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Metformin use and risk of ischemic stroke in patients with type 2 diabetes: A cohort study
Received date: 2023-02-28
Online published: 2023-06-12
Supported by
the National Natural Science Foundation of China(81703291)
Objective: To explore the association between the use of metformin and the risk of ischemic stroke in patients with type 2 diabetes. Methods: A prospective cohort study was designed from the Fangshan family cohort in Beijing. According to metformin use at baseline, 2 625 patients with type 2 diabetes in Fangshan, Beijing were divided into metformin group or non-metformin group and the incidence of ischemic stroke between the different groups during follow-up was estimated and compared by Cox proportional hazard regression model. The participants with metformin were first compared with all the parti-cipants who did not use metformin, and then were further compared with those who did not use hypoglycemic agents and those who used other hypoglycemic agents. Results: The patients with type 2 diabetes were with an average age of (59.5±8.7) years, and 41.9% of them were male. The median follow-up time was 4.5 years. A total of 84 patients developed ischemic stroke during follow-up, with a crude incidence of 6.4 (95%CI: 5.0-7.7) per 1 000 person-years. Among all the participants, 1 149 (43.8%) took metformin, 1 476 (56.2%) were metformin non-users, including 593 (22.6%) used other hypoglycemic agents, and 883 (33.6%) did not use any hypoglycemic agents. Compared with metformin non-users, the Hazard ratio (HR) for ischemic stroke in metformin users was 0.58 (95%CI: 0.36-0.93; P = 0.024). Compared with other hypoglycemic agents, HR was 0.48 (95%CI: 0.28-0.84; P < 0.01); Compared with the group without hypoglycemic agents, HR was 0.65 (95%CI: 0.37-1.13; P=0.13). The association between metformin and ischemic stroke was statistically significant in the patients ≥ 60 years old compared with all the metformin non-users and those who used other hypoglycemic agents (HR: 0.48, 95%CI: 0.25-0.92; P < 0.05). Metformin use was associated with a lower incidence of ischemic stroke in the patients with good glycemic control (0.32, 95%CI: 0.13-0.77; P < 0.05). In the patients with poor glycemic control, and the association was not statistically significant (HR: 0.97, 95%CI: 0.53-1.79; P>0.05). There was an interaction between glycemic control and metformin use on incidence of ischemic stroke (Pinteraction < 0.05). The results of the sensitivity analysis were consistent with the results in the main analysis. Conclusion: Among patients with type 2 diabetic in rural areas of northern China, metformin use was associated with lower incidence of ischemic stroke, especially in patients older than 60 years. There was an interaction between glycemic control and metformin use in the incidence of ischemic stroke.
Key words： Cohort study; Metformin; Ischemic stroke; Type 2 diabetes
Huan YU , Ruo-tong YANG , Si-yue WANG , Jun-hui WU , Meng-ying WANG , Xue-ying QIN , Tao WU , Da-fang CHEN , Yi-qun WU , Yong-hua HU . Metformin use and risk of ischemic stroke in patients with type 2 diabetes: A cohort study[J]. Journal of Peking University(Health Sciences), 2023 , 55(3) : 456 -464 . DOI: 10.19723/j.issn.1671-167X.2023.03.011
| 1 | Zhou M , Wang H , Zeng X , et al.Mortality, morbidity, and risk factors in China and its provinces, 1990—2017: A systematic analysis for the Global Burden of Disease Study 2017[J].Lancet,2019,394(10204):1145-1158. |
| 2 | Wang YJ , Li ZX , Gu HQ , et al.China stroke statistics: An update on the 2019 report from the National Center for Healthcare Quality Management in Neurological Diseases, China National Clinical Research Center for Neurological Diseases, the Chinese Stroke Association, National Center for Chronic and Non-communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention and Institute for Global Neuroscience and Stroke Collaborations[J].Stroke Vasc Neurol,2022,7(5):415-450. |
