Real-World Data

CKD, which affects an estimated 35.5 million people in the United States alone,1 is associated with increased risk for losing kidney function, kidney failure, cardiovascular (CV) disease, and premature mortality. Fortunately for people living with CKD and the clinicians that care for them, recent therapeutic advances have dramatically improved the standard of care management of CKD. Specifically, sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists, and finerenone are now considered guideline-directed medical therapies (GDMTs) recommended as add-on to optimized angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy in patients with type 2 diabetes (T2D) and CKD.2,3 Although SGLT2 inhibitors now represent an established pillar of GDMT in T2D and CKD, their recommended use has expanded into nondiabetic CKD to prevent loss of kidney function and kidney failure.4 The path of SGLT2 inhibitors into the CKD space was somewhat fortuitous and continues to evolve with rapid emergence of new evidence. Owing to the US Food and Drug Administration requirement for drug manufacturers to conduct dedicated CV outcome trials (CVOTs) for new glucose-lowering therapies in T2D to establish CV safety, early dedicated SGLT2 inhibitor CV outcome trials not only demonstrated CV benefit but also suggested benefit of SGLT2 inhibition on exploratory kidney disease outcomes.2 Subsequent dedicated kidney outcome trials confirmed early signals of kidney protection, with each trial incrementally expanding the evidence base for CKD populations who derive benefit,5–7 collectively inclusive of CKD patients with and without T2D and with a range of eGFR and albuminuria levels at baseline (Figure 1). Based largely on these data, the Kidney Disease Improving Global Outcomes 2024 Clinical Practice Guideline for the Evaluation and Management of CKD provides the following evidence-rated recommendations:4 Recommend treating patients with T2D, CKD and eGFR ≥20 ml/min per 1.73 m2 with an SGLT2 inhibitor (1A). Recommend treating adults with CKD with an SGLT2 inhibitor for the following (1A): ○ eGFR ≥20 ml/min per 1.73 m2 with a urinary albumin-to-creatine ratio (UACR) ≥200 mg/g. ○ Heart failure, irrespective of level of albuminuria. Suggest treating adults with eGFR 20–45 ml/min per 1.73 m2 with UACR <200 mg/g with an SGLT2 inhibitor (2B). Figure 1: Summary populations enrolled in SGLT2 inhibitor kidney outcome trials. 5–7 CREDENCE, canagliflozin and renal events in diabetes with established nephropathy clinical evaluation; DAPA-CKD, dapagliflozin and prevention of adverse outcomes in CKD; EMPA-KIDNEY, study of heart and kidney protection with empagliflozin; SGLT2, sodium-glucose cotransporter 2.As illustrated by the evidence-rated Kidney Disease Improving Global Outcomes recommendations listed above, randomized clinical trial evidence supporting the use of SGLT2 inhibitors in adults with CKD and lower baseline levels of albuminuria (UACR <200 mg/g) is somewhat less robust when compared with patients with CKD with moderately to severely increased albuminuria at baseline. As illustrated in Figure 1, the Study of Heart and Kidney Protection with Empagliflozin (EMPA-KIDNEY) trial was the only dedicated SGLT2 inhibitor kidney outcome trial that included patients with baseline UACR values <200 mg/g.7 Although empagliflozin treatment resulted in an overall 28% risk reduction for the primary composite outcome (hazard ratio: 0.72; 95% confidence interval: 0.64 to 0.82; P < 0.001), relatively few primary outcome events occurred in participants with a baseline UACR between ≥30 and ≤300 mg/g (67 and 78 events in the empagliflozin and placebo groups, respectively) and even less in the subgroup of participants with a baseline UACR <30 mg/g (42 events in the empagliflozin and placebo groups, respectively). The primary outcome finding in EMPA-KIDNEY was therefore largely driven by events in participants with a baseline UACR >300 mg/g. A prespecified secondary analysis of EMPA-KIDNEY, however, examined the effect of empagliflozin treatment versus placebo on the annualized rate of change in eGFR, concluding that SGLT2 inhibitor treatment slowed eGFR decline in all albuminuria subgroups,8 suggesting baseline albuminuria may not be a modifier of kidney benefit with SGLT2 inhibition. Clearly, SGLT2 inhibitor kidney outcome trials have dramatically informed clinical practice guidelines and the accepted standard of care for patients with CKD. Questions remain, however, about the use of SGLT2 inhibitors and other GDMTs for individuals whose clinical profile does not fully align with populations enrolled in these landmark randomized controlled trials (Figure 1). Because all clinical scenarios cannot be reasonably addressed by costly time and resource intensive randomized controlled trials, real-world evidence represents a critical source of evidence to better understand the potential kidney benefits of SGLT2 inhibitors in populations where robust evidence is lacking. In this issue of Kidney360, Matsui and colleagues report findings from a retrospective, observational study that sheds additional light on SGLT2 inhibitor use in patients with nondiabetic, nonproteinuric CKD.9 The study included patients seen between January 1, 2019, and December 31, 2022, in the hospital setting in Japan, and used propensity score analysis to assess annualized eGFR change in SGLT2 inhibitor users (n=211) and nonusers (n=151). Although the total eGFR decline over a 3-year period was similar between SGLT2 inhibitor users and nonusers, Matsui et al. found a significantly reduced decline in eGFR between 3 months after baseline and 2-year follow-up in SGLT2 inhibitors versus nonusers, with a mean difference of 1.23 ml/min per 1.73 m2 per year (95% confidence interval, 0.43 to 2.02; P = 0.002) in eGFR slope, suggesting a slower postinitial dip eGFR decline in SGLT2 inhibitor users when compared with nonusers.9 An additional analysis using propensity score matching additionally indicated slower eGFR decline in SGLT2 inhibitor users versus nonusers. Although limited by the relatively small sample size and single-center observational study design, the study by Matsui and colleagues provides important real-world evidence suggesting benefit of SGLT2 inhibitor therapy on kidney disease progression in patients with nondiabetic CKD without albuminuria. Notably, these findings align with previously published real-world evidence reporting attenuation of eGFR slope decline in new users of dapagliflozin versus noninitiators in a population with CKD and a baseline UACR <200 mg/g.10 Together, these studies provide important evidence supporting kidney protection in patients with CKD and normal to moderately increased albuminuria. We commend Matsui and colleagues for their study that furthers our collective understanding of subpopulations of patients with CKD who may benefit from SGLT2 inhibition. High-quality real-world evidence will continue to be essential to supplement and complement randomized clinical trial data to inform clinical practice guidelines and kidney care, with the ultimate goal of optimizing use of SGLT2 inhibitors and other GDMT to save kidneys, hearts, and lives.