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

Silvio E Inzucchi, Bernard Zinman, Christoph Wanner, Roberto Ferrari, David Fitchett, Stefan Hantel, Rosa-Maria Espadero, Hans-Jürgen Woerle, Uli C Broedl, Odd Erik Johansen, Silvio E Inzucchi, Bernard Zinman, Christoph Wanner, Roberto Ferrari, David Fitchett, Stefan Hantel, Rosa-Maria Espadero, Hans-Jürgen Woerle, Uli C Broedl, Odd Erik Johansen

Abstract

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.

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

Conflict of interest statement

Declaration of conflicting interests: S.E.I. has served as a consultant to Merck, Boehringer Ingelheim, Bristol-Meyers Squibb, Novo-Nordisk, Eisai, and Lexicon. He serves on data monitoring committees for Novo Nordisk and Intarcia. B.Z. has served as a consultant for Astra Zeneca, Boehringer Ingelheim, Eli Lilly,Janssen, Merck, Novo Nordisk, Takeda and Sanofi. He has received grant support from Merck, Novo Nordisk and Boehringer Ingelheim. C.W. has served as a consultant to Boehringer Ingelheim. R.F. has received honorarium for steering committee membership, consulting, speaking, and support for travel to study meetings, from Servier. He has served as a consultant to Abbott, Amgen, Boehringer-Ingelheim, Novartis, Merck Serono and Irbtech and he is a stockholder in Medical Trials Analyis. D.F. has served as a consultant to Merck, Boehringer-Ingelheim, Bristol-Meyers Squibb, and Amgen. He serves on data monitoring committees for Novo Nordisk. S.H., R.-M.E., H.J.W., U.C.B. and O.E.J. are employees of BI, the developer of empagliflozin.

© The Author(s) 2015.

Figures

Figure 1.
Figure 1.
Identified potential and novel pathways associated with CV effects of SGLT-2 inhibitors based on clinical and mechanistic studies.

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