Effects of empagliflozin in patients with chronic kidney disease from Japan: exploratory analyses from EMPA-KIDNEY

Abstract

Background: EMPA-KIDNEY assessed the effects of empagliflozin 10 mg once daily vs. placebo in 6609 patients with chronic kidney disease (CKD) at risk of progression, including 612 participants from Japan.

Methods: Eligibility required an estimated glomerular filtration rate (eGFR) of ≥ 20 < 45; or ≥ 45 < 90 ml/min/1.73m² with a urinary albumin-to-creatinine ratio (uACR) of ≥ 200 mg/g. The primary outcome was a composite of kidney disease progression (end-stage kidney disease, a sustained eGFR decline to < 10 ml/min/1.73m² or ≥ 40% from randomization, or renal death) or cardiovascular death. In post-hoc analyses, we explored the effects of empagliflozin in participants from Japan vs. non-Japan regions, including additional models assessing whether differences in treatment effects between these regions could result from differences in baseline characteristics.

Results: Japanese participants had higher levels of albuminuria and eGFR than those from non-Japan regions. During a median of 2.0 year follow-up, a primary outcome occurred in 432 patients (13.1%) in the empagliflozin group and in 558 patients (16.9%) in the placebo group (hazard ratio [HR], 0.72, 95% confidence interval [95%CI] 0.64-0.82; P < 0.0001). Among the participants from non-Japan regions, there were 399 vs. 494 primary outcomes (0.75, 0.66-0.86), and 33 vs. 64 (0.49, 0.32-0.75; heterogeneity p = 0.06) in Japan. Results were similar when models explicitly considered treatment interactions with diabetes status, categories of eGFR/uACR, and recruitment in Japan (heterogeneity p = 0.08). Safety outcomes were broadly comparable between the two groups, and by Japanese status.

Conclusions: Empagliflozin safely reduced the risk of "kidney disease progression or cardiovascular death" in patients with CKD, with consistent effects in participants from Japan.

Keywords: Cardiovascular disease; Kidney function; Randomised trial; Sodium–glucose co-transporter-2 inhibitor.

Fig. 1

Effect of empagliflozin on primary composite outcome of progression of kidney disease or death from cardiovascular causes, by Japan vs. non-Japan regions (post-hoc exploratory analyses). Footnote: Hazard ratios and confidence intervals were estimated from Cox models, with pre-specified adjustment for age, sex, history of diabetes, estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (uACR), and region. The heterogeneity P value (P_het) is calculated from a relevant interaction term in the pre-specified Cox model. Results were robust in a sensitivity analysis following inclusion of pre-specified covariates plus treatment interactions with diabetes status, categories of eGFR/uACR & recruitment in Japan (exploratory model P_het = 0.08). These non-significant heterogeneity p values suggest the best estimate of the effect of empagliflozin on the primary outcome in the two subgroups is the overall result (i.e., there is no statistical evidence for a difference between the subgroup-specific HRs for Japan vs. non-Japan regions)