Antidiabetic drugs and stroke risk. Current evidence

Published:September 20, 2017DOI:


      • Diabetes may be responsible for >8% of first ischemic strokes.
      • Until recently, no antidiabetic drug has been proven to reduce stroke risk.
      • Moreover, several antidiabetics (i.e., sulfonylureas) increased the risk of stroke.
      • Currently, metformin, pioglitazone and semaglutide have shown to reduce this risk.
      • Further studies will help to select the best treatment for decreasing stroke risk.


      Cardiovascular disease (CVD) is the major cause of morbidity and mortality for individuals with type 2 diabetes (T2D). In particular, the risk for stroke is twice that of patients without diabetes, and diabetes may be responsible for >8% of first ischemic strokes. Therefore, the way to prevent stroke in these patients has become an important issue.
      Traditionally, glucose-lowering drugs had not been shown to protect against stroke. Moreover, several antidiabetic drugs (i.e., sulfonylureas, rosiglitazone) have been reported to be associated with increased risks of CVD and stroke. On the contrary, data on the CV risks and benefits associated with new antidiabetic treatment in patients with T2D are emerging - and look promising. Therefore, it could be of great value to find out if any type of these new antidiabetic agents has protective effect against stroke.
      We review the available evidence regarding the risk of stroke in individuals taking non-insulin antidiabetic agents.
      To date, several antidiabetic agents have shown to have a positive effect on stroke prevention. The accumulated evidence suggests that metformin, pioglitazone and semaglutide reduce stroke risk. These agents do not represent only a way of controlling blood glucose and but also offer the opportunity to reduce stroke risk.
      Surely, new data from ongoing and future studies will provide additional information to select the best treatment for decreasing stroke risk in T2D patients.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to European Journal of Internal Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Laakso M.
        Cardiovascular disease in type 2 diabetes from population to man to mechanisms.
        Diabetes Care. 2010; 33: 442-449
        • Azimova K.
        • San Juan Z.
        • Mukherjee D.
        Cardiovascular safety profile of currently available diabetic drugs.
        Ochsner J. 2014; 14: 616-632
        • Sarwar N.
        • Gao P.
        • Seshasai S.R.
        • Gobin R.
        • Kaptoge S.
        • Di Angelantonio E.
        • et al.
        Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies.
        Lancet. 2010; 375: 2215-2222
        • Kernan W.N.
        • Ovbiagele B.
        • Black H.R.
        • Bravata D.M.
        • Chimowitz M.I.
        • Ezekowitz M.D.
        • et al.
        Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.
        Stroke. 2014; 45: 2160-2236
        • Schernthaner G.
        • Jarvis S.
        • Lotan C.
        • Prázný M.
        • Wanner C.
        • Wascher T.C.
        Advances in the management of cardiovascular risk for patients with type 2 diabetes: perspectives from the Academy for Cardiovascular Risk, Outcomes and Safety Studies in Type 2 Diabetes.
        Ther Clin Risk Manag. 2017; 13: 69-79
        • U.S. Department of Health and Human Services FDA
        • Center for Drug Evaluation and Research (CDER)
        Guidance for Industry. Diabetes mellitus—evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes.
        • European Medicines Agency
        Guideline on the Investigation of Drug Interactions.
        • Chawla H.
        • Tandon N.
        Interpreting cardiovascular endpoints in trials of antihyperglycemic drugs.
        Am J Cardiovasc Drugs. 2017; 17: 203-215
        • Parkinson F.E.
        • Hatch G.M.
        Is there enhanced risk of cerebral ischemic stroke by sulfonylureas in type 2 diabetes?.
        Diabetes. 2016; 65: 2479-2481
        • Kunte H.
        • Schmidt S.
        • Eliasziw M.
        • del Zoppo G.J.
        • Simard J.M.
        • Masuhr F.
        • et al.
        Sulfonylureas improve outcome in patients with type 2 diabetes and acute ischemic stroke.
        Stroke. 2007; 38: 2526-2530
        • Weih M.
