Sodium–Glucose co-Transporter 2 Inhibitors in Severe Estimated Glomerular Filtration Rate Deterioration Across Cardiovascular-Kidney-Metabolic Conditions: A Pooled Analysis of Randomized Trials

Abstract Aims The efficacy of sodium–glucose co-transporter 2 inhibitors (SGLT2i) among patients with cardiovascular-kidney-metabolic (CKM) conditions who experience severe estimated glomerular filtration rate (eGFR) deterioration during follow-up is not well established. The aim of this study was to assess the risk of cardiovascular outcomes and mortality after eGFR deterioration to 25 ml/min/1.73 m2 (and 20 ml/min/1.73 m2), and whether such eGFR deterioration modified the effect of SGLT2i across CKM populations. Methods and results Pooled analysis of placebo-controlled trials: EMPEROR-Preserved, EMPEROR-Reduced, EMPA-REG OUTCOME, CANVAS-R, and CREDENCE. Time-updated models with stratification by study were used. The median follow-up to eGFR deterioration was 17 months and total follow-time was 29 months. Studied outcomes included heart failure hospitalization or cardiovascular mortality, the composite of cardiovascular mortality, stroke or myocardial infarction, and all-cause mortality. Overall, 26 946 patients were included, of these 1392 (5.2%) experienced eGFR deterioration to 25 ml/min/1.73 m2 (and 613 2.3% to 20 ml/min/1.73 m2). Factors independently associated with a higher risk of eGFR deterioration were lower baseline eGFR and higher albuminuria, whereas allocation to SGLT2i was protective. eGFR deterioration was independently associated with a nearly twofold higher risk of subsequent cardiovascular outcomes and mortality. The beneficial impact of SGLT2i treatment on cardiovascular outcomes and mortality was maintained irrespective of patients experiencing eGFR deterioration (interaction-p 0.1 for all outcomes). Patients who experienced eGFR deterioration were more likely to permanently discontinue treatment, without significant differences in treatment discontinuation rates between the SGLT2i and placebo groups. Conclusions Severe eGFR deterioration during follow-up was associated with an increased risk of subsequent cardiovascular events and mortality. SGLT2i reduced the probability and were beneficial irrespective of severe eGFR deterioration.