001), and glucose fractional clearance (P < 0.001) versus placebo. All changes reversed completely after treatment withdrawal. GFR changes correlated inversely with changes in renal plasma flow (RPF) (P = 0.010) and positively with changes in postglomerular resistance (P < 0.001) but did not correlate with changes in preglomerular resistance. There were no serious adverse events.

Conclusion: Dapagliflozin safely ameliorates (compensatory) glomerular hyperfiltration and proteinuria and is glycosuric in nondiabetic patients with preterminal CKD. GFR reduction is likely because of postglomerular vasodilation rather than preglomerular vasoconstriction.

Keywords: CKD; GFR; SGLT2 inhibitors; dapagliflozin; hyperfiltration; proteinuria.

Graphical abstract

Figure 1

Study design. HbA1c, glycated hemoglobin; OGTT, oral glucose tolerance test.

Figure 2

Study flow chart. ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin 2 receptor blocker; CRC, clinical research center; eGFR, estimated glomerular filtration rate; HBV, hepatitis B virus; OGTT, oral glucose tolerance test.

Figure 3

Changes in the primary outcome and confirmatory outcomes. Changes in (a) normalized GFR (primary outcome), (b) absolute GFR, (c) CKD-Epi, and (d) MDRD estimated GFR (confirmatory outcomes), during the different study periods. Boxes indicate mean values. Points represent individual patients’ data. CKD-Epi, CKD-Epidemiology Collaboration equation; Dapa, changes between pre-post-dapagliflozin treatment periods; GFR, glomerular filtration rate; MDRD, Modification of Diet in Renal Disease equation; Plac, changes between pre-post placebo treatment periods; WoD, changes between pre-and post-wash-out periods after dapagliflozin treatment; WoP, changes between pre- and post-wash-out periods after placebo treatment (WoP). All P values are calculated by paired t test with the exception of P-values between changes during dapagliflozin and placebo treatment periods that are calculated by Linear Mixed Effect model.

Figure 4

Changes in co–primary outcome and confirmatory outcomes. Changes in (a) 24-hour proteinuria (co–primary outcome), (b) 24-hour albuminuria, (c) total protein fractional clearance, and (d) albumin fractional clearance (confirmatory outcomes), during the different study periods. Boxes indicate median values. Points represent individual patients’ data. Dapa, changes between pre- and post-dapagliflozin treatment periods; F.C., fractional clearance; Plac, changes between pre- and post-placebo treatment period; WoD, changes between pre- and post-wash-out period after dapagliflozin treatment; WoP, changes between pre- and post-wash-out periods after placebo treatment. All P values are calculated using the Wilcoxon signed-rank test with the exception of P values between changes during dapagliflozin and placebo treatment periods that are calculated using Linear Mixed Effect model.

Figure 5

Changes in (a) 24-hour glycosuria, (b) glucose fractional clearance, and (c) serum active renin, during the different study periods. Boxes indicate median values. Points represent individual patients’ data. Dapa, changes between pre- and post-dapagliflozin treatment period; F.C., fractional clearance; Plac, changes between pre- and post-placebo treatment period; WoD, changes between pre- and post-wash-out period after dapagliflozin treatment; WoP, changes between pre- and post-wash-out period after placebo treatment. All P-values are calculated using Wilcoxon signed-rank test, with the exception of P-values between changes during dapagliflozin and placebo treatment periods that are calculated using Linear Mixed Effect model.

Figure 6

Linear regression model and Pearson correlation coefficient between changes in normalized GFR (or filtration fraction [FF]) and corresponding changes in (a and c) normalized renal plasma flow (RPF), and (b and d) efferent glomerular vascular resistance (GRRE) during the dapagliflozin treatment period. GFR, glomerular filtration rate.