SGLT2 inhibitors slow CKD progression, may delay dialysis

SGLT2 inhibitors: Major breakthrough in delaying kidney failure
“Although kidney transplantation is the best treatment for kidney failure, de­laying or preventing kidney failure is even better. SGLT2 inhibitors represent a ma­jor breakthrough in this regard,” said Eckardt.

“Originally developed as glucose-lowering therapies for type 2 diabetes mellitus [T2DM], SGLT2 inhibitors have unexpectedly demonstrated significant cardiorenal benefits in cardiovascular [CV] outcome trials involving T2DM pa­tients with high CV risk,” he said. [Clin J Am Soc Nephrol 2021;16:1590-1600]

In the EMPA-REG OUTCOME trial in T2DM patients with established ath­erosclerotic CV disease (ASCVD) and baseline estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m², for example, empagliflozin demonstrated a 46 percent relative risk reduction (RRR) vs placebo in the renal composite out­come of doubling of serum creatinine level accompanied by eGFR ≤45 mL/min/1.73 m², initiation of renal replacement therapy, or death from renal disease (haz­ard ratio [HR], 0.54; 95 percent confi­dence interval [CI], 0.40–0.75; p<0.001). [N Engl J Med 2016;375:323-334]

RCTs of SGLT2 inhibitors in patients with heart failure (HF) with or without T2DM also demonstrated a renoprotec­tive effect across the spectrum of left ventricular ejection fraction. [N Engl J Med 2020;383:1413-1424; N Engl J Med 2021;385:1451-1461; Circula­tion 2021;143:298-309; JAMA Cardiol 2023;8:56-65]

Unprecedented benefits in CKD trials
“Subsequently, three RCTs of SGLT2 inhibitors in patients with CKD with or without T2DM all demonstrated clear evidence of benefits and were therefore stopped early,” said Eckardt. [N Engl J Med 2019;380:2295-2306; N Engl J Med 2020;383:1436-1446; N Engl J Med 2023;388:117-127] “This is un­precedented in kidney disease trials. Previously, what we encountered was early discontinuation of trials due to safety concerns.”

“This trilogy of CKD trials evaluated SGLT2 inhibitors vs placebo for a similar primary outcome: substantial reduction in eGFR decline, kidney failure, or death due to renal or CV causes. Although their inclusion criteria differed in terms of presence or absence of T2DM, eGFR category and albuminuria stage, the pri­mary outcome results were very similar, with the curves beginning to separate after approximately 6 months of treat­ment,” Eckardt continued.

The EMPA-KIDNEY trial, for ex­ample, included a broad population of CKD patients with eGFR ≥20–<45 mL/min/1.73 m² or eGFR ≥45–<90 mL/min/1.73 m² and urinary albumin-to-creatinine ratio (UACR) ≥200 mg/g, with or without T2DM, who were already taking a clinically appropri­ate dose of a renin-angiotensin system inhibitor. At baseline, median UACR was 329 mg/g, and 48.3 percent of patients had UACR <30 mg/g or ≥30–≤300 mg/g. Results showed a 28 per­cent RRR with empagliflozin vs place­bo in the composite primary outcome of kidney disease progression (end-stage kidney disease [ESKD], sus­tained decrease in eGFR to <10 mL/min/1.73 m², sustained decrease in eGFR of ≥40 percent from baseline, or death from renal causes) or CV death (HR, 0.72; 95 percent CI, 0.64–0.82; p<0.001) after a median follow-up of 2 years. [N Engl J Med 2023;388:117-127]

Meta-analysis: Reductions in kidney disease progression and AKI
A meta-analysis of 13 large RCTs of SGLT2 inhibitors (n=90,413; with di­abetes, 82.7 percent) with follow-up duration of ≥6 months was conduct­ed to assess treatment effects on kid­ney disease progression according to a standardized outcome definition (ie, sustained ≥50 percent decrease in eGFR from randomization, a sustained low eGFR, ESKD, or death from kidney failure), as well as on AKI, death, HF, and key safety outcomes by diabetes status. [Lancet 2022;400:1788-1801]

“Results showed that overall, SGLT2 inhibitors were associated with a 37 per­cent RRR in kidney disease progression vs placebo [relative risk (RR), 0.63; 95 percent CI, 0.58–0.69], with similar RRs in patients with or without diabetes,” said Eckardt. (Figure 1) In the CKD tri­als, RRs of kidney disease progression were similar irrespective of primary kidney diagnosis.

“Notably, SGLT2 inhibitors were also associated with a 23 percent RRR in AKI [RR, 0.77; 95 percent CI, 0.70–0.84],” pointed out Eckardt. (Figure 1) The RRRs were 23 percent for CV death or hospi­talization for HF (RR, 0.77; 95 percent CI, 0.74–0.81) and 14 percent for CV death (RR, 0.86; 95 percent CI, 0.81–0.92), with similar effects in patients with or without diabetes.

Potential in delaying dialysis and transplantation
Extrapolation of long-term benefit based on data from CKD RCTs suggests that SGLT2 inhibitors may delay ESKD by 15 years if a “typical” 63-year-old pa­tient is started on treatment at an eGFR of 56 mL/min/1.73 m². (Figure 2) [Kidney360 2021:2:1042-1047]
 
“This would be a very substantial ef­fect,” commented Eckardt. “Delaying kidney failure would impact the need for kidney transplantation or allow changes in kidney transplant allocation.”