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Combination therapy for kidney disease in people with diabetes mellitus

Nature Reviews Nephrology (2024)Cite this article

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Abstract

Diabetic kidney disease (DKD), defined as co-existing diabetes and chronic kidney disease in the absence of other clear causes of kidney injury, occurs in approximately 20–40% of patients with diabetes mellitus. As the global prevalence of diabetes has increased, DKD has become highly prevalent and a leading cause of kidney failure, accelerated cardiovascular disease, premature mortality and global health care expenditure. Multiple pathophysiological mechanisms contribute to DKD, and single lifestyle or pharmacological interventions have shown limited efficacy at preserving kidney function. For nearly two decades, renin–angiotensin system inhibitors were the only available kidney-protective drugs. However, several new drug classes, including sodium glucose cotransporter-2 inhibitors, a non-steroidal mineralocorticoid antagonist and a selective endothelin receptor antagonist, have now been demonstrated to improve kidney outcomes in people with type 2 diabetes mellitus. In addition, emerging preclinical and clinical evidence of the kidney-protective effects of glucagon-like-peptide-1 receptor agonists has led to the prospective testing of these agents for DKD. Research and clinical efforts are geared towards using therapies with potentially complementary efficacy in combination to safely halt kidney disease progression. As more kidney-protective drugs become available, the outlook for people living with DKD should improve in the next few decades.

Key points

  • Diabetic kidney disease (DKD) is associated with substantial morbidity and cardiovascular mortality, and for nearly two decades, the only kidney-protective treatment for DKD was renin–angiotensin system blockade.

  • Positive kidney outcome data have now been reported for SGLT2 inhibitors, the mineralocorticoid antagonist finerenone and endothelin receptor antagonists.

  • GLP1 receptor agonists have been shown to have beneficial effects on surrogate kidney end points, and a kidney outcomes trial is underway.

  • The advent of novel kidney-protective drugs provides new therapeutic options for people living with diabetes and kidney disease but increases the complexity of treatment decisions for caregivers.

  • Combining drugs may enhance their kidney protective efficacy and could potentially reduce the risk of adverse effects that are associated with specific drug classes.

  • An important goal for the future pharmacological management of DKD is to individualize treatment with optimal drug combinations based on the underlying pathophysiology and guided by tissue or serum biomarkers.

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Fig. 1: The pathophysiology of diabetic kidney disease.

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Acknowledgements

D.H.V.R. is supported by a senior fellowship of the Dutch Diabetes Foundation and by a PIONEER + grant of the Dutch Kidney Foundation. P.B. receives salary and research support from the NIDDK (R01 DK129211, R01 DK132399, RO1 HL165433, R21 DK129720 and UC2 DK114886), JDRF (3-SRA-2022-1097-M-B, 3-SRA-2022-1243-M-B, and 3-SRA-2022-1230-M-B), the Boettcher Foundation, the American Heart Association (20IPA35260142), the Ludeman Family Center for Women’s Health Research at the University of Colorado, the Department of Paediatrics, Section of Endocrinology, and the Barbara Davis Center for Diabetes at University of Colorado School of Medicine. I.H.D.B. is supported by NIH grants R01DK125084, R01DK132399, R01DK126373, and grant funding from JDRF. D.G. is supported by Wilhelm and Else Stockmann Foundation, Liv och Hälsa Society, Medical Society of Finland (Finska Läkaresällskapet), Sigrid Juselius Foundation, Helsinki University Hospital, University of Helsinki, Minerva Foundation Institute for Medical Research Clinician Scientist, and Academy of Finland (UAK1021MRI). S.E.R. reports research support from AstraZeneca, Bayer and NIH/NIDDK [U01DK133092 and U01DK116102] to Joslin Diabetes Center. She also benefited from participation in the Joslin Diabetes research enrichment program funded by P30 DK03836. J.A.S. received salary support provided by K08DK124449. K.T. is supported by NIH research grants R01MD014712, U2CDK114886, UL1TR002319, U54DK083912, U01DK100846, OT2HL161847, UM1AI109568, OT2OD032581 and CDC project number 75D301-21-P-12254. S.S.W. is supported by research grants R01DK108803, U01DK130060, U01DK133092, U01AG076789 and R25DK128858.

Author information

Authors and Affiliations

  1. Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, VUMC, Amsterdam, The Netherlands

    Daniël H. van Raalte

  2. Diabetes Center, Amsterdam University Medical Centers, VUMC, Amsterdam, The Netherlands

    Daniël H. van Raalte

  3. Research Institute for Cardiovascular Sciences, VU University, Amsterdam, The Netherlands

    Daniël H. van Raalte

  4. University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA

    Petter Bjornstad

  5. Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada

    David Z. I. Cherney

  6. Division of Nephrology and Kidney Research Institute, University of Washington, Seattle, Washington, USA

    Ian H. de Boer

  7. Department of Medicine, University of Padua, Unit of Medical Clinic 3, Padua, Italy

    Paola Fioretto

  8. Minerva Foundation Institute for Medical Research, Helsinki, Finland

    Daniel Gordin

  9. Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

    Daniel Gordin

  10. Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA

    Daniel Gordin & Sylvia E. Rosas

  11. Steno Diabetes Center, Copenhagen, Denmark

    Frederik Persson & Peter Rossing

  12. Nephrology Division, Department of Medicine, University of Michigan, Ann Arbor, Michigan, USA

    Jennifer A. Schaub

  13. Providence Medical Research Center, Providence Inland Northwest Health, Spokane, Washington, USA

    Katherine Tuttle

  14. Department of Medicine, University of Washington School of Medicine, Spokane and Seattle, Washington, USA

    Katherine Tuttle

  15. Nephrology Division, Kidney Research Institute and Institute of Translational Health Sciences, University of Washington, Spokane and Seattle, Washington, USA

