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

Abstract

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; P < .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 post hoc 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.

Keywords: RAS blockers; SGLT2 inhibitor; chronic kidney disease; normoalbuminuria; primary prevention; treatment.

Figure 1:

The DAPA-CKD and EMPA-KIDNEY trials enrolled different populations of participants with CKD and had different outcomes: their results should be integrated. (A) Baseline clinical characteristics. EMPA-KIDNEY participants had a lower prevalence of DM and DKD and a higher prevalence of non-diabetic cause of CKD than DAPA-CKD participants (see Table 1). Additionally, the prevalence of CVD was lower, likely because of the lower prevalence of DM and the exclusion of T2DM participants with baseline CVD when eGFR was >60 mL/min/1.73 m². Thus, the population was less enriched for persons at higher risk of CVD and all-cause mortality than DAPA-CKD. (B) Baseline severity of kidney disease and treatment. In EMPA-KIDNEY participants, CKD was characterized by a lower baseline eGFR (i.e. potentially more severe CKD from the point of view of kidney function) but also by lower values of albuminuria, i.e. less severe CKD from the point of view of albuminuria. EMPA-KIDNEY enrolled a high number of participants not on RAS blockade. (C) While the incidence of the primary outcome was numerically higher in the placebo arm of EMPA-KIDNEY than in the placebo arm of DAPA-CKD, the incidence of mortality outcomes was higher in the placebo arm of DAPA-CKD than in the placebo arm of EMPA-KIDNEY. Note that in DAPA-CKD, kidney disease progression was defined as sustained decline of ≥50% in eGFR from randomization, kidney replacement therapy, sustained decrease in eGFR to <15 mL/min/1.73 m² or renal death, while in EMPA-kidney, it was defined as a sustained decline of ≥40% in eGFR from randomization, kidney replacement therapy, sustained decrease in eGFR to <10 mL/min/1.73 m² or renal death. In both cases, the composite primary outcome included both CKD progression and cardiovascular death. Potential differences highlighted in this figure are based on numerical data as no formal statistical comparisons were made [9, 17].

Figure 2:

Chronic eGFR slopes according to baseline UACR category in EMPA-KIDNEY. (A) Absolute difference in chronic GFR slopes for albuminuria categories A1, A2 and A3 between the placebo and empagliflozin arms. Note that the largest difference is observed for participants with UACR >300 mg/g, i.e. in absolute terms, these participants obtained the largest preservation of chronic eGFR slope on empagliflozin vs placebo. (B) Fold-difference in chronic eGFR slopes for albuminuria categories A1, A2 and A3 between the placebo and empagliflozin arms. Note that in relative terms, the largest improvement in chronic eGFR slopes was observed for participants with UACR <30 mg/g. (C) On-treatment chronic eGFR slope. Note that the best outcome (i.e. the slowest eGFR slope) was observed in participants randomized to empagliflozin that had UACR <30 mg/g. These figures were generated using data from [9].

Figure 3:

Hypothetical transformation of chronic eGFR slopes into time to kidney failure, defined as eGFR 10 mL/min/1.73 m², in the EMPA-KIDNEY trial. (A) Time to kidney failure in years, according to baseline eGFR, estimated from each baseline eGFR value by applying the chronic eGFR slopes corresponding to participants on placebo and on empagliflozin within the pre-specified eGFR subgroups (eGFR cut-off points to define subgroups set at 30 and 45 mL/min/1.73 m²) as per reference [9]. (B) Delay in time (years) to kidney failure on empagliflozin vs placebo, according to baseline eGFR, obtained by subtracting the time to kidney failure on empagliflozin from the time to kidney failure on placebo in (A). (C) Graphical presentation of representative chronic eGFR slopes from baseline to kidney failure, i.e. to the need for kidney replacement therapy. Hypothetical lines have been traced starting from extremes of the baseline eGFR inclusion criteria values (20 and 85 mL/min/1.73 m²) to eGFR 10 mL/min/1.73 m², corresponding to chronic eGFR slopes of participants on placebo and on empagliflozin within each baseline eGFR subgroup, as per reference [9]. The difference in the time to kidney failure corresponds to the values in (B) for baseline 20 and 85 mL/min/1.73 m². (D) Number of hemodialysis sessions potentially avoided by delaying the need for kidney replacement therapy by prescribing empagliflozin instead of placebo at each baseline eGFR value. The model assumes that patients will live up to the point where they need kidney replacement therapy and that they would continue hemodialysis throughout. While this is not expected to occur in every patient, it is a real possibility for some of them.

Figure 4:

Blind men and the elephant of CKD prevention and treatment. Over the years, different trials testing different SGLT2 inhibitors in different populations with different primary or secondary outcomes and post hoc analyses have provided insight into the potential of CKD inhibitors to prevent and treat CKD. The results of these trials should be integrated for a better appreciation of the role of SGLT2 inhibition in kidney protection, in a similar manner that the different touching experiences of the blind men in the Indian parable of the blind men and an elephant should be integrated to learn about the elephant. Adapted from reference [37] (artist: G. Renee Guzlas). All rights reserved ©. Reproduced by permission of J. Himmelfarb, P. Stenvinkel, T.A. Ikizler and R. M. Hakim.