title: Stroke paradox with SGLT-2 inhibitors: a play of chance or a viscosity-mediated reality?
abstract: Diabetes mellitus is a major risk factor for cardiovascular morbidity and mortality. Current therapeutic strategies have not provided constant beneficial cardiovascular-related results. Sodium-glucose co-transporters 2 (SGLT-2) inhibitors have emerged as a novel antidiabetic class of drugs that exert favourable results in a variety of other cardiovascular risk factors too, such as increased blood pressure and body weight. The Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME) study was the first trial that evaluated cardiovascular outcomes in patients with diabetes with the use of empagliflozin, a member of this new class of drugs. Empagliflozin was associated with remarkable reduction of cardiovascular morbidity and mortality and all-cause death. On the contrary, stroke incidence was slightly increased, although the result did not reach statistical significance. It could be assumed that a drug providing such beneficial effects on cardiovascular outcomes, would have also the same impact in stroke risk. This finding could theoretically be attributed to 'play of chance'. However, an increase of haematocrit was observed in EMPA-REG and other SGLT-2 inhibitors studies. Accumulating evidence suggests a direct association between increased haematocrit and stroke risk. Could this 'stroke paradox' be a result of the increased haematocrit levels noted with SGLT-2 inhibitors? The aim of this review is to critically assess both possibilities, given that increased stroke rates (if indeed true) should not be neglected and unattended.
authors.affiliation: Second Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: Konstantinos P
authors.initials: KP
authors.lastname: Imprialos
authors.affiliation: Second Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: Chrysoula
authors.initials: C
authors.lastname: Boutari
authors.affiliation: Second Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Stavropoulos
authors.affiliation: George Washington University, Washington DC, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Doumas
authors.affiliation: Second Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: Asterios I
authors.initials: AI
authors.lastname: Karagiannis
mesh_terms: D001559:Benzhydryl Compounds / Q000627:therapeutic use; D001809:Blood Viscosity; D002318:Cardiovascular Diseases / Q000209:etiology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D005960:Glucosides / Q000627:therapeutic use; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D012307:Risk Factors; D020521:Stroke / Q000097:blood / Q000209:etiology*
chemical_list: D001559:Benzhydryl Compounds; D005960:Glucosides; D007004:Hypoglycemic Agents; C570240:empagliflozin
keywords: CEREBROVASCULAR DISEASE; DIABETES MELLITUS