| 3 | Ma Q , L iR , Wang L , et al.Temporal trend and attributable risk factors of stroke burden in China, 1990—2019: An analysis for the Global Burden of Disease Study 2019[J].Lancet Public health,2021,6(12):e897-e906. |
| 4 | Van STT , Sedaghat S , Carnethon MR , et al.Cerebral microvascular complications of type 2 diabetes: Stroke, cognitive dysfunction, and depression[J].Lancet Diabetes Endocrinol,2020,8(4):325-336. |
| 5 | Sarwar N , Gao P , Swshasai SR , et al.Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: A collaborative meta-analysis of 102 prospective studies[J].Lancet,2010,375(9733):2215-2222. |
| 6 | 韩荣荣, 唐爱奇, 方杭燕, 等.2型糖尿病患者并发脑卒中的前瞻性研究[J].预防医学,2017,29(2):139-141. |
| 7 | Wang L , Gao P , Zhang M , et al.Prevalence and ethnic pattern of diabetes and prediabetes in China in 2013[J].JAMA,2017,317(24):2515-2523. |
| 8 | Wang L , Peng W , Zhao Z , et al.Prevalence and treatment of diabetes in China, 2013—2018[J].JAMA,2021,326(24):2498-2506. |
| 9 | Ma RCW .Epidemiology of diabetes and diabetic complications in China[J].Diabetologia,2018,61(6):1249-1260. |
| 10 | Inzucchi SE , Bergenstal RM , Buse JB , et al.Management of hyperglycemia in type 2 diabetes, 2015: A patient-centered approach: Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes[J].Diabetes Care,2015,38(1):140-149. |
| 11 | 中华医学会糖尿病学分会.中国2型糖尿病防治指南(2020年版)[J].中华糖尿病杂志,2021,13(4):95. |
| 12 | Oliveira WH , Nunes AK , Fran?a ME , et al.Effects of metformin on inflammation and short-term memory in streptozotocin-induced diabetic mice[J].Brain Res,2016,1644,149-160. |
| 13 | Mandwie M , Karunia J , Niaz A , et al.Metformin treatment attenuates brain inflammation and rescues PACAP/VIP neuropeptide alterations in mice fed a high-fat diet[J].Int J Mol Sci,2021,22(24):13660. |
| 14 | Asgharzadeh F , Barneh F , Fakhraie M , et al.Metformin inhibits polyphosphate-induced hyper-permeability and inflammation[J].Int Immunopharmacol,2021,99,107937. |
| 15 | Ismail HF , Didari T , Baeeri M , et al.Metformin attenuates brain injury by inhibiting inflammation and regulating tight junction proteins in septic rats[J].Cell J,2020,22(Suppl 1):S29-S37. |
| 16 | Pescador N , Francisco V , Vázquez P , et al.Metformin reduces macrophage HIF1α-dependent proinflammatory signaling to restore brown adipocyte function in vitro[J].Redox Biol,2021,48,102171. |
| 17 | Xiang X , Zhou L , Lin Z , et al.Metformin regulates macrophage polarization via the Shh signaling pathway to improve pulmonary vascular development in bronchopulmonary dysplasia[J].IUBMB life,2022,74(3):259-271. |
| 18 | Katila N , Bhurtel S , Park PH , et al.Activation of AMPK/aPKCζ/CREB pathway by metformin is associated with upregulation of GDNF and dopamine[J].Biochem Pharmacol,2020,180,114193. |
| 19 | Ghadernezhad N , Khalaj L , Pazoki-toroudi H , et al.Metformin pretreatment enhanced learning and memory in cerebral forebrain ischaemia: The role of the AMPK/BDNF/P70SK signalling pathway[J].Pharm Biol,2016,54(10):2211-2219. |
| 20 | Yuan R , Wang Y , Li Q , et al.Metformin reduces neuronal damage and promotes neuroblast proliferation and differentiation in a cerebral ischemia/reperfusion rat model[J].Neuroreport,2019,30(3):232-240. |
| 21 | Ahmed S , Mahmood Z , Javed A , et al.Effect of metformin on adult hippocampal neurogenesis: Comparison with donepezil and links to cognition[J].J Mol Neurosci,2017,62(1):88-98. |
| 22 | Sharma S , Nozohouri S , Vaidya B , et al.Repurposing metformin to treat age-related neurodegenerative disorders and ischemic stroke[J].Life Sci,2021,274,119343. |
