Neuen, BL; Fletcher, RA; Anker, SD; Bhatt, DL; Butler, J; Cherney, DZI; Docherty, KF; ... Heerspink, HJL; + view all Neuen, BL; Fletcher, RA; Anker, SD; Bhatt, DL; Butler, J; Cherney, DZI; Docherty, KF; Inzucchi, SE; Jardine, MJ; Mahaffey, KW; Mccausland, FR; Mcguire, DK; Mcmurray, JJV; Neal, B; Packer, M; Patel, SM; Perkovic, V; Sabatine, MS; Sardell, RJ; Solomon, SD; Vaduganathan, M; Wanner, C; Wheeler, DC; Zannad, F; Haynes, R; Staplin, N; Herrington, WG; Heerspink, HJL; - view fewer (2025) SGLT2 Inhibitors and Kidney Outcomes by Glomerular Filtration Rate and Albuminuria: A Meta-Analysis. Journal of the American Medical Association 10.1001/jama.2025.20834. (In press).

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Abstract

Importance: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce chronic kidney disease (CKD) progression in individuals with type 2 diabetes, CKD, or heart failure. However, their effects in those with stage 4 CKD or little to no albuminuria remain uncertain. Objective: To assess whether estimated glomerular filtration rate (eGFR) or degree of albuminuria, measured by urinary albumin to creatinine ratio (UACR), modifies the effects of SGLT2 inhibitors on kidney outcomes. Data Sources: SGLT2 inhibitor trials participating in the SGLT2 Inhibitor Meta-Analysis Cardio-Renal Trialists' Consortium (SMART-C). Study Selection: Randomized, double-blind, placebo-controlled trials within SMART-C evaluating an SGLT2 inhibitor with label indications for reducing CKD progression including at least 500 participants in each group with at least 6 months of follow-up. Data Extraction and Synthesis: Treatment effects in individual trials were pooled using inverse variance-weighted meta-analysis. Main Outcomes and Measures: CKD progression, defined as kidney failure, at least 50% reduction in eGFR, or death due to kidney failure. Other outcomes included annual rate of eGFR decline and kidney failure. Results: Among 70361 participants (mean [SD] age, 64.8 [8.7] years; 24595 [35.0%] females) in 10 randomized trials, 2314 (3.3%) experienced CKD progression and 988 (1.4%) reached kidney failure. SGLT2 inhibitors reduced the risk of CKD progression (25.4 vs 40.3 events per 1000 patient-years; hazard ratio [HR], 0.62 [95% CI, 0.57-0.68]), irrespective of baseline eGFR (HR of 0.61 [95% CI, 0.52-0.71] for eGFR ≥60 mL/min/1.73 m²; 0.57 [95% CI, 0.47-0.70] for eGFR of 45 to <60 mL/min/1.73 m²; 0.64 [95% CI, 0.54-0.75] for eGFR of 30 to <45 mL/min/1.73 m²; and 0.71 [95% CI, 0.60-0.83] for eGFR <30 mL/min/1.73 m²; P for trend =.16) and baseline albuminuria (HR of 0.58 [95% CI, 0.44-0.76] for albuminuria ≤30 mg/g; 0.74 [95% CI, 0.57-0.96] for >30-300 mg/g; and 0.57 [95% CI, 0.52-0.64] for more than 300 mg/g; P for trend =.49). Although the magnitude of protection varied, SGLT2 inhibitors reduced the annual rate of eGFR decline across all eGFR and UACR subgroups, including when participants with and without diabetes were analyzed separately. SGLT2 inhibitors also reduced the risk of kidney failure alone (HR, 0.66 [95% CI, 0.58-0.75]). Conclusions and Relevance: In this meta-analysis, SGLT2 inhibitors were found to lower the risk of CKD progression regardless of baseline eGFR or albuminuria, including in patients with stage 4 CKD or minimal albuminuria, supporting their routine use to improve kidney outcomes across the full spectrum of kidney function among patients with type 2 diabetes, CKD, or heart failure.

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