Data availability
Data of this clinical trial are accessible through the University of Groningen Datalogue catalogues (https://umcgresearchdatacatalogue.nl/l).
Code availability
Software code used for the statistical analysis is accessible through the University of Groningen Datalogue catalogues (https://umcgresearchdatacatalogue.nl/).
References
World Health Organization. Obesity and overweight. https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight (2024).
Non-Communicable Disease Risk Factor Collaboration. Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults. Lancet 403, 1027–1050 (2024).
Global Burden Disease Collaborators. Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: a systematic analysis for the Global Burden of Disease Study 2021. Lancet 402, 203–234 (2023).
Kovesdy, C. P., Furth, S. L. & Zoccali, C & World Kidney Day Steering Committee. Obesity and kidney disease: hidden consequences of the epidemic. Kidney Int. 91, 260–262 (2017).
Garofalo, C. et al. A systematic review and meta-analysis suggests obesity predicts onset of chronic kidney disease in the general population. Kidney Int. 91, 1224–1235 (2017).
Jiang, Z. et al. Obesity and chronic kidney disease. Am. J. Physiol. Endocrinol. Metab. 324, E24–E41 (2023).
Hall, J. E., do Carmo, J. M., da Silva, A. A., Wang, Z. & Hall, M. E. Obesity, kidney dysfunction and hypertension: mechanistic links. Nat. Rev. Nephrol. 15, 367–385 (2019).
Kidney Disease: Improving Global Outcomes CKD Work Group. KDIGO 2024 Clinical Practice Guideline for the evaluation and management of chronic kidney disease. Kidney Int. 105, S117–S314 (2024).
Kidney Disease: Improving Global Outcomes Diabetes Work Group. KDIGO 2022 Clinical Practice Guideline for diabetes management in chronic kidney disease. Kidney Int. 102, S1–S127 (2022).
Oshima, M. et al. Early change in albuminuria with canagliflozin predicts kidney and cardiovascular outcomes: a post hoc analysis from the CREDENCE trial. J. Am. Soc. Nephrol. 31, 2925–2936 (2020).
de Zeeuw, D. et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int. 65, 2309–2320 (2004).
Heerspink, H. J. et al. Is a reduction in albuminuria associated with renal and cardiovascular protection? A post hoc analysis of the ALTITUDE trial. Diabetes Obes. Metab. 18, 169–177 (2016).
Michos, E. D., Bakris, G. L., Rodbard, H. W. & Tuttle, K. R. Glucagon-like peptide-1 receptor agonists in diabetic kidney disease: a review of their kidney and heart protection. Am. J. Prev. Cardiol. 14, 100502 (2023).
Muskiet, M. H. A. et al. GLP-1 and the kidney: from physiology to pharmacology and outcomes in diabetes. Nat. Rev. Nephrol. 13, 605–628 (2017).
Marso, S. P. et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N. Engl. J. Med. 375, 1834–1844 (2016).
Lincoff, A. M. et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N. Engl. J. Med. 389, 2221–2232 (2023).
Perkovic, V. et al. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes. N. Engl. J. Med. 391, 109–121 (2024).
Colhoun, H. M. et al. Long-term kidney outcomes of semaglutide in obesity and cardiovascular disease in the SELECT trial. Nat. Med. 30, 2058–2066 (2024).
Heerspink, H. J. L. et al. Effects of semaglutide on albuminuria and kidney function in people with overweight or obesity with or without type 2 diabetes: exploratory analysis from the STEP 1, 2, and 3 trials. Diabetes Care 46, 801–810 (2023).
Shaman, A. M. et al. Effect of the glucagon-like peptide-1 receptor agonists semaglutide and liraglutide on kidney outcomes in patients with type 2 diabetes: pooled analysis of SUSTAIN 6 and LEADER. Circulation 145, 575–585 (2022).
Apperloo, E. M. et al. Effect of semaglutide on kidney function across different levels of baseline HbA1c, blood pressure, body weight and albuminuria in SUSTAIN 6 and PIONEER 6. Nephrol. Dial. Transplant. gfae150 (2024).
