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SGLT2 inhibition in diabetes mellitus: rationale and clinical prospects

Nature Reviews Endocrinology volume 8, pages 495–502 (2012)Cite this article

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Abstract

This Review covers the rationale, physiological consequences and clinical application of pharmacological sodium–glucose cotransporter 2 (SGLT2) inhibition. In patients with type 2 diabetes mellitus, in whom renal glucose reabsorption might be upregulated, orally active, selective SGLT2 inhibitors improve glycaemic control to a therapeutically useful extent. Chronic administration of several SGLT2 inhibitors dose-dependently lowers HbA1c levels by 0.5–1.5% without causing hypoglycaemia. The unique mechanism of action of SGLT2 inhibitors—which does not hinge upon β-cell function or tissue insulin sensitivity—means that they can exert their antihyperglycaemic effects in combination with any other oral antidiabetic drug as well as insulin. Available phase III studies confirm a good tolerability profile. Weight loss owing to urinary calorie leakage may be less than expected, but the negative energy balance offers a valuable clinical benefit. Offloading of sodium can assist blood pressure control. The progressive loss of efficacy in patients with reduced glomerular function will have to be balanced against the possibility of renal protection. The safety issues of genitourinary infections and cancer risk requires careful, proactive monitoring and analysis of robust exposure data, particularly in elderly, frail patients and in patients with impaired kidney function and/or high cardiovascular/cancer risk, who represent an increasing fraction of the population with diabetes mellitus.

Key Points

  • Sodium–glucose cotransporter 2 (SGLT2) is the major cotransporter involved in reabsorption of filtered glucose in the tubular nephron of the kidney

  • Chronic hyperglycaemia in patients with diabetes mellitus might upregulate glucose reabsorption in the kidneys above normal levels

  • SGLT2 inhibitors lower the threshold for glycosuria by lowering the maximum transport capacity or, more likely, by reducing the affinity of the transporter for glucose without causing hypoglycaemia

  • SGLT2 inhibitors cause proximal diuresis and calorie leakage into the urine; therefore, the benefits of these agents could include blood pressure lowering and weight control

  • Increased risk of genitourinary infections is a consistent adverse effect of SGLT2 inhibitors

  • Gauging the effect of SGLT2 inhibitors in the population at high risk for kidney failure and cancer will require analysis of robust exposure data in large populations

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Figure 1: Schematic representation of the distribution of sodium–glucose cotransporters along an unrolled nephron.
Figure 2: Numerical simulation of renal glucose reabsorption (blue lines) and excretion (red lines) in an individual with a glomerular filtration rate of 120ml/min/1.73 m2 and a renal glucose threshold of 180mg/dl (10mmol/l).
Figure 3: Numerical simulation of renal glucose reabsorption (blue lines) and excretion (red lines) in a individual with a glomerular filtration rate of 120ml/min/1.73 m2 and a renal glucose threshold of 180mg/dl (10mmol/l).

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  1. Department of Internal Medicine, University of Pisa School of Medicine, Via Roma 67, Pisa, 56100, Italy

    Ele Ferrannini & Anna Solini

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E. Ferrannini declares associations with the following companies: Astellas (consultant), Bristol-Myers Squibb/AstraZeneca (consultant), Boehringer Ingelheim (consultant, grant/research support). See the article online for full details of the relationships. A. Solini declares no competing interests.

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Ferrannini, E., Solini, A. SGLT2 inhibition in diabetes mellitus: rationale and clinical prospects. Nat Rev Endocrinol 8, 495–502 (2012). https://doi.org/10.1038/nrendo.2011.243

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