Correlates and Consequences of an Acute Change in eGFR in Response to the SGLT2 Inhibitor Dapagliflozin in Patients with CKD

Abstract

Background: Dapagliflozin reduces kidney failure risk in patients with CKD but can result in a reversible acute reduction in eGFR upon treatment initiation. Determinants of this eGFR reduction and its associations with efficacy and safety outcomes are unknown.

Methods: The DAPA-CKD trial randomized 4304 adults with CKD and albuminuria to once-daily dapagliflozin 10 mg or placebo, added to standard care. We prespecified an analysis comparing the effects of dapagliflozin among patients who experienced relative reductions in eGFR (>10% or >0%-10%) or an increase in eGFR from baseline to 2 weeks and assessed long-term efficacy and safety thereafter.

Results: A total of 4157 (96.6%) patients had eGFR data available at baseline and at 2 weeks. In the dapagliflozin and placebo groups, 1026 (49.4%) and 494 (23.7%), respectively, experienced an acute reduction in eGFR >10%. Among patients receiving dapagliflozin, those with an acute reduction in eGFR >10% experienced a long-term eGFR decline of -1.58 ml/min per 1.73 m² per year compared with -2.44 and -2.48 ml/min per 1.73 m² per year among those experiencing a less pronounced reduction or increase in eGFR, respectively (P-interaction=0.05). In the placebo group, long-term eGFR decline was -3.27, -3.84, and -3.77 ml/min per 1.73 m² per year for acute eGFR reduction subgroups of >10%, >0%-10%, or increase in eGFR (P-interaction=0.48). Rates of serious adverse events and adverse events of special interest in patients randomized to dapagliflozin were unrelated to the acute eGFR change.

Conclusions: Among patients with CKD and albuminuria treated with dapagliflozin, an acute reduction in eGFR (from baseline to 2 weeks) is not associated with higher rates of CKD progression.Clinical Trial registration number: A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease (Dapa-CKD) NCT03036150.

Keywords: chronic kidney disease; dapagliflozin; renal function; sodium-glucose transporter 2 inhibitors.

Graphical abstract

Figure 1.

Proportional distribution of eGFR decline by treatment arm.

Figure 2.

Odds ratios and 95% confidence intervals (95% CIs) of dapagliflozin versus placebo for the risk of an acute decline (>10% or >3 ml/min per 1.73 m²) in eGFR across participant subgroups defined by baseline characteristics.

Figure 3.

eGFR by acute percentage decline categories for dapagliflozin and placebo. The annual eGFR decline from week 2 to the end of treatment for (A) the dapagliflozin group and (B) the placebo group. (C) The annual eGFR decline from week 2 to the end of treatment as a function of acute changes in eGFR in the placebo and dapagliflozin group.

Figure 4.

Risk of primary and secondary outcomes according to initial change in eGFR in the dapagliflozin and placebo groups separately. Patients with an increase in eGFR (eGFR decline ≤0%) are used as reference group for the subgroups of patients with modest acute decline (>0 to ≤10%) and acute decline (>10%).

Figure 5.

Hazard ratio as function of acute eGFR slope fitted as a continuous variable with a restricted cubic spline model. Graphs showing acute eGFR change for (A) primary composite outcome; (B) secondary kidney outcome; (C) composite of ESKD and kidney death; and (D) all-cause death.

Figure 6.

Safety events according to acute eGFR change in the dapagliflozin and placebo groups separately.

Figure 7.

Safety events according to acute eGFR change fitted as a continuous variable in the dapagliflozin and placebo groups separately. Graphs showing acute eGFR change for (A) any AE leading to discontinuation of study drug, (B) any serious AE (SAE), (C) any kidney AE, and (D) symptoms of volume depletion.