EMPA-KIDNEY: expanding the range of kidney protection by SGLT2 inhibitors

In the EMPA-KIDNEY (The Study of Heart and Kidney Protection With Empagliflozin) trial, empagliflozin reduced cardiorenal outcomes by 28% (hazard ratio 0.72; 95% confidence interval 0.64-0.82; <i>P</i> < .0001) in a diverse population of over 6000 chronic kidney disease (CKD) patients, of whom >50% were not diabetic. It expanded the spectrum of CKD that may benefit from sodium-glucose cotransporter 2 (SGLT2) inhibition to participants with urinary albumin: creatinine ratio <30 mg/g and estimated glomerular filtration rate (eGFR) >20 mL/min/1.73 m² or even lower (254 participants had an eGFR 15-20 mL/min/1.73 m²). EMPA-KIDNEY was stopped prematurely because of efficacy, thus limiting the ability to confirm benefit on the primary outcome in every pre-specified subgroup, especially in those with more slowly progressive CKD. However, data on chronic eGFR slopes were consistent with benefit at any eGFR or urinary albumin:creatinine ratio level potentially delaying kidney replacement therapy by 2-27 years, depending on baseline eGFR. The representation of diverse causes of CKD (>1600 participants with glomerular disease, >1400 with hypertensive kidney disease, >450 with tubulointerstitial disease and >600 with unknown cause) was higher than in prior SGLT2 inhibitor trials, although polycystic kidney disease was excluded. Around 15% (almost 1000) of participants were not on renin-angiotensin system blockade. The clinical characteristics of the cohort differed from DAPA-CKD (A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease), as did the frequency of individual components of the primary outcome in the placebo arm. Thus, rather than compare EMPA-KIDNEY with DAPA-CKD, the results of both trials should be seen as complementary to those of other SGLT2 inhibitor trials. Overall, EMPA-KIDNEY, a recent meta-analysis and <i>post hoc</i> analyses of participants with type 2 diabetes mellitus (T2DM) but no baseline CKD in other trials, indicates that SGLT2 inhibitor treatment will benefit an expanded CKD population with diverse baseline albuminuria or eGFR values, presence of T2DM or cause of CKD, as well as providing primary prevention of CKD in at least the T2DM setting.