title: SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials.
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.
authors.affiliation: Section of Endocrinology, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Silvio E
authors.initials: SE
authors.lastname: Inzucchi
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
authors.forename: Bernard
authors.initials: B
authors.lastname: Zinman
authors.affiliation: Division of Nephrology, University of Würzburg, Würzburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Wanner
authors.affiliation: 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.
authors.forename: Roberto
authors.initials: R
authors.lastname: Ferrari
authors.affiliation: St Michael's Hospital, University of Toronto, Toronto, ON, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Fitchett
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hantel
authors.affiliation: Boehringer Ingelheim España S.A, Barcelona, Spain.
authors.forename: Rosa-Maria
authors.initials: RM
authors.lastname: Espadero
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Woerle
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.
authors.forename: Uli C
authors.initials: UC
authors.lastname: Broedl
authors.affiliation: Boehringer Ingelheim Norway K.S, Asker, Norway Odd_erik.johansen@boehringer-ingelheim.com.
authors.forename: Odd Erik
authors.initials: OE
authors.lastname: Johansen
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000097:blood / Q000175:diagnosis / Q000503:physiopathology / Q000517:prevention & control*; D002986:Clinical Trials as Topic; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D058990:Molecular Targeted Therapy; D065667:Renal Elimination / Q000187:drug effects; D065608:Renal Reabsorption / Q000187:drug effects; D018570:Risk Assessment; D012307:Risk Factors; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D016896:Treatment Outcome
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors
keywords: Type 2 diabetes; cardiovascular complications; macrovascular; review; sodium glucose cotransporter-2 inhibitors