Metformin-inclusive Therapy Reduces the Risk of Stroke in Patients with Diabetes: A 4-Year Follow-up Study

      Metformin is a kind of oral hypoglycemic agents commonly prescribed to patients with diabetes mellitus. Although past studies had proven its protective effect on cardiovascular risk and related mortality, the evidence of metformin on stroke prevention was still insufficient and conflicting. Our study randomly selected 14,856 patients with diabetes from the database provided by the Taiwan National Health Research Institute, and 2 cohorts were formulated according to whether metformin was in the prescription record. All cases were followed up for 4 years to track their stroke incidence. As a result, 701 (17.5%) of 3999 diabetic patients had stroke without metformin use, whereas 994 (9.2%) of 10,857 patients had stroke with metformin use. Cox proportional hazard regressions showed that the stroke hazard ratio (HR) of metformin was .383. After adjustment for the patients' age, gender, hypertension, atrial fibrillation, hyperlipidemia, coronary artery disease, and medications including antiplatelets, coumadin, statin, and estrogen use, the HR was still .468. Further stratified analysis revealed that metformin had more protective effect in the patients with higher risk of stroke. Therefore, metformin should be placed in priority when prescribing oral hypoglycemic agents for diabetic patients when considering stroke prevention according to our study.

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      1. Data provided by Ministry of Health and Welfare, Taiwan. Available at: Accessed on September 26, 2013.

