In a prespecified secondary analysis of EMPA-KIDNEY, empagliflozin reduced progression of CKD in different subgroups of patients with CKD, including in patients with little albuminuria.

This summary is based on the publication of EMPA-KIDNEY Collaborative Group - Effects of empagliflozin on progression of chronic kidney disease: a prespecified secondary analysis from the EMPA-KIDNEY trial. Lancet Diabetes Endocrinol. 2024 Jan;12(1):39-50. doi: 10.1016/S2213-8587(23)00321-2

Introduction and methods

Background

Large trials with SGLT2 inhibitors have shown that SGLT2 inhibitors reduce the risk of progression of kidney disease in patients with CKD with or without diabetes [1-3]. These outcome trials used dichotomous composite outcomes such as the composite of kidney failure and decline in kidney function, which occur at different frequencies in patient subpopulations. It remains unclear how SGLT2 inhibitors affect kidney disease in certain subgroups of patients with CKD, as few clinical kidney outcomes occurred in some patient groups – which greatly impacts the sensitivity of these analyses. In order to improve the statistical sensitivity, it has been proposed to use the annualized rate of decline of kidney function (eGFR slope) as an alternative kidney outcome as this can be calculated for all participants.

Aim of the study

The aim of this prespecified secondary analysis of the EMPA-KIDNEY trial was to determine the effects of empagliflozin on progression of CKD in all participants and in different subgroups of patients with CKD.

Methods

EMPA-KIDNEY was a randomized, placebo-controlled phase 3 trial in which 6609 adults with CKD were enrolled. Patients were eligible when they had an eGFR of 20 to <45 mL/min/1.73 m² or an eGFR of 45 to <90 mL/min/1.73 m² with a urinary albumin-to-creatine ratio (uACR) of ≥200 mg/g. Patients were randomized to oral empagliflozin 10 mg once daily or matching placebo. In this analysis, key patient subgroups were: diabetes present (n=3040) or absent (n=3569) at randomization; eGFR of <30 (n=2282), ≥30 to <45 (n=2928) or ≥45 (n=1399) mL/min/1.73 m²; uACR of <30 (n=1328), 30 to 300 (n=1864) or <300 (n=3417) mg/g.

Outcomes

Tertiary outcomes of the EMPA-KINDEY trial were included in this analysis. These outcomes were the annual rate of change in eGFR calculated from randomisation to 2 months (acute slope) and from 2 months to final follow-up visit (chronic slope).

Main results

• Treatment with empagliflozin led to a placebo-corrected acute dip in eGFR of -2.12 mL/min/1.73 m² (95%CI: -2.41 to -1.83) in all participants (relative difference of -6%; 95%CI: -6 to -5).
• The effects of empagliflozin on acute changes in eGFR, in relative terms, varied across key patient subgroups:
  • Relative difference of -7% vs. -4% in patients with or without diabetes, respectively (Pheterogeneity=0.0010).
  • Relative difference of -6% in the eGFR <30 group, -6% for in the eGFR ≥30 to <45 group, and -4% in the eGFR ≥45 group (Ptrend=0.016).
  • Relative difference of -7% in the uACR <30 group, -7% in the uACR 30 to 300 group, and -5% in the uACR >300 group (Ptrend=0.050).
• Treatment with empagliflozin slowed the rate of eGFR decline (chronic slope) by 1.37 mL/min/1.73 m² per year in all participants compared with placebo (relative difference of 50%; 95%CI: 42 to 58).
• The effects of empagliflozin on chronic slope varied between key patient subgroups:
  • Empagliflozin had a greater effect on chronic slope in patients with diabetes compared with patients without diabetes (relative differences of 62% vs. 40%, respectively, Pheterogeneity=0.0074).
  • Smaller relative effects on the chronic slope were detected in patients with a lower eGFR (relative difference of -18% in the <20 group, -38% in the 20 to <30 group, -53% in the 30 to <45 group, and -56% in the ≥45 group, Ptrend=0.012).
  • Empagliflozin had greater effects on the chronic slope in patients with uACR <30 mg/g compared with patients with uACR ≥2000 mg/g (relative reduction 86% and 29%, respectively, Ptrend<0.0001).
• Empagliflozin reduced the total slope (from randomisation to final follow-up visit) in all participants compared with placebo (absolute difference of 0.75; 95%CI: 0.54 to 0.96; relative difference -26%; 95%CI: -33 to -19). These effects were similar across subgroups.

Conclusion

In this prespecified secondary analysis of the EMPA-KIDNEY trial, empagliflozin caused an acute dip in eGFR and reduced the longer-term rate of decline in kidney function in all participants. The longer-term beneficial effects of empagliflozin on the progression of kidney disease varied across CKD subgroups. In particular among patients with little albuminuria, empagliflozin had clear benefits on CKD progression. The authors highlight that “[a]lthough the trial stopped early because of clear benefits emerging based on results in patients at highest risk, these analyses show that patients at lower risk such as those with lower levels of albuminuria […] could benefit in terms of preservation of kidney function”.

References

1. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380(24):2295–2306.
2. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383(15):1436–1446.
3. The EMPA-KIDNEY Collaborative Group. Empagliflozin in patients with chronic kidney disease. N Engl J Med. 2023;388(2):117–127.

Find this article online at Lancet Diabetes Endocrinol.