Tuttle, K. R. et al. Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial. Lancet Diabetes Endocrinol. 6, 605–617 (2018).
Heerspink, H. J. L. et al. Change in albuminuria as a surrogate endpoint for progression of kidney disease: a meta-analysis of treatment effects in randomised clinical trials. Lancet Diabetes Endocrinol. 7, 128–139 (2019).
Mann, J. F. E. 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. https://doi.org/10.1038/s41591-024-03133-0 (2024).
Neuen, B. L. et al. Cardiovascular, kidney and safety outcomes with GLP-1 receptor agonists alone and in combination with SGLT2 inhibitors in type 2 diabetes: a systematic review and meta-analysis. Circulation https://doi.org/10.1161/CIRCULATIONAHA.124.071689 (2024).
Apperloo, E. M. et al. Efficacy and safety of SGLT2 inhibitors with and without glucagon-like peptide 1 receptor agonists: a SMART-C collaborative meta-analysis of randomised controlled trials. Lancet Diabetes Endocrinol. 12, 545–557 (2024).
Heerspink, H. J. L. et al. Effects of tirzepatide versus insulin glargine on kidney outcomes in type 2 diabetes in the SURPASS-4 trial: post-hoc analysis of an open-label, randomised, phase 3 trial. Lancet Diabetes Endocrinol. 10, 774–785 (2022).
Tuttle, K. R. et al. Body weight and eGFR during dulaglutide treatment in type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7). Diabetes Obes. Metab. 21, 1493–1497 (2019).
Heerspink, H. J. L. et al. Effects of tirzepatide versus insulin glargine on cystatin c-based kidney function: a SURPASS-4 post hoc analysis. Diabetes Care 46, 1501–1506 (2023).
Diabetes Care (American Diabetes Association, accessed 1 September 2024); https://diabetesjournals.org/diabetes/issue/73/Supplement_1
Li, K. et al. Effects of bariatric surgery on renal function in obese patients: a systematic review and meta analysis. PLoS ONE 11, e0163907 (2016).
Bilha, S. C. et al. The effects of bariatric surgery on renal outcomes: a systematic review and meta-analysis. Obes. Surg. 28, 3815–3833 (2018).
Clerte, M. et al. The measured glomerular filtration rate (mGFR) before and 6 months after bariatric surgery: a pilot study. Nephrol. Ther. 13, 160–167 (2017).
Fawaz, S. et al. Adiponectin reduces glomerular endothelial glycocalyx disruption and restores glomerular barrier function in a mouse model of type 2 diabetes. Diabetes 73, 964–976 (2024).
Sasson, A. N. & Cherney, D. Z. Renal hyperfiltration related to diabetes mellitus and obesity in human disease. World J. Diabetes 3, 1–6 (2012).
Chagnac, A. & Friedman, A. N. Measuring albuminuria in individuals with obesity: pitfalls of the urinary albumin-creatinine ratio. Kidney Med. 6, 100804 (2024).
Wilding, J. P. H. et al. Once-weekly semaglutide in adults with overweight or obesity. N. Engl. J. Med. 384, 989–1002 (2021).
Levey, A. S. et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann. Intern. Med. 130, 461–470 (1999).
Stevens, J. et al. UHPLC-MS/MS method for iohexol determination in human EDTA and lithium-heparin plasma, human urine and in goat- and pig EDTA plasma. Bioanalysis 12, 981–990 (2020).
Tuttle, K. R. et al. Efficacy and safety of aldosterone synthase inhibition with and without empagliflozin for chronic kidney disease: a randomised, controlled, phase 2 trial. Lancet 403, 379–390 (2024).
de Zeeuw, D. et al. Efficacy of a novel inhibitor of vascular adhesion protein-1 in reducing albuminuria in patients with diabetic kidney disease (ALBUM): a randomised, placebo-controlled, phase 2 trial. Lancet Diabetes Endocrinol. 6, 925–933 (2018).
