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 and chronic kidney disease have a high risk for kidney failure and cardiovascular complications. Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors (SGLT2i) independently reduce cardiovascular and kidney events, but the effect of combining both is unclear. FLOW trial participants with type 2 diabetes and chronic kidney disease were stratified by baseline SGLT2i use (N=550) or no use (N=2,983) and randomized to semaglutide or placebo. The primary outcome was a composite of kidney failure, ≥50% eGFR reduction, kidney death or cardiovascular death. The risk of the primary outcome was 24% lower overall with semaglutide versus placebo. In participants on SGLT2i at baseline, primary outcome occurred in 41/277 (semaglutide) versus 38/273 (placebo) (HR 1.07; 95% CI 0.69, 1.67; P=0.755), and in those not taking SGLT2i at baseline in 290/1,490 versus 372/1,493 (HR 0.73; 95% CI 0.63, 0.85; P<0.001; Pinteraction 0.109). Three confirmatory secondary outcomes were predefined. Treatment differences favoring semaglutide for total eGFR slope (ml min−1/1.73 m2/year) were 0.75 (−0.01, 1.50) with SGLT2i and 1.25 (0.91, 1.58) without SGLT2i (Pinteraction 0.237). Semaglutide benefits on major adverse cardiovascular events and all-cause death were similar regardless of SGLT2i use (Pinteraction 0.741 and 0.901). Benefits of semaglutide in reducing kidney outcomes were consistent with or without baseline SGLT2i use; power was limited to detect smaller effects. ClinicalTrials.gov: NCT03819153.

Johannes F. E. Mann, Peter Rossing, George Bakris, Nicolas Belmar, Heidrun Bosch-Traberg, Robert Busch, David M. Charytan, Samy Hadjadj, Pieter Gillard, José Luis Górriz, Thomas Idorn, Linong Ji, Kenneth W. Mahaffey, Vlado Perkovic, Søren Rasmussen, Roland E. Schmieder, Richard E. Pratley, Katherine R. Tuttle