Effects of semaglutide with and without concomitant SGLT2 inhibitor use in participants with type 2 diabetes and chronic kidney disease in the FLOW trial.

People with type-2-diabetes (T2D) and chronic kidney disease (CKD), have a high risk for kidney failure and cardiovascular (CV) complications. Glucagon-like-peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose co-transporter-2 inhibitors (SGLT2i) independently reduce cardiovascular and kidney events. The effect of combining both is unclear. FLOW trial participants with T2D and CKD were stratified by baseline SGLT2i use (N = 550) or no use (N = 2,983) and randomized to semaglutide/placebo. The primary outcome was a composite of kidney failure, ≥50% eGFR reduction, kidney or cardiovascular death. The risk of the primary outcome was 24% lower in all participants treated with semaglutide vs placebo (95% confidence interval [CI] 34%, 12%). The primary outcome occurred in 41/277 (semaglutide) versus 38/273 (placebo) participants on SGLT2i at baseline (HR 1.07; 95% CI 0.69, 1.67; P=0.755), and in 290/1,490 versus 372/1,493 participants not taking SGLT2i at baseline (HR 0.73; 0.63, 0.85; P<0.001; P-interaction 0.109). Three confirmatory secondary outcomes were predefined. Treatment differences favoring semaglutide for total eGFR slope (ml/min/1.73m 2 /year) were 0.75 (-0.01, 1.5) in the SGLT2i subgroup and 1.25 (0.91, 1.58) in non-SGLT2i-subgroup, P-interaction 0.237. Semaglutide benefits on major cardiovascular events and all-cause death were similar regardless of SGLT2i use (P-interaction 0.741 and 0.901, respectively). The benefits of semaglutide in reducing kidney outcomes were consistent in participants with/without baseline SGLT2i use; power was limited to detect smaller but clinically relevant effects. ClinicalTrials.gov identifier: NCT03819153 .