Heerspink, H. J. L. et al. Zibotentan in combination with dapagliflozin compared with dapagliflozin in patients with chronic kidney disease (ZENITH-CKD): a multicentre, randomised, active-controlled, phase 2b, clinical trial. Lancet 402, 2004–2017 (2023).
Heerspink, H. J. L. et al. Effect of avenciguat on albuminuria in patients with CKD: two randomized placebo-controlled trials. J. Am. Soc. Nephrol. 25, 1227–1239 (2024).
Heerspink, H. J. L. et al. Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial. Lancet 401, 1584–1594 (2023).
Acknowledgements
We express our gratitude to all patients who participated in this trial. The authors thank J. Stevens, S. Galgey, H. Kamp-Nijmeijer, J. Beernink and B. Haandrikman for their continuous support in the conduct of this trial. D.Z.I.C. is supported by a Department of Medicine, University of Toronto Merit Award and receives support from the Canadian Institutes of Health Research (CIHR), Diabetes Canada and the Heart & Stroke/Richard Lewar Centre of Excellence in Cardiovascular Research. D.Z.I.C. is also the recipient of a 5-year CIHR-Kidney Foundation of Canada Team Grant award. The study was funded through a research grant from Novo Nordisk to the University Medical Center Groningen.
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Authors and Affiliations
Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
Ellen M. Apperloo,Niels Jongs&Hiddo J. L. Heerspink
Department of Nephrology, University Clinical Hospital, INCLIVA, University of Valencia, Valencia, Spain
Jose L. Gorriz&Maria Jesús Puchades
Department of Nephrology, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Research, Barcelona, Spain
Maria Jose Soler&Marina López-Martínez
Nephrology Service Hospital Ribera-Polusa Lugo, Lugo, Spain
Secundino Cigarrán Guldris
Department of Nephrology, Hospital Universitari Bellvitge, Bellvitge Biomedical Research Institute, University of Barcelona, Barcelona, Spain
Josep M. Cruzado
Department of Internal Medicine, Isala, Zwolle, The Netherlands
Femke Waanders
Department of Internal Medicine, ZiekenhuisGroep Twente, Almelo, The Netherlands
Gozewijn D. Laverman
Department of Internal Medicine, Martini Hospital, Groningen, The Netherlands
Annemarie van der Aart-van der Beek&Klaas Hoogenberg
Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
André P. van Beek
Department Internal Medicine, Rijnstate Ziekenhuis, Arnhem, The Netherlands
Jacobien Verhave
Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
Sofia B. Ahmed
Women and Children’s Health Research Institute, University of Alberta, Edmonton, AB, Canada
Sofia B. Ahmed
Department of Nephrology and Hypertension, University Hospital Erlangen Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
Roland E. Schmieder
Division of Nephrology, Department of Medicine, University Hospital Würzburg, Würzburg, Germany
Christoph Wanner
Division of Nephrology, Department of Medicine, Toronto General Hospital, University of Toronto, Toronto, ON, Canada
David Z. I. Cherney
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Contributions
E.M.A. and H.J.L.H. drafted the paper. N.J. conducted the analyses. All authors were involved in the study design, collection of the data and interpretation of the data and critically reviewed and edited the draft. The decision to submit the paper for publication was made jointly by all authors.
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Correspondence to Hiddo J. L. Heerspink.
