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

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 (pheterogeneity=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

Fig 2 -

Spline Analysis of the Relationship Between Baseline Myeloperoxidase (MPO) Level and the Hazard Ratio of (A) Cardiovascular Death and (B) Non-Cardiovascular Death at 5 Years After Assessment of MPO Level and (C) Change in Hazard Ratio for All Cause Death at 5 Years After Initial Assessment of MPO as a Function of Change in MPO During 5 Years.</p

Fig 1 -

Kaplan Meier Curves Depicting Event Rate of (A) Myocardial Infarction, (B) All-Cause Death, (C) Cardiovascular (CV) Death, and (D) Non-CV Death in Patients with an Initial Myeloperoxidase (MPO) Level That Was Low (Light Gray, Dashed Line), Moderately Elevated (Gray, Dashed Line), or Highly Elevated (Black, Solid Line).</p

Causes of death as recorded in medical chart reported as percent of total deaths.

Causes of death as recorded in medical chart reported as percent of total deaths.</p

S1 Data -

BackgroundLevels of free myeloperoxidase (MPO), a cardiovascular risk marker, have been reported to decline with standard care. Whether such declines signify decreased risk of mortality remains unknown.DesignCox proportional hazard models were generated using data from a retrospective cohort study of prospectively collected measures.ParticipantsPatients (3,658) who had MPO measurements and LDL-C ≥ 90 mg/dL during 2011–2015 were selected based on a stratified random sampling on MPO risk level. Baseline MPO was either low (Main outcomes and measuresFirst occurrence of MACE (myocardial infarction, stroke, coronary revascularization, or all-cause death).ResultsMean age was 66.5 years, and 64.7% were women. During a mean 6.5-year follow-up, crude incidence per 1000 patient years was driven by death. The incidence and all-cause death was highest for patients with high MPO (21.2; 95% CI, 19.0–23.7), then moderate (14.6; 95% CI, 11.5–18.5) and low (2.3; 95% CI, 1.2–4.6) MPO. After adjusting for age, sex, and cardiovascular risk factors, risk of cardiovascular death did not differ significantly between patients with high and low MPO (HR, 1.57; 95% CI, 0.56–4.39), but patients with high MPO had greater risk of non-cardiovascular (HR, 6.15; 95% CI, 2.27–16.64) and all-cause (HR, 3.83; 95% CI, 1.88–7.78) death. During follow-up, a 100 pmol/L decrease in MPO correlated with a 5% reduction in mortality (HR, 0.95; 95% CI, 0.93–0.97) over 5 years.ConclusionsFree circulating MPO is a strong marker of risk of mortality. Monitoring changes in MPO levels over time may provide insight into changes in physiology that mark a patient for increased risk of mortality.</div

Crude incidence rates (95% CI) per 1000 patient years for components of MACE and all-cause death for the entire cohort and by level of MPO elevation at first measure.

Crude incidence rates (95% CI) per 1000 patient years for components of MACE and all-cause death for the entire cohort and by level of MPO elevation at first measure.</p

Characteristics of baseline MPO cohort and “change in MPO cohort” (patients with multiple MPO measures).

Characteristics of baseline MPO cohort and “change in MPO cohort” (patients with multiple MPO measures).</p