Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

Abstract

Background: The EMPA-KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population.

Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m², or 45 to less than 90 mL/min per 1·73 m² with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m², or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110.

Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5-2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62-0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (p_{heterogeneity}=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m² per year (95% CI 1·16-1·59), representing a 50% (42-58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all >0·1).

Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease.

Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council.

Figure 1. Kidney disease progression outcome by primary kidney disease

A Cox proportional-hazards regression model with adjustment for baseline variables specified in the minimisation algorithm (age, sex, diabetes, estimated GFR, urinary albumin-to-creatinine ratio, and region) and a treatment by primary kidney disease interaction term was used to estimate the hazard ratios and 95% CIs for empagliflozin as compared with placebo.

Figure 2. Effect of empagliflozin on annual rate of change in estimated GFR by primary kidney disease

Mean annual rates of change in estimated GFR from baseline to the final follow-up visit (“total slopes”), and from 2 months to the final follow-up visit (“chronic slopes”) by treatment allocation were estimated using shared parameter models adjusted for age, sex, prior diabetes, urinary ACR category, and region. Models estimating chronic slope were additionally adjusted for baseline estimated GFR (as a continuous variable) and the interaction between baseline estimated GFR and follow-up time. This approach jointly models the annual rate of change in estimated GFR and the time to event for end-stage kidney disease (ESKD) or death. Analyses used all available central laboratory estimated GFR measurements prior to the development of ESKD. Relative difference is the absolute difference as a fraction of the mean slope in the placebo group, expressed as a percentage. The heterogeneity p values shown are calculated from the relative differences.