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.

Keywords: Cardiovascular‐kidney‐metabolic conditions; Kidney function deterioration; Sodium–glucose co‐transporter 2 inhibitors; Treatment effect.