        • Amberger N.
        • Wegener S.
        • Dirnagl U.
        • Reuter T.
        • Einhäupl K.
        Sulfonylurea drugs do not influence initial stroke severity and in-hospital outcome in stroke patients with diabetes.
        Stroke. 2001; 32: 2029-2032
        • Bannister C.A.
        • Holden S.E.
        • Jenkins-Jones S.
        • Morgan C.L.
        • Halcox J.P.
        • Schernthaner G.
        • et al.
        Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls.
        Diabetes Obes Metab. 2014; 16: 1165-1173
        • Stephan D.
        • Winkler M.
        • Kühner P.
        • Russ U.
        • Quast U.
        Selectivity of repaglinide and glibenclamide for the pancreatic over the cardiovascular K(ATP) channels.
        Diabetologia. 2006; 49: 2039-2048
        • Liu R.
        • Wang H.
        • Xu B.
        • Chen W.
        • Turlova E.
        • Dong N.
        • et al.
        Cerebrovascular safety of sulfonylureas: the role of KATP channels in neuroprotection and the risk of stroke in patients with type 2 diabetes.
        Diabetes. 2016; 65: 2795-2809
        • Chaudhury A.
        • Duvoor C.
        • Reddy Dendi V.S.
        • Kraleti S.
        • Chada A.
        • Ravilla R.
        • et al.
        Clinical review of antidiabetic drugs: implications for type 2 diabetes mellitus management.
        Front Endocrinol (Lausanne). 2017; 8: 6
        • UK Prospective Diabetes Study Group
        Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes (UKPDS 38).
        Br Med J. 1998; 317: 703-713
        • Triggle C.R.
        • Ding H.
        Metformin is not just an antihyperglycaemic drug but also has protective effects on the vascular endothelium.
        Acta Physiol (Oxf). 2017; 219: 138-151
        • Li J.
        • Benashski S.E.
        • Venna V.R.
        • McCullough L.D.
        Effects of metformin in experimental stroke.
        Stroke. 2010; 41: 2645-2652
        • Jia J.
        • Cheng J.
        • Ni J.
        • Zhen X.
        Neuropharmacological actions of metformin in stroke.
        Curr Neuropharmacol. 2015; 13: 389-394
        • Cheng Y.Y.
        • Leu H.B.
        • Chen T.J.
        • Chen C.L.
        • Kuo C.H.
        • Lee S.D.
        • et al.
        Metformin-inclusive therapy reduces the risk of stroke in patients with diabetes: a 4-year follow-up study.
        J Stroke Cerebrovasc Dis. 2014; 23: e99-105
        • Dormandy J.A.
        • Charbonnel B.
        • Eckland D.J.
        • Erdmann E.
        • Massi-Benedetti M.
        • Moules I.K.
        • et al.
        Secondary prevention of macrovascular events in patients with Type 2 diabetes: a randomized trial of pioglitazone. The PROactive Study (PROspective pioglitAzone Clinical Trial in macroVascular Events).
        Lancet. 2005; 366: 1279-1289
        • Wilcox R.
        • Bousser M.G.
        • Betteridge D.J.
        • Schernthaner G.
        • Pirags V.
        • Kupfer S.
        • et al.
        Effects of pioglitazone in patients with type 2 diabetes with or without previous stroke: results from PROactive (PROspective pioglitAzone Clinical Trial in macroVascular Events 04).
        Stroke. 2007; 38: 865-873
        • Kernan W.N.
        • Viscoli C.M.
        • Furie K.L.
        • Young L.H.
        • Inzucchi S.E.
        • Gorman M.
        • et al.
        Pioglitazone after ischemic stroke or transient ischemic attack.
        N Engl J Med. 2016; 374: 1321-1331
        • Lee M.
        • Saver J.L.
        • Liao H.W.
        • Lin C.H.
        • Ovbiagele B.
        Pioglitazone for secondary stroke prevention: a systematic review and meta-analysis.
        Stroke. 2017; 48: 388-393
        • Ou H.T.
