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

Nature Medicine (2024)Cite this article

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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

  1. KfH Kidney Centre, München, Germany

    Johannes F. E. Mann

  2. University Hospital Erlangen, Friedrich Alexander University, Erlangen, Germany

    Johannes F. E. Mann

  3. Steno Diabetes Center Copenhagen, Herlev, Denmark

    Peter Rossing

  4. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

    Peter Rossing

  5. Department of Medicine, AHA Comprehensive Hypertension Center, University of Chicago Medicine, Chicago, IL, USA

    George Bakris

  6. Novo Nordisk A/S, Søborg, Denmark

    Nicolas Belmar, Heidrun Bosch-Traberg, Thomas Idorn & Søren Rasmussen

  7. Albany Medical Center Division of Community Endocrinology, Albany, NY, USA

    Robert Busch

  8. Nephrology Division, Department of Medicine, New York University Grossman School of Medicine, and NYU Langone Health, New York, NY, USA

    David M. Charytan

  9. L’Institut du Thorax, CHU Nantes, CNRS, INSERM, Nantes Université, Nantes, France

    Samy Hadjadj

  10. Department of Endocrinology, University Hospitals Leuven - KU Leuven, Leuven, Belgium

    Pieter Gillard

  11. Department of Nephrology, Hospital Clínico Universitario de Valencia (INCLIVA), Valencia, Spain

    José Luis Górriz

  12. Department of Medicine, Universitat de València, Valencia, Spain

    José Luis Górriz

  13. Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing, China

    Linong Ji

  14. Stanford Center for Clinical Research, Department of Medicine, Stanford School of Medicine, Palo Alto, CA, USA

    Kenneth W. Mahaffey

  15. Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia

    Vlado Perkovic

  16. Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich Alexander University, Erlangen, Germany

    Roland E. Schmieder

  17. AdventHealth Translational Research Institute, Orlando, FL, USA

    Richard E. Pratley

  18. Division of Nephrology, University of Washington, Seattle, WA, USA

    Katherine R. Tuttle

  19. Providence Medical Research Center, Providence Inland Northwest Health, Spokane, WA, USA

    Katherine R. Tuttle

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  1. Johannes F. E. Mann
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  2. Peter Rossing
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  4. Nicolas Belmar
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  14. Vlado Perkovic
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  15. Søren Rasmussen
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  16. Roland E. Schmieder
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  18. Katherine R. Tuttle
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Correspondence to Johannes F. E. Mann.

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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

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