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SGLT inhibitors: a serendipitous glycaemic tale

Nature Reviews Endocrinology volume 20, page 65 (2024)Cite this article

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Humans have evolved to conserve energy: bipedalism, for example, is widely claimed to use less energy than quadrupedal knuckle walking. Sodium–glucose co-transporters (SGLTs) might similarly have emerged in the kidneys over time to prevent glucose being excreted (and thus, energy being wasted) by the body. SGLT2 present in the early proximal convoluted tubule of nephrons reabsorbs the majority of glucose from the glomerular filtrate, whereas SGLT1 reabsorbs the remaining glucose in the late proximal convoluted tubule.

In individuals with diabetes mellitus, although excess glucose arising from hyperglycaemia is filtered by the glomerulus, a compensatory increase in the levels of SGLT2 in the proximal convoluted tubule reabsorbs this filtered glucose, thus further exacerbating the hyperglycaemia. Eventually, once a threshold of glucose reabsorption is crossed, glycosuria ensues in the setting of hyperglycaemia. Although blocking SGLT2 in the nephrons reduces hyperglycaemia, the development of SGLT2 inhibitors (SGLT2i) for lowering glucose levels in individuals with type 2 diabetes mellitus was initially met with a hefty dose of scepticism, being viewed as a non-physiological approach that did not address the underlying disease pathology. However, the turn of events that led to the subsequent development of these agents for indications way beyond glucose lowering was serendipitous.

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References

Original article

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  • Abdul-Ghani, M. A. et al. Role of sodium–glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. Endocr. Rev. 32, 515–531 (2011)

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Authors and Affiliations

  1. Division of Endocrinology, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA

    Shubham Agarwal & Ildiko Lingvay

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  1. Shubham Agarwal
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  2. Ildiko Lingvay
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Correspondence to Shubham Agarwal.

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Competing interests

S.A. declares no competing interests. I.L. has received grants paid to The University of Texas Southwestern Medical Center from Novo Nordisk, Pfizer, Merck, Sanofi, Boehringer Ingelheim and Mylan, and has received consulting fees and travel expenses from Novo Nordisk, Eli Lilly, Johnson & Johnson, Merck, Pfizer, Sanofi, Boehringer Ingelheim, Zealand, Bayer, Intercept, Valeritas, Structure, Carmot, Shionoghi, Mediflix and WebMD.

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Agarwal, S., Lingvay, I. SGLT inhibitors: a serendipitous glycaemic tale. Nat Rev Endocrinol 20, 65 (2024). https://doi.org/10.1038/s41574-023-00923-3

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