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Sodium–glucose cotransporter type 2 inhibitors for the treatment of type 2 diabetes mellitus

Abstract

The management of type 2 diabetes mellitus (T2DM) is becoming increasingly complex. Sodium–glucose cotransporter type 2 inhibitors (SGLT2is) are the newest antidiabetic agents for T2DM. By targeting the kidney, they have a unique mechanism of action, which results in enhanced glucosuria, osmotic diuresis and natriuresis, thereby improving glucose control with a limited risk of hypoglycaemia and exerting additional positive effects such as weight loss and the lowering of blood pressure. Several outcome studies with canagliflozin, dapagliflozin or empagliflozin reported a statistically significant reduction in major cardiovascular events, hospitalization for heart failure and progression to advanced renal disease in patients with T2DM who have established atherosclerotic cardiovascular disease, several cardiovascular risk factors, albuminuric mild to moderate chronic kidney disease or heart failure. Current guidelines proposed a new paradigm in the management of T2DM, with a preferential place for SGLT2is, after metformin, in patients with atherosclerotic cardiovascular disease, heart failure and progressive kidney disease. Ongoing trials might extend the therapeutic potential of SGLT2is in patients with, but also without, T2DM. This Review provides an update of the current knowledge on SGLT2is, moving from their use as glucose-lowering medications to their new positioning as cardiovascular and renal protective agents.

Key points

  • Sodium–glucose cotransporter type 2 inhibitors (SGLT2is) improve glucose control through direct and indirect mechanisms, with limited risk of hypoglycaemia, and exert other positive effects on body weight, blood pressure, blood uric acid levels and inflammation.

  • SGLT2is, added to standard care, reduce the incidence of major cardiovascular events (cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke) in patients with type 2 diabetes mellitus (T2DM) who are at high cardiovascular risk.

  • SGLT2is reduce the risk of hospitalization for heart failure and progression to end-stage renal disease in patients with T2DM who have high cardiovascular risk, an effect independent of improved glucose control.

  • SGLT2is can be associated with several adverse events, including genital infections, volume depletion, diabetic ketoacidosis and lower-limb amputations, which deserve caution by the physician and further pharmacovigilance studies.

  • SGLT2is are now considered preferential, after metformin, in patients with T2DM and atherosclerotic cardiovascular disease (as alternative to glucagon-like peptide 1 receptor agonists), heart failure or chronic kidney disease.

  • Ongoing trials in patients with heart failure, renal disease and fatty liver, with and without T2DM, will give new insights on the potential role of SGLT2is in a broader population.

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Fig. 1: Multiple beneficial effects related to enhanced sodium excretion by SGLT2is.
Fig. 2: Pleiotropic effects of SGLT2is that can contribute to improving cardiovascular outcomes.
Fig. 3: Position of SGLT2is in international guidelines.

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Correspondence to André J. Scheen.

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A.J.S. has received lecturer, scientific advisory and clinical investigator fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Novartis, NovoNordisk, Sanofi and Servier. He worked as a clinical investigator in the EMPA-REG OUTCOME, CANVAS-R and DECLARE-TIMI 58 trials.

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Scheen, A.J. Sodium–glucose cotransporter type 2 inhibitors for the treatment of type 2 diabetes mellitus. Nat Rev Endocrinol 16, 556–577 (2020). https://doi.org/10.1038/s41574-020-0392-2

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