    Katherine Tuttle

  16. Section of Nephrology, Boston University Chobanian & Avedisian School of Medicine and Boston Medical Center, Boston, Massachusetts, USA

    Sushrut S. Waikar

  17. Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

    Hiddo J. L. Heerspink

  18. The George Institute for Global Health, Sydney, New South Wales, Australia

    Hiddo J. L. Heerspink

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  1. Daniël H. van Raalte
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  2. Petter Bjornstad
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Contributions

All authors researched data for the article, contributed substantially to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Daniël H. van Raalte.

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Competing interests

D.H.V.R. has consulting relationships with Bayer, Boehringer Ingelheim, Eli Lilly, Merck and Sanofi, and receives research operating funding from AstraZeneca, Boehringer Ingelheim-Eli Lilly Diabetes Alliance and MSD. Honoraria are transferred to employer Amsterdam UMC. P.B. reports serving or having served as a consultant for AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, LG Chemistry, Sanofi, Novo Nordisk and Horizon Pharma. P.B. also serves or has served on the advisory boards and/or steering committees of AstraZeneca, Bayer, Boehringer Ingelheim, Novo Nordisk and XORTX. P.B. receives grant support from Eli Lilly, Novo Nordisk, AstraZeneca, Merck, and Horizon Pharma. D.Z.I.C. reports serving or having served as a consultant for Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, AbbVie, Janssen, Bayer, Prometic, BMS, Maze, Gilead, CSL-Behring, Otsuka, Novartis, Youngene, Lexicon, Inversago, GSK and Novo-Nordisk. He has received operational funding from Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL-Behring and Novo-Nordisk. I.H.D.B. has received consulting fees from AstraZeneca, Bayer, Boehringer-Ingelheim, Cyclerion Therapeutics, George Clinical, Gilead, Goldfinch Bio, Ironwood, Medscape and Otsuka. P.F. has received fees as consultant and speaker for AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly company and Novo Nordisk. D.G. has received lecture or Advisory Board Honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Delta Medical Communications, EASD eLearning, Finnish Association for Vascular Surgery, Finnish Nephrology Association, Kidney and Liver Foundation in Finland. F.P. has served as a consultant, on advisory boards or as educator for AstraZeneca, Novo Nordisk, Boehringer Ingelheim, Sanofi, Mundipharma, MSD, Novartis and Amgen, and has received research grants to institution from Novo Nordisk, Boehringer Ingelheim, Amgen and AstraZeneca. S.E.R. has participated as a member of scientific advisory boards for AstraZeneca, Bayer, and Travere. P.R. has received research support and personal fees from AstraZeneca, Bayer, and Novo Nordisk and personal fees from Abbott, Astellas, Bayer, Boehringer Ingelheim, Eli Lilly, Gilead and Sanofi. All fees are given to Steno Diabetes Center Copenhagen. K.T. reports consulting relationships with Eli Lilly, Boehringer Ingelheim, AstraZeneca, Pfizer, Bayer and Novo Nordisk, and receives research grants from Travere paid to employer, Providence Inland Northwest Health. S.S.W. is consultant for Wolters Kluwer, Bain, BioMarin, Goldfinch, GSK, Ikena, Strataca, Google, CANbridge, NovoNordisk, PepGen, Sironax and NovoNordisk, and expert witness for Davita, Pfizer, Dechert and Aurinia Pharmaceuticals. S.S.W. receives research funding from Vertex, Pfizer, JNJ and Natera. H.J.L.H. is consultant for AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, CSL Behring, Dimerix, Eli-Lilly, Gilead, Janssen, Merck, Novo Nordisk, ProKidney, Travere Therapeutics and Vifor Fresenius. He has received research support from AstraZeneca, Boehringer Ingelheim, Janssen and Novo Nordisk.

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Nature Reviews Nephrology thanks Mark Cooper, Beatriz Fernandez-Fernandez and Pierre-Jean Saulnier for their contribution to the peer review of this work.

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Glossary

Diabetes case-finding

A systematic approach to identifying patients with a disease. Active screening for hyperglycaemia has increased the detection of diabetes in the general population.

Mediation analyses

Statistical models that seek to explain a mechanism that underlies a relationship between two variables or conditions by including a mediation variable.

Steno Type 1 Risk Engine

A risk calculator that estimates the 10-year risk of fatal or non-fatal cardiovascular disease in patients with type 1 diabetes mellitus. The calculator incorporates clinical and biochemical risk parameters.

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van Raalte, D.H., Bjornstad, P., Cherney, D.Z.I. et al. Combination therapy for kidney disease in people with diabetes mellitus. Nat Rev Nephrol (2024). https://doi.org/10.1038/s41581-024-00827-z

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