Abstract
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/1.73m2/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.
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Authors and Affiliations
KfH Kidney Centre, München, Germany
Johannes F. E. Mann
University Hospital Erlangen, Friedrich Alexander University, Erlangen, Germany
Johannes F. E. Mann
Steno Diabetes Center Copenhagen, Herlev, Denmark
Peter Rossing
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
Peter Rossing
Department of Medicine, AHA Comprehensive Hypertension Center, University of Chicago Medicine, Chicago, IL, USA
George Bakris
Novo Nordisk A/S, Søborg, Denmark
Nicolas Belmar,Heidrun Bosch-Traberg,Thomas Idorn&Søren Rasmussen
Albany Medical Center Division of Community Endocrinology, Albany, NY, USA
Robert Busch
Nephrology Division, Department of Medicine, New York University Grossman School of Medicine, and NYU Langone Health, New York, NY, USA
David M. Charytan
L’Institut du Thorax, CHU Nantes, CNRS, INSERM, Nantes Université, Nantes, France
Samy Hadjadj
Department of Endocrinology, University Hospitals Leuven - KU Leuven, Leuven, Belgium
Pieter Gillard
Department of Nephrology, Hospital Clínico Universitario de Valencia (INCLIVA), Valencia, Spain
José Luis Górriz
Department of Medicine, Universitat de València, Valencia, Spain
José Luis Górriz
Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing, China
Linong Ji
Stanford Center for Clinical Research, Department of Medicine, Stanford School of Medicine, Palo Alto, CA, USA
Kenneth W. Mahaffey
Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia
Vlado Perkovic
Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich Alexander University, Erlangen, Germany
Roland E. Schmieder
AdventHealth Translational Research Institute, Orlando, FL, USA
Richard E. Pratley
Division of Nephrology, University of Washington, Seattle, WA, USA
Katherine R. Tuttle
Providence Medical Research Center, Providence Inland Northwest Health, Spokane, WA, USA
Katherine R. Tuttle
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- Nicolas Belmar
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Mann, J.F.E., Rossing, P., Bakris, G. et al. Effects of semaglutide with and without concomitant SGLT2 inhibitor use in participants with type 2 diabetes and chronic kidney disease in the FLOW trial. Nat Med (2024). https://doi.org/10.1038/s41591-024-03133-0
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DOI: https://doi.org/10.1038/s41591-024-03133-0