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Diab Vasc Dis Res. 2015 Mar;12(2):90-100. doi: 10.1177/1479164114559852. Epub 2015 Jan 14.

SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials.

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Section of Endocrinology, Yale School of Medicine, New Haven, CT, USA.
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
Division of Nephrology, University of Würzburg, Würzburg, Germany.
Department of Cardiology and LTTA Centre, University Hospital of Ferrara, Ferrara, Italy Maria Cecilia Hospital, GVM Care & Research, E.S: Health Science Foundation, Cotignola, Italy.
St Michael's Hospital, University of Toronto, Toronto, ON, Canada.
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
Boehringer Ingelheim España S.A, Barcelona, Spain.
Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.
Boehringer Ingelheim Norway K.S, Asker, Norway


Given the multi-faceted pathogenesis of atherosclerosis in type 2 diabetes mellitus (T2DM), it is likely that interventions to mitigate this risk must address cardiovascular (CV) risk factors beyond glucose itself. Sodium glucose cotransporter-2 (SGLT-2) inhibitors are newer antihyperglycaemic agents with apparent multiple effects. Inherent in their mode of action to decrease glucose reabsorption by the kidneys by increasing urinary glucose excretion, these agents improve glycaemic control independent of insulin secretion with a low risk of hypoglycaemia. In this review, we outline those CV risk factors that this class appears to influence and provide the design features and trial characteristics of six ongoing outcome trials involving more than 41,000 individuals with T2DM. Those risk factors beyond glucose that can potentially be modulated positively with SGLT-2 inhibitors include blood pressure, weight, visceral adiposity, hyperinsulinaemia, arterial stiffness, albuminuria, circulating uric acid levels and oxidative stress. On the other hand, small increases in low-density lipoprotein (LDL)-cholesterol levels have also been observed for the class, which theoretically might offset some of these benefits. The potential translational impact of these effects is being tested with outcome trials, also reviewed in this article, powered to assess both macrovascular as well as certain microvascular outcomes in T2DM. These are expected to begin to report in late 2015.


Type 2 diabetes; cardiovascular complications; macrovascular; review; sodium glucose cotransporter-2 inhibitors

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