1. Empagliflozin led to a lower risk of kidney disease progression in patients with chronic kidney disease (CKD) as compared to placebo control.

2. Compared to placebo, empagliflozin was associated with a lower risk of death from cardiovascular causes in patients with CKD.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Chronic kidney disease (CKD) is a progressive disease. Slowing the disease process while avoiding the need for dialysis or kidney transplant is one of the primary goals of care. Notably, dialysis and kidney transplantation have significant impacts on the quality of life and cardiovascular morbidity and mortality. Sodium-glucose Cotransporter-2 (SGLT2) inhibitors have been shown to reduce the risk of progression to kidney failure in patients with diabetic kidney disease. There is a gap in knowledge as to understanding how empagliflozin, an SGLT2 inhibitor, would impact CKD progression in patients with an estimated glomerular filtration rate (GFR) of less than 30 ml per minute per 1.73 m^2 of body-surface area. Overall, this study found that compared to placebo, empagliflozin treatment led to a lower risk of progression of kidney disease or death from cardiovascular causes in patients across a broad range of CKD. This included patients without diabetes, with an estimated GFR of less than 30 ml per minute per 1.73 m^2, and with a low urinary albumin-to-creatinine ratio. This study was limited by a lower-than-expected number of cardiovascular events, which reduced the statistical power for the assessment of the secondary and tertiary cardiovascular outcomes. Nevertheless, these study’s findings are significant, as they demonstrate that empagliflozin provides a significantly reduced risk of CKD progression and lower risk of cardiovascular-related death.

Click to read the study in NEJM

Relevant Reading: Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction

In-Depth [randomized controlled trial]: This randomized, parallel-group, double-blind, placebo-controlled clinical trial was conducted at 241 centers across eight countries. Patients who were adults with a race-adjusted eGFR (calculated with the use of the Chronic Kidney Disease Epidemiology Collaboration formula) of at least 20 but less than 45 ml per minute per 1.73 m^2, regardless of the level of albuminuria, or with an eGFR of at least 45 but less than 90 ml per minute per 1.73 m^2 with a urinary albumin to- creatinine ratio of at least 200 were eligible for the study. Patients with or without diabetes were also eligible. Patients with polycystic kidney disease and those who had received kidney transplants were excluded from the study. The primary outcome measured was the first occurrence of the progression of kidney disease or death from cardiovascular causes. Progression of kidney disease was defined as end-stage kidney disease (ESKD; the initiation of maintenance dialysis or receipt of a kidney transplant), a sustained decrease in the eGFR to less than 10 ml per minute per 1.73 m^2, or a sustained decrease from baseline in the eGFR of at least 40%, or death from renal causes. Outcomes in the primary analysis were assessed via the intention-to-treat principle and a Cox proportional hazards regression model was used. Based on the primary analysis, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3,304 patients (13.1%) in the empagliflozin group and in 558 of 3,305 patients (16.9%) in the placebo group (Hazard Ratio [HR], 0.72; 95% Confidence Interval [CI], 0.64 to 0.82). Results were consistent among patients regardless of diabetes status. The rate of hospitalization from any cause was lower in the empagliflozin group than in the placebo group (HR, 0.86; 95% CI, 0.78 to 0.95), but there were no significant between-group differences with respect to the composite outcome of hospitalization for heart failure, death from cardiovascular causes, or death from any cause. The present study demonstrated that SGLT2 inhibitors may represent an effective management strategy for preventing worsening renal and cardiovascular function in CKD patients.

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