        • Chang K.C.
        • Li C.L.
        • Wu J.S.
        Risks of cardiovascular diseases associated with dipeptidyl peptidase-4 inhibitors and other antidiabetic drugs in patients with type 2 diabetes: a nation-wide longitudinal study.
        Cardiovasc Diabetol. 2016; 15: 41
        • Scirica B.M.
        • Bhatt D.L.
        • Braunwald E.
        • Steg P.G.
        • Davidson J.
        • Hirshberg B.
        • et al.
        Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus.
        N Engl J Med. 2013; 369: 1317-1326
        • White W.B.
        • Cannon C.P.
        • Heller S.R.
        • Nissen S.E.
        • Bergenstal R.M.
        • Bakris G.L.
        • et al.
        Alogliptin after acute coronary syndrome in patients with type 2 diabetes.
        N Engl J Med. 2013; 369: 1327-1335
        • Green J.B.
        • Bethel M.A.
        • Armstrong P.W.
        • Buse J.B.
        • Engel S.S.
        • Garg J.
        • et al.
        Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes.
        N Engl J Med. 2015; 373: 232-242
        • US Food and Drug Administration
        Diabetes medications containing saxagliptin and alogliptin: drug safety communication – risk of heart failure.
        Safety Information and Adverse Event Reporting Program, Silver Spring, MD2016 ([Accessed 20 June, 2017. Available from:])
        • Barkas F.
        • Elisaf M.
        • Tsimihodimos V.
        • Milionis H.
        Dipeptidyl peptidase-4 inhibitors and protection against stroke: a systematic review and meta-analysis.
        Diabetes Metab. 2016; 43: 1-8
        • Lund A.
        • Knop F.K.
        • Vilsboll T.
        Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes: differences and similarities.
        Eur J Intern Med. 2014; 25: 407-414
        • Pfeffer M.A.
        • Claggett B.
        • Diaz R.
        • Dickstein K.
        • Gerstein H.C.
        • Køber L.V.
        • et al.
        Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.
        N Engl J Med. 2015; 373: 2247-2257
        • Marso S.P.
        • Daniels G.H.
        • Brown-Frandsen K.
        • Kristensen P.
        • Mann J.F.
        • Nauck M.A.
        • et al.
        Liraglutide and cardiovascular outcomes in type 2 diabetes.
        N Engl J Med. 2016; 375: 311-322
        • Marso S.P.
        • Bain S.C.
        • Consoli A.
        • Eliaschewitz F.G.
        • Jódar E.
        • Leiter L.A.
        • et al.
        Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
        N Engl J Med. 2016; 375: 1834-1844
        • Inzucchi S.E.
        • Zinman B.
        • Wanner C.
        • Ferrari R.
        • Fitchett D.
        • Hantel S.
        • et al.
        SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials.
        Diab Vasc Dis Res. 2015; 12: 90-100
        • Zinman B.
        • Wanner C.
        • Lachin J.M.
        • Fitchett D.
        • Bluhmki E.
        • Hantel S.
        • et al.
        Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
        N Engl J Med. 2015; 373: 2117-2128
        • Imprialos K.P.
        • Boutari C.
        • Stavropoulos K.
        • Doumas M.
        • Karagiannis A.I.
        Stroke paradox with SGLT-2 inhibitors: a play of chance or a viscosity-mediated reality?.
        J Neurol Neurosurg Psychiatry. 2017; 88: 249-253
        • Wu J.H.
        • Foote C.
        • Blomster J.
        • Toyama T.
        • Perkovic V.
        • Sundström J.
        • et al.
        Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis.
        Lancet Diabetes Endocrinol. 2016; 4: 411-419
        • Neal B.
        • Perkovic V.
        • Mahaffey K.W.
        • de Zeeuw D.
        • Fulcher G.
        • Erondu N.
        • et al.
        Canagliflozin and cardiovascular and renal events in type 2 diabetes.
        N Engl J Med. Jun 12 2017; ([Epub ahead of print])