Effects of empagliflozin on progression of chronic kidney disease: a prespecified secondary analysis from the empa-kidney trial

Abstract

Background: Sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce progression of chronic kidney disease and the risk of cardiovascular morbidity and mortality in a wide range of patients. However, their effects on kidney disease progression in some patients with chronic kidney disease are unclear because few clinical kidney outcomes occurred among such patients in the completed trials. In particular, some guidelines stratify their level of recommendation about who should be treated with SGLT2 inhibitors based on diabetes status and albuminuria. We aimed to assess the effects of empagliflozin on progression of chronic kidney disease both overall and among specific types of participants in the EMPA-KIDNEY trial.

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), and included individuals aged 18 years or older with an estimated glomerular filtration rate (eGFR) of 20 to less than 45 mL/min per 1·73 m², or with an eGFR of 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. We explored the effects of 10 mg oral empagliflozin once daily versus placebo on the annualised rate of change in estimated glomerular filtration rate (eGFR slope), a tertiary outcome. We studied the acute slope (from randomisation to 2 months) and chronic slope (from 2 months onwards) separately, using shared parameter models to estimate the latter. Analyses were done in all randomly assigned participants by intention to treat. EMPA-KIDNEY is registered at ClinicalTrials.gov, NCT03594110.

Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and then followed up for a median of 2·0 years (IQR 1·5-2·4). Prespecified subgroups of eGFR included 2282 (34·5%) participants with an eGFR of less than 30 mL/min per 1·73 m², 2928 (44·3%) with an eGFR of 30 to less than 45 mL/min per 1·73 m², and 1399 (21·2%) with an eGFR 45 mL/min per 1·73 m² or higher. Prespecified subgroups of uACR included 1328 (20·1%) with a uACR of less than 30 mg/g, 1864 (28·2%) with a uACR of 30 to 300 mg/g, and 3417 (51·7%) with a uACR of more than 300 mg/g. Overall, allocation to empagliflozin caused an acute 2·12 mL/min per 1·73 m² (95% CI 1·83-2·41) reduction in eGFR, equivalent to a 6% (5-6) dip in the first 2 months. After this, it halved the chronic slope from -2·75 to -1·37 mL/min per 1·73 m² per year (relative difference 50%, 95% CI 42-58). The absolute and relative benefits of empagliflozin on the magnitude of the chronic slope varied significantly depending on diabetes status and baseline levels of eGFR and uACR. In particular, the absolute difference in chronic slopes was lower in patients with lower baseline uACR, but because this group progressed more slowly than those with higher uACR, this translated to a larger relative difference in chronic slopes in this group (86% [36-136] reduction in the chronic slope among those with baseline uACR <30 mg/g compared with a 29% [19-38] reduction for those with baseline uACR ≥2000 mg/g; p_trend<0·0001).

Interpretation: Empagliflozin slowed the rate of progression of chronic kidney disease among all types of participant in the EMPA-KIDNEY trial, including those with little albuminuria. Albuminuria alone should not be used to determine whether to treat with an SGLT2 inhibitor.

Funding: Boehringer Ingelheim and Eli Lilly.

Figure 1. Effect of allocation to empagliflozin on acute changes in estimated glomerular filtration rate, by key subgroups

P values for test of heterogeneity between absolute differences for patients with and without diabetes and tests for trend in absolute differences across eGFR and UACR categories are 0.0010, 0.016 and 0.050 respectively.

Figure 2. Absolute and relative effects of allocation to empagliflozin on ‘total slopes’ and ‘chronic slopes’, by pre-specified diabetes subgroup, and post-hoc expanded eGFR and uACR subgroups

P values for test of heterogeneity between absolute differences in chronic slopes for patients with and without diabetes and tests for trend in absolute differences in chronic slope across eGFR and UACR categories are 0.0085, 0.0013 and <0.0001 respectively. P values for test of heterogeneity between absolute differences in total slopes for patients with and without diabetes and tests for trend in absolute differences in total slope across eGFR and UACR categories are 0.19, 0.023 and <0.0001 respectively.

Figure 3. Effect of allocation to empagliflozin on ‘chronic slopes’, by other subgroups