Kidney and Survival Outcomes with Semaglutide by CKD Severity in the FLOW Trial

KEY POINTS: Semaglutide reduced kidney outcome risk across broad CKD severity strata (eGFR; albuminuria). Reduced risk for all-cause death also carried through strata of CKD severity. In a population with type 2 diabetes, semaglutide improved kidney and survival outcomes irrespective of CKD severity, including advanced CKD. BACKGROUND: Semaglutide improved kidney and overall survival in participants with type 2 diabetes (T2D) and CKD in the Evaluate Renal Function with Semaglutide Once Weekly (FLOW) trial. The aim of the present analyses was to quantify these benefits across broad strata of CKD severity. METHODS: FLOW was a double-blind, randomized, placebo-controlled trial (median follow-up 3.4 [interquartile range, 2.9-4.0] years). Participants with T2D and eGFR 50-75 ml/min per 1.73 m 2 and urine albumin-to-creatinine ratio (UACR) >300 to <5000 mg/g, or eGFR 25 to <50 ml/min per 1.73 m 2 and UACR >100 to <5000 mg/g, were randomized to subcutaneous semaglutide 1 mg once-weekly or placebo. Subgroups were categorized by baseline eGFR (<30 to ≥60 ml/min per 1.73 m 2 ) or UACR (<100 to ≥2000 mg/g) to assess the primary outcome and individual components (≥50% eGFR decline, eGFR <15 ml/min per 1.73 m 2 , dialysis, kidney transplant, and death due to kidney or cardiovascular causes), all-cause death, eGFR, and UACR. RESULTS: At baseline, the mean±SD eGFR was 47±15 ml/min per 1.73 m 2 , and the median (5th-95th percentile) UACR was 568 (51-3225) mg/g. The primary outcome occurred in 19% (331 of 1767) versus 23% (410 of 1766) with semaglutide treatment versus placebo (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.66 to 0.88). Death occurred in 13% (227 of 1767) versus 16% (279 of 1766), respectively (HR, 0.80; 95% CI, 0.67 to 0.95). Across eGFR and UACR subgroups, HRs for the primary outcome remained consistent ( P for interaction 0.83 and 0.42, respectively). For death, HRs were consistent among eGFR subgroups ( P for interaction 0.54), but the HR was lowest (0.47; 95% CI, 0.31 to 0.70) for those with UACR ≥2000 mg/g ( P for interaction 0.02). Estimated treatment effects on eGFR and UACR were generally consistent among subgroups. CONCLUSIONS: Semaglutide reduced risks of major kidney disease events and all-cause death across wide-ranging categories of baseline eGFR and UACR, supporting semaglutide treatment in T2D throughout the spectrum of CKD severity represented in FLOW, including advanced CKD.Clinical Trial registry name and registration number: NCT03819153 .