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Competing interests
E.M., F.W., J.M.C., M.L.-M., J.V., K.H. and A.v.d.A. report no conflicts of interest. J.L.G. declares funding to conduct clinical trials from AstraZeneca, Bayer, Boehringer Ingelheim and Novo Nordisk (all to the INCLIVA Research Institute); consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim and Novo Nordisk; and payment of honoraria for lectures from AstraZeneca, Novo Nordisk, Bayer, Menarini, Boehringer Ingelheim and Eli Lilly. N.J. received travel support from AstraZeneca. S.C.G. declares funding to conduct clinical trials from AstraZeneca, Bayer, Boehringer Ingelheim and Novo Nordisk (all to the FIDES Research Foundation) and payment of honoraria for lectures from AstraZeneca, Novo Nordisk, Baxter, Chiesi, ChemoCentrix, Clarion and Boehringer Ingelheim. M.J.P. received board speaker fees and travel expenses from AstraZeneca, NovoNordisk, Boehringer Ingelheim, Eli Lilly, Bayer and Menarini. G.D.L. received lecture fees from Sanofi, AstraZeneca and Janssen and has served as a consultant for AbbVie, Sanofi, Novo Nordisk, AstraZeneca, Boehringer Ingelheim and Merck Sharp & Dohme. A.v.B. declares being contracted via the University of Groningen (no personal payment) to undertake consultancy for Novo Nordisk, Eli Lilly and Boehringer Ingelheim. D.Z.I.C. has received honoraria from Boehringer Ingelheim, Eli Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, AbbVie, Janssen, Bayer, Prometic, Bristol Myers Squibb, Maze, Gilead, CSL-Behring, Otsuka, Novartis, Youngene and Novo Nordisk and has received operational funding for clinical trials from Boehringer Ingelheim, Eli Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL-Behring and Novo Nordisk. S.B.A. reports no conflicts of interest. She receives research support from the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada. R.E.S. received grants to the institution from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim and NovoNordisk and speaker and advisor honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Servier and TAD. C.W. has received grants and served on steering committees for Boehringer Ingelheim; served on advisory boards for Boehringer Ingelheim, Merck Sharp & Dohme and Bayer; and received lecture fees from Boehringer Ingelheim, Eli Lilly, AstraZeneca, Merck Sharp & Dohme, Novo Nordisk and Bayer. H.J.L.H. is a consultant for AstraZeneca, Alexion, Bayer, Boehringer Ingelheim, CSL-Behring, DIMERIX, Eli Lilly, Gilead, Janssen, Novartis, Novo Nordisk, Roche, Travere Pharmaceuticals and VIFOR Pharma. He received research support through his institution from AstraZeneca, Boehringer Ingelheim, Janssen and Novo Nordisk. He received lecture fees from AstraZeneca, Bayer and Novo Nordisk.
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Extended data
Extended Data Fig. 1 Patient disposition.
Of 125 participants assessed for eligibility, 101 were randomly assigned to semaglutide (n = 51) or placebo (n = 50). Of these, 47 participants in the semaglutide group and 46 participants in the placebo group completed the study.
Extended Data Fig. 2 Urinary Albumin Concentration over time.
Change from baseline in urinary albumin concentration over the study treatment period. Adjusted geometric mean change from baseline in the semaglutide and placebo group is shown. The error bars represent 95% confidence interval.
Extended Data Fig. 3 eGFR in subset of participants.
Change in eGFR in 47 participants with iohexol measured GFR. The effect of semaglutide compared to placebo on estimated GFR was calculated using a MMRM model with two-sided P-values and with fixed effects for treatment, visit, baseline log-transformed UACR, the interaction between treatment and visit, and the interaction between baseline and estimated GFR. Numbers in the lower panel represent the numbers contributing to the mean.
Extended Data Fig. 4 Diastolic blood pressure over time.
Change from baseline in diastolic blood pressure. The effect of semaglutide compared to placebo on estimated diastolic blood pressure was calculated using a MMRM model with two-sided P-values and with fixed effects for treatment, visit, baseline log-transformed UACR, the interaction between treatment and visit, and the interaction between baseline and diastolic blood pressure. Numbers in the lower panel represent the numbers contributing to the mean.
Extended Data Fig. 5 Correlation graphs.
Correlation between changes after 24 weeks treatment in body weight and creatinine eGFR (A), cystatin-C eGFR (B) and iohexol mGFR (C). The correlations were calculated with Spearman correlation. Two-side p-values are reported.
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SMART investigator teams.
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Apperloo, E.M., Gorriz, J.L., Soler, M.J. et al. Semaglutide in patients with overweight or obesity and chronic kidney disease without diabetes: a randomized double-blind placebo-controlled clinical trial. Nat Med (2024). https://doi.org/10.1038/s41591-024-03327-6
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DOI: https://doi.org/10.1038/s41591-024-03327-6