        • Lucke-Wold B.P.
        • Turner R.C.
        • Lucke-Wold A.N.
        • et al.
        Age and the metabolic syndrome as risk factors for ischemic stroke: improving preclinical models of ischemic stroke.
        Yale J Biol Med. 2012; 85: 523-539
        • Zou M.H.
        • Kirkpatrick S.S.
        • Davis B.J.
        • et al.
        Activation of the AMP-activated protein kinase by the anti-diabetic drug metformin in vivo. Role of mitochondrial reactive nitrogen species.
        J Biol Chem. 2004; 279: 43940-43951
        • Zou M.H.
        • Wu Y.
        AMP-activated protein kinase activation as a strategy for protecting vascular endothelial function.
        Clin Exp Pharmacol Physiol. 2008; 35: 535-545
        • Li J.
        • Benashski S.E.
        • Venna V.R.
        • et al.
        Effects of metformin in experimental stroke.
        Stroke. 2010; 41: 2645-2652
        • Elgebaly M.M.
        • Prakash R.
        • Li W.
        • et al.
        Vascular protection in diabetic stroke: role of matrix metalloprotease-dependent vascular remodeling.
        J Cereb Blood Flow Metab. 2010; 30: 1928-1938
        • UK Prospective Diabetes Study (UKPDS) Group
        Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).
        Lancet. 1998; 352: 854-865
        • Kahn S.E.
        • Haffner S.M.
        • Heise M.A.
        • et al.
        Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy.
        N Engl J Med. 2006; 355: 2427-2443
        • Chen Z.Y.
        • Chiang C.H.
        • Huang C.C.
        • et al.
        The association of tooth scaling and decreased cardiovascular disease: a nationwide population-based study.
        Am J Med. 2012; 125: 568-575
        • Chiang C.H.
        • Huang C.C.
        • Chan W.L.
        • et al.
        Association between Mycoplasma pneumonia and increased risk of ischemic stroke: a nationwide study.
        Stroke. 2011; 42: 2940-2943
        • Panicker G.K.
        • Karnad D.R.
        • Salvi V.
        • et al.
        Cardiovascular risk of oral antidiabetic drugs: current evidence and regulatory requirements for new drugs.
        J Assoc Physicians India. 2012; 60: 56-61
        • Selvin E.
        • Bolen S.
        • Yeh H.C.
        • et al.
        Cardiovascular outcomes in trials of oral diabetes medications: a systematic review.
        Arch Intern Med. 2008; 168: 2070-2080
        • Roumie C.L.
        • Hung A.M.
        • Greevy R.A.
        • et al.
        Comparative effectiveness of sulfonylurea and metformin monotherapy on cardiovascular events in type 2 diabetes mellitus: a cohort study.
        Ann Intern Med. 2012; 157: 601-610
        • Qaseem A.
        • Humphrey L.L.
        • Sweet D.E.
        • et al.
        Oral pharmacologic treatment of type 2 diabetes mellitus: a clinical practice guideline from the American College of Physicians.
        Ann Intern Med. 2012; 156: 218-231
        • Ido Y.
        • Carling D.
        • Ruderman N.
        Hyperglycemia-induced apoptosis in human umbilical vein endothelial cells: inhibition by the AMP activated protein kinase activation.
        Diabetes. 2002; 51: 159-167
        • Kukidome D.
        • Nishikawa T.
        • Sonoda K.
        • et al.
        Activation of AMP activated protein kinase reduces hyperglycemia-induced mitochondrial reactive oxygen species production and promotes mitochondrial biogenesis in human umbilical vein endothelial cells.
        Diabetes. 2006; 55: 120-127
        • Ouslimani N.
        • Peynet J.
        • Bonnefont-Rousselot D.
        • et al.
        Metformin decreases intracellular production of reactive oxygen species in aortic endothelial cells.
        Metabolism. 2005; 54: 829-834
        • Davis B.J.
        • Xie Z.
        • Viollet B.
        • et al.
        Activation of the AMP-activated kinase by antidiabetes drug metformin stimulates nitric oxide synthesis in vivo by promoting the association of heat shock protein 90 and endothelial nitric oxide synthase.
        Diabetes. 2006; 55: 496-505
        • Morrow V.A.
        • Foufelle F.
        • Connell J.M.
        • et al.
        Direct activation of AMP-activated protein kinase stimulates nitric-oxide synthesis in human aortic endothelial cells.
        J Biol Chem. 2003; 278: 31629-31639
        • Isoda K.
        • Young J.L.
        • Zirlik A.
        • et al.
        Metformin inhibits proinflammatory responses and nuclear factor-kappaB in human vascular wall cells.
        Arterioscler Thromb Vasc Biol. 2006; 26: 611-617
        • Harrison D.G.
        • Marvar P.J.
        • Titze J.M.
        Vascular inflammatory cells in hypertension.
        Front Physiol. 2012; 3: 128
        • Ikonomidis I.
        • Michalakeas C.A.
        • Parissis J.
        • et al.
        Inflammatory markers in coronary artery disease.
        Biofactors. 2012; 38: 320-328
        • Siasos G.
        • Tousoulis D.
        • Oikonomou E.
        • et al.
        Inflammatory markers in hyperlipidemia: from experimental models to clinical practice.
        Curr Pharm Des. 2011; 17: 4132-4146
        • El-Mir M.Y.
        • Detaille D.
        • R-Villanueva G.
        • et al.
        Neuroprotective role of antidiabetic drug metformin against apoptotic cell death in primary cortical neurons.
        J Mol Neurosci. 2008; 34: 77-87
        • Ullah I.
        • Ullah N.
        • Naseer M.I.
        • et al.
        Neuroprotection with metformin and thymoquinone against ethanol-induced apoptotic neurodegeneration in prenatal rat cortical neurons.
        BMC Neurosci. 2012; 13: 11
        • Lee A.
        • Morley J.E.
        Metformin decreases food consumption and induces weight loss in subjects with obesity with type II non-insulin-dependent diabetes.
        Obes Res. 1998; 6: 47-53
        • Chan J.C.
        • Tomlinson B.
        • Critchley J.A.
        • et al.
        Metabolic and hemodynamic effects of metformin and glibenclamide in normotensive NIDDM patients.
        Diabetes Care. 1993; 16: 1035-1038
        • Giugliano D.
        • De Rosa N.
        • Di Maro G.
        • et al.
        Metformin improves glucose, lipid metabolism, and reduces blood pressure in hypertensive, obese women.
        Diabetes Care. 1993; 16: 1387-1390
        • Landin K.
        • Tengborn L.
        • Smith U.
        Treating insulin resistance in hypertension with metformin reduces both blood pressure and metabolic risk factors.
        J Intern Med. 1991; 229: 181-187
        • Giugliano D.
        • Quatraro A.
        • Consoli G.
        • et al.
        Metformin for obese, insulin-treated diabetic patients: improvement in glycaemic control and reduction of metabolic risk factors.
        Eur J Clin Pharmacol. 1993; 44: 107-112
        • Muntzel M.S.
        • Hamidou I.
        • Barrett S.
        Metformin attenuates salt-induced hypertension in spontaneously hypertensive rats.
        Hypertension. 1999; 33: 1135-1140
        • Xing X.Y.
        • Li Y.F.
        • Fu Z.D.
        • et al.
        Antihypertensive effect of metformin in essential hypertensive patients with hyperinsulinemia.
        Zhonghua Nei Ke Za Zhi. 2010; 49: 14-18
        • Eleftheriadou I.
        • Grigoropoulou P.
        • Katsilambros N.
        • et al.
        The effects of medications used for the management of diabetes and obesity on postprandial lipid metabolism.
        Curr Diabetes Rev. 2008; 4: 340-356
        • Grant P.J.
        Beneficial effects of metformin on haemostasis and vascular function in man.
        Diabetes Metab. 2003; 29: 6S44-52
        • Germino F.W.
        Noninsulin treatment of type 2 diabetes mellitus in geriatric patients: a review.
        Clin Ther. 2011; 33: 1868-1882
        • Goldstein L.B.
        • Bushnell C.D.
        • Adams R.J.
        • et al.
        Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.
        Stroke. 2011; 42: 517-584