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Applications of SGLT2 inhibitors beyond glycaemic control

Abstract

Sodium–glucose cotransporter 2 (SGLT2) inhibitors were initially developed for their glucose-lowering effects and have shown a modest glycaemic benefit in people with type 2 diabetes mellitus (T2DM). In the past decade, a series of large, robust clinical trials of these therapies have demonstrated striking beneficial effects for various care goals, transforming the chronic disease therapeutic landscape. Cardiovascular safety studies in people with T2DM demonstrated that SGLT2 inhibitors reduce cardiovascular death and hospitalization for heart failure. Subsequent trials in participants with heart failure with reduced or preserved left ventricular ejection fraction demonstrated that SGLT2 inhibitors have beneficial effects on heart failure outcomes. In dedicated kidney outcome studies, SGLT2 inhibitors reduced the incidence of kidney failure among participants with or without diabetes. Post hoc analyses have suggested a range of other benefits of these drugs in conditions as diverse as metabolic dysfunction-associated steatotic liver disease, kidney stone prevention and anaemia. SGLT2 inhibitors have a generally favourable adverse effect profile, although patient selection and medication counselling remain important. Concerted efforts are needed to better integrate these agents into routine care and support long-term medication adherence to close the gap between clinical trial outcomes and those achieved in the real world.

Key points

  • Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of kidney disease progression in people with or without diabetes as well as the risk of acute kidney injury and hyperkalaemia.

  • SGLT2 inhibitors reduce the risk of cardiovascular death and heart failure hospitalization among people with type 2 diabetes mellitus and have beneficial effects on key heart failure outcomes irrespective of diabetes status or left ventricular ejection fraction.

  • SGLT2 inhibitors modestly lower systolic and diastolic blood pressure without a significant increase in risk of hypotensive episodes and have modest benefits for weight loss.

  • Other benefits of SGLT2 inhibitors include improvements in liver outcomes in people with metabolic dysfunction-associated steatotic liver disease, reduced risk of symptomatic kidney stone events, improvements in anaemia outcomes and potential reductions in the risk of new-onset atrial fibrillation and new-onset diabetes.

  • SGLT2 inhibitors have a generally favourable adverse effect profile but are associated with increased risk of genital mycotic infections and a small increased risk of diabetic ketoacidosis; they should be used with caution in people with unstable volume status owing to the risk of hypovolaemia.

  • Prescription of SGLT2 by clinicians and patient adherence are suboptimal despite strong evidence for the efficacy and cost-effectiveness of these therapies.

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Fig. 1: Putative mechanisms of action of SGLT2 inhibitors.
Fig. 2: The effects of SGLT2 inhibitors on kidney and cardiovascular outcomes in meta-analyses.

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Acknowledgements

D.V.O. receives support through an Australian Government Research Training Program Scholarship, the Royal Australian Society of Nephrology Jacquot Research Entry Scholarship and the NHMRC Clinical Trials Centre Postgraduate Research Scholarship. C.S.P.L. is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore. T.W.Y. is supported by the BC Renal Scholar Award. M.J.J. is supported by an Australian Government NHMRC Investigator Fellowship. The authors thank R. Morton for her valuable input on the cost-effectiveness discussion.

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Correspondence to Meg J. Jardine.

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C.S.P.L. has received research support from Novo Nordisk and Roche Diagnostics; has served as consultant or on the Advisory Board/Steering Committee/Executive Committee for Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb (BMS), CardioRenal, Cytokinetics, Darma Inc., EchoNous Inc., Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc., Quidel Corporation, Radcliffe Group Ltd, Recardio Inc., ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics and Us2.ai; and serves as co-founder and non-executive director of Us2.ai. J.J.V.M. reports payments through Glasgow University from work on clinical trials, consulting and other activities from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GSK, KBP Biosciences and Novartis; personal consultancy fees from Alnylam Pharma, Bayer, BMS, George Clinical PTY Ltd, Ionis Pharma, Novartis, Regeneron Pharma, River 2 Renal Corporation; and personal lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions Ltd, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharma Ltd, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharma, J. B. Chemicals & Pharma Ltd, Lupin Pharma, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharma, The Corpus, Translation Research Group, Translational Medicine Academy; and is a director of Global Clinical Trial Partners Ltd. S.H. was an investigator on CANVAS, CANVAS-R, CREDENCE and VERTIS CV trials assessing SGLT2 inhibitors and has received honoraria from AstraZeneca, Boehringer Ingelheim and Merck Sharp & Dohme (MSD), which produce SGLT2 inhibitors. M.J.J. is responsible for research projects that have received unrestricted funding from Amgen, Baxter, Eli Lilly, Gambro and MSD; has served on advisory boards sponsored by AstraZeneca, Baxter, Bayer, Boehringer Ingelheim, Cesas Linx, MSD, OccuRx and Vifor; serves or has served on steering committee for trials sponsored by Chinook, CSL and Janssen; serves on a steering committee for an investigator-initiated trial with funding support from Dimerix, received speakers fees from Janssen, Medcon International PACE CME (Physician’s Academy for Cardiovascular Education), Medscape and Vifor; with any consultancy, honoraria or travel support paid to her institution. D.V.O., T.W.Y., J.D., S.R. and A.S.J. declare no competing interests.

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Nature Reviews Nephrology thanks Richard Haynes who co-reviewed with Doreen Zhu, and the other, anonymous, reviewer for their contribution to the peer review of this work.

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O’Hara, D.V., Lam, C.S.P., McMurray, J.J.V. et al. Applications of SGLT2 inhibitors beyond glycaemic control. Nat Rev Nephrol 20, 513–529 (2024). https://doi.org/10.1038/s41581-024-00836-y

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