Effect of dapagliflozin on the rate of decline in kidney function in patients with chronic kidney disease with and without type 2 diabetes: a prespecified analysis from the DAPA-CKD

Literature - Heerspink HJL, Jongs N, Chertow GM et al., - Lancet Diabetes Endocrinol 2021, 9(11):743-754. doi: 10.1016/S2213-8587(21)00242-4

Introduction and methods

Aim of the study

The SGLT2 inhibitor dapagliflozin lowered the risk of kidney failure in a broad population of patients with chronic kidney disease (CKD) with and without T2DM in the DAPA-CKD trial [1]. In an analysis using a clinical dichotomous outcome, such as kidney failure, the treatment effect depends on the subgroup of patients who progress to these events. Drug efficacy estimations using decline in kidney function over time (GFR slope) are more sensitive to the treatment effect in all patients [2].

In this prespecified analysis of DAPA-CKD, the effect of dapagliflozin on eGFR slope was examined during the acute phase (the first 2 weeks of treatment) and during maintenance phase (starting after 2 weeks of treatment).

Study design

The DAPA-CKD trial was a double-blind, randomized, placebo-controlled trial of 4304 patients with CKD, defined as an eGFR of 25-75 mL/min/1.73 m² and a urinary albumin-to-creatinine ratio (UACR) of 200-5000 mg/g. Patients with and without T2DM were included and all patients were on stable ACEi or ARB treatment. They were randomized (1:1) to dapagliflozin or matched placebo. Median on-treatment follow-up was 2.3 years (IQR 1.8-2.6) and the trial was stopped because the primary endpoint was met.

Outcomes

The primary prespecified outcome was the rate of change in eGFR from baseline to the end of treatment.

Main results

• Mean eGFR slope from baseline to 2.3 years in the dapagliflozin group was -2.88 mL/min per 1.73 m² per year (SE 0.1) and in the placebo group was -3.83 mL/min/1.73 m² per year (SE 0.12): a between-group difference of 0.95 mL/min/1.73 m² per year (95%CI:0.63-1.27).
• The difference in the mean acute decline in eGFR at week 2 between the dapagliflozin and the placebo group in patients with T2DM was 2.61 mL/min/1.73 m² (95%CI:2.16-3.06) and in patients without T2DM was 2.10 mL/min/1.73 m² (95%CI: 1.36-2.66).
• Dapagliflozin compared with placebo resulted in a slower decrease in the chronic eGFR slope with a larger effect in T2DM patients (difference between dapagliflozin and placebo was 2.26 mL/min/1.73 m² per year, 95%CI:1.88 to 2.64) than in patients without T2DM (difference 1.29 mL/min/1.73 m², 95%CI:0.73-1.85)(Pinteraction=0.0049).
• When the effect of the acute eGFR change and change during the chronic phase of the trial was combined, dapagliflozin attenuated the total slope by 1.18 mL/min/1.73 m² (95%CI:0.79-1.56, P<0.0001) in patient with T2DM and by 0.46 mL/min/1.73 m² (95%CI:-0.10 to 1.03) in patients without T2DM (Pinteraction=0.040).
• The effect of dapagliflozin on eGFR decline (total and chronic eGFR slopes) was more pronounced in subgroups with higher HbA1c (Pinteraction=0.028 for total slope and Pinteraction=0.070 for chronic slope).
• Dapagliflozin attenuated the decline in eGFR irrespective of the underlying cause of CKD.
• Dapagliflozin attenuated the chronic eGFR slope with a significantly larger effect in the 2 highest UACR subgroups than in the two lowest UACR subgroups (across all UACR subgroups Pinteraction=0.016). For the total slope, dapagliflozin attenuated the slope compared to placebo in each UACR subgroup with a larger benefit in higher UACR subgroups (Pinteraction<0.0001).
• Of 385 composite kidney endpoints, 368 (96%) occurred in patients with eGFR decline > 5 mL/min/1.73 m² per year (fast progressors). The composite hospitalization due to heart failure or CV death and all-cause mortality endpoints occurred more at a similar rate in subgroups of patients with or without fast progression.

Conclusion

References

Find this article online at Lancet Diabetes Endocrinol