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  • Review Article
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Cardiometabolic and renal benefits of sodium–glucose cotransporter 2 inhibitors

Nature Reviews Endocrinology (2025)Cite this article

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Abstract

The therapeutic scope of sodium–glucose cotransporter 2 (SGLT2) inhibitors has expanded beyond glycaemic regulation in the management of diabetes mellitus. Studies published in the past few years highlight their substantial effect on cardiovascular outcomes, notably in decreasing mortality and the need for heart failure-related hospitalization. These agents also lead to pronounced improvements in a range of renal outcomes. The primary actions of SGLT2 inhibition, glycosuria and natriuresis, are pivotal in enhancing glucose control, promoting weight loss and lowering blood pressure. These effects initiate a series of beneficial mechanisms: facilitating haemodynamic improvement by reducing interstitial volume, enhancing cardiac function, boosting energy efficiency through altered ketone body metabolism and mitigating inflammation and oxidative stress. Additional effects include heightened erythropoiesis, reduced hyperuricaemia and increased levels of angiotensin-converting enzyme 2 and angiotensin (1–7). SGLT2 inhibitors also attenuate sympathetic overactivity by modulating neurohumoral activation and renal afferent signalling, contributing to their cardioprotective and renoprotective profiles. This Review provides a comprehensive overview of the diverse mechanisms underpinning the cardiometabolic and renal effects of SGLT2 inhibitors, emphasizing their clinical relevance and therapeutic potential.

Key points

  • Clinical trials have demonstrated the therapeutic role of SGLT2 inhibitors beyond glycaemic control, and have demonstrated clinical benefits for cardiometabolic and renal outcomes mediated through multiple direct and indirect mechanisms.

  • SGLT2 inhibition in the kidney induces glycosuria and natriuresis, resulting in reduced blood levels of glucose and sodium, which in turn contribute to weight loss and blood pressure reduction.

  • Haemodynamic effects combined with attenuation of sympathetic activity through SGLT2 inhibition are crucial for preventing progression of heart failure and chronic kidney disease.

  • SGLT2 inhibition can systematically induce metabolic shifts (reprogramming) towards ketogenesis and promote autophagy with anti-inflammatory and anti-fibrotic effects.

  • Major adverse effects of SGLT2 inhibitors include hypovolaemia due to osmotic diuresis, genital tract infection and euglycaemic ketoacidosis.

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Fig. 1: Effects of sodium–glucose cotransporter 2 inhibitors on the liver.
Fig. 2: Cardiometabolic and renal mechanisms of sodium–glucose cotransporter 2 inhibition.

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Acknowledgements

The authors appreciate the Medical Illustration & Design (MID) team, a member of Medical Research Support Services of Yonsei University College of Medicine, Seoul, South Korea, for their excellent support with medical illustration and M. Sohn for her valuable assistance in the preparation of the tables.

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Authors and Affiliations

  1. Department of Internal Medicine, Institute for Innovation in Digital Healthcare (IIDH), Institute for Endocrine Research, Yonsei University College of Medicine, Seoul, Republic of Korea

    Yong-ho Lee

  2. Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Bundang Hospital, Seongnam, Republic of Korea

    Soo Lim

  3. Diabetes Research Centre, University of Leicester, Leicester, UK

    Melanie J. Davies

  4. Leicester NIHR Biomedical Research Centre, Leicester General Hospital, University of Leicester, Leicester, UK

    Melanie J. Davies

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  1. Yong-ho Lee
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  2. Soo Lim
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The authors contributed equally to all aspects of the article.

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Correspondence to Soo Lim or Melanie J. Davies.

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Competing interests

Y.L. has received research grants from Asen, Chong Kun Dang Pharmaceutical, Daewoong Pharmaceutical, Jeil Pharmaceutical and Yuhan Corporation; and clinical investigator fees from Eli Lilly, Hanmi Pharmaceutical and Novo Nordisk. S.L. has received research grants from LG Chem, Merck Sharp & Dohme and Novo Nordisk, and honoraria as a consultant or speaker from Abbott, AstraZeneca, Boehringer Ingelheim, Chong Kun Dang Pharmaceutical, Daewoong Pharmaceutical, LG Chem and Novo Nordisk. M.J.D. has acted as consultant, advisory board member and speaker for Boehringer Ingelheim, Lilly, Novo Nordisk and Sanofi; has been an advisory board member and speaker for AstraZeneca; has acted as an advisory board member for Janssen, Lexicon, Pfizer and ShouTi Pharma; has acted as a speaker for Napp Pharmaceuticals, Novartis and Takeda Pharmaceuticals International; and has received grants in support of investigator-initiated trials from AstraZeneca, Boehringer Ingelheim, Lilly, Janssen, Novo Nordisk and Sanofi-Aventis.

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Lee, Yh., Lim, S. & Davies, M.J. Cardiometabolic and renal benefits of sodium–glucose cotransporter 2 inhibitors. Nat Rev Endocrinol (2025). https://doi.org/10.1038/s41574-025-01170-4

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