| 23 | 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)[J].Lancet,1998,352(9131):854-865. |
| 24 | Griffin SJ , Leaver JK , Irving GJ .Impact of metformin on cardiovascular disease: A meta-analysis of randomised trials among people with type 2 diabetes[J].Diabetologia,2017,60(9):1620-1629. |
| 25 | Benn M , Emanuelsson F , Tybj?rg-hansen A , et al.Impact of high glucose levels and glucose lowering on risk of ischaemic stroke: A mendelian randomisation study and meta-analysis[J].Diabetologia,2021,64(7):1492-1503. |
| 26 | Roumie CL , Hung AM , Greevy RA , et al.Comparative effectiveness of sulfonylurea and metformin monotherapy on cardiovascular events in type 2 diabetes mellitus: A cohort study[J].Ann Intern Med,2012,157(9):601-610. |
| 27 | Holman RR , Paul SK , Bethel MA , et al.10-year follow-up of intensive glucose control in type 2 diabetes[J].N Engl J Med,2008,359(15):1577-1589. |
| 28 | Cryer DR , Nicholas SP , Henry DH , et al.Comparative outcomes study of metformin intervention versus conventional approach the COSMIC approach study[J].Diabetes Care,2005,28(3):539-543. |
| 29 | Kooy A , De JJ , Lehert P , et al.Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus[J].Arch Intern Med,2009,169(6):616-625. |
| 30 | Gram J , Henriksen JE , Grodum E , et al.Pharmacological treatment of the pathogenetic defects in type 2 diabetes: The randomized multicenter South Danish diabetes study[J].Diabetes Care,2011,34(1):27-33. |
| 31 | 王梦莹, 任涛, 吴涛, 等.北方农村地区居民常见慢性非传染性疾病的家系队列研究进展[J].中华流行病学杂志,2018,39(1):4. |
| 32 | Glueck DH .Sample size calculations in clinical research[J].Biometrics,2008,64(4):1307-1308. |
| 33 | Matsumoto M , Harada S , Iida M , et al.Validity assessment of self-reported medication use for hypertension, diabetes, and dyslipidemia in a pharmacoepidemiologic study by comparison with health insurance claims[J].J Epidemiol,2021,31(9):495-502. |
| 34 | 中华医学会糖尿病学分会.中国2型糖尿病防治指南(2017年版)[J].中国实用内科杂志,2018,38(4):53. |
| 35 | Chen R , Ovbiagele B , Feng W .Diabetes and stroke: Epidemiology, pathophysiology, pharmaceuticals and outcomes[J].Am J Med Sci,2016,351(4):380-386. |
| 36 | Roumie CL , Chipman J , Min JY , et al.Association of treatment with metformin vs sulfonylurea with major adverse cardiovascular events among patients with diabetes and reduced kidney function[J].JAMA,2019,322(12):1167-1177. |
| 37 | Douros A , Dell'aniello S , Yu OHY , et al.Sulfonylureas as second line drugs in type 2 diabetes and the risk of cardiovascular and hypoglycaemic events: Population based cohort study[J].BMJ,2018,362,k2693. |
| 38 | Chen TH , Li YR , Chen SW , et al.Sodium-glucose cotransporter 2 inhibitor versus metformin as first-line therapy in patients with type 2 diabetes mellitus: A multi-institution database study[J].Cardiovasc Diabetol,2020,19(1):189. |
| 39 | Sato A , Sunayama J , Okada M , et al.Glioma-initiating cell elimination by metformin activation of FOXO3 via AMPK[J].Stem Cells Transl Med,2012,1(11):811-824. |
| 40 | Chiang MC , Cheng YC , Chen SJ , et al.Metformin activation of AMPK-dependent pathways is neuroprotective in human neural stem cells against amyloid-beta-induced mitochondrial dysfunction[J].Exp Cell Res,2016,347(2):322-331. |
| 41 | Isoda K , Young JL , Zirlik A , et al.Metformin inhibits proinflammatory responses and nuclear factor-kappaB in human vascular wall cells[J].Arterioscler Thromb Vasc Biol,2006,26(3):611-617. |
| 42 | Liu Y , Tang G , Li Y , et al.Metformin attenuates blood-brain barrier disruption in mice following middle cerebral artery occlusion[J].J Neuroinflammation,2014,11,177. |
| 43 | Campvell JM , Bellman SM , Stephenson MD , et al.Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: A systematic review and meta-analysis[J].Ageing Res Rev,2017,40,31-44. |
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