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Journal of Peking University (Health Sciences) ›› 2023, Vol. 55 ›› Issue (3): 456-464. doi: 10.19723/j.issn.1671-167X.2023.03.011

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Metformin use and risk of ischemic stroke in patients with type 2 diabetes: A cohort study

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   

  1. Department of Epidemiology and Biostatistics, Peking University School of Public Health; Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing 100191, China
  • Received:2023-02-28 Online:2023-06-18 Published:2023-06-12
  • Contact: Yi-qun WU E-mail:qywu118@163.com
  • Supported by:
    the National Natural Science Foundation of China(81703291)

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Abstract:

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

CLC Number: 

  • R186.4

Table 1

Basic characteristics of participants"

Characteristics Met users (n=1 149) Non-Met users (n =1 476) Overall (n =2 625) P
Age/years, $\bar x \pm s$ 59.6 ± 8.2 59.3 ± 9.0 59.5 ± 8.7 0.41
Gender, n (%) < 0.01
  Male 419 (36.5) 681 (46.1) 1 100 (41.9)
  Female 730 (63.5) 795 (53.9) 1 525 (58.1)
Marriage, n (%) 0.05
  Married 988 (86.0) 1 285 (87.1) 2 273 (86.6)
  Unmarried 160 (13.9) 182 (12.3) 342 (13.0)
AHI/thousands yuan，M(P25, P75) 12.0 (5.0, 36.0) 14.0 (7.2, 36.0) 12.8 (6.0, 36.0) 0.06
BMI/(kg/m2)，$\bar x \pm s$ 26.5 ± 3.6 26.6 ± 6.0 26.5 ± 5.1 0.54
Obesity, n (%) 0.83
  Yes 345 (30.0) 449 (30.4) 794 (30.3)
  No 859 (70.0) 1 027 (69.6) 1 831 (69.8)
Smoking, n (%) 0.04
  Current/past smoker 442 (38.5) 624 (42.3) 1 556 (59.3)
  Never 707 (61.5) 849 (57.5) 1 066 (40.6)
Drinking, n (%) 0.32
  Current/past drinker 342 (29.8) 464 (31.4) 1 813 (69.1)
  Never 807 (70.2) 1 006 (68.2) 806 (30.7)
Habitual sports, n (%) < 0.01
  Yes 632 (55.0) 546 (37.0) 1 178 (44.9)
  No 517 (45.0) 930 (63.0) 1 447 (55.1)
Comorbidity, n (%)
  Hyperlipidemia 1 003 (87.3) 1 319 (89.4) 2 322 (88.5) 0.10
  Hypertension 487 (42.4) 727 (49.3) 1 214 (46.3) < 0.01
Family history of IS, n (%) < 0.01
  Yes 539 (46.9) 887 (60.1) 1 426 (54.3)
  No 610 (53.1) 589 (39.9) 1 199 (45.7)

Table 2

Incidence of ischemic stroke in the participants"

Groups Events of IS, n Median follow-up time/years, M(P25, P75) Overall follow-up time/person-years Crude incidence rate/per 1 000 person-years, M(P25, P75)
Met users 25 4.4 (3.5, 6.4) 5 604.0 4.5 (2.7, 6.2)
Non-Met users 59 5.3 (4.2, 6.4) 7 574.0 7.8 (5.8, 9.8)
  OHA 27 4.5 (3.5, 6.4) 2 924.4 9.2 (5.8, 12.7)
  NHA 32 5.4 (4.4, 6.5) 4 649.6 6.9 (4.5, 9.3)

Table 3

Association of metformin use with ischemic stroke"

Groups Events of IS, n Adjusted incidence rate/per 1 000 person-years (95%CI) HR (95%CI) P
Overall
  Non-Met users 59 7.7 (6.1-9.4) -
  Met users 25 4.5 (3.6-5.5) 0.58 (0.36-0.93) 0.02
Male
  Non-Met users 27 7.7 (6.0-9.3) -
  Met Users 8 4.1 (3.2-4.9) 0.52 (0.23-1.17) 0.11
Female
  Non-Met users 32 7.7 (6.1-9.4) -
  Met Users 17 4.8 (3.8-5.8) 0.61 (0.33-1.12) 0.11
   < 60 years old
  Non-Met users 22 7.0 (5.5-8.4) -
  Met Users 12 5.5 (4.3-6.7) 0.79 (0.38-1.63) 0.52
  ≥60 years old
  Non-Met users 37 8.1 (6.4-9.8) -
  Met Users 13 4.0 (3.1-4.8) 0.48 (0.25-0.92) 0.03

Table 4

Association of metformin use with ischemic stroke referenced to different control groups"

CharacteristicsCompared with OHA group Compared with NHA group
Events of IS, n HR (95%CI) P Events of IS, n HR (95%CI) P
Overall 52 0.48 (0.28-0.84) < 0.01 57 0.65 (0.37-1.13) 0.13
Age/years
   < 60 21 0.69 (0.29-1.67) 0.41 25 1.00 (0.42-2.35) 1.00
  ≥60 31 0.39 (0.19-0.83) 0.01 32 0.48 (023-1.00) 0.05
Gender
  Female 29 0.56 (0.26-1.20) 0.13 37 0.59 (0.29-1.18) 0.13
  Male 23 0.39 (0.16-0.95) 0.04 20 0.78 (0.30-2.00) 0.60

Table 5

Interaction between glycemic control and metformin use on the risk of ischemic stroke"

Glycemic control HR (95%CI) P Pinteraction
Met users vs. Non-Met users 0.01
  Under control 0.32 (0.13-0.77) < 0.01
  Lose control 0.97 (0.53-1.79) 0.92
Met users vs. OHA 0.03
  Under control 0.28 (0.10-0.77) 0.01
  Lose control 0.69 (0.34-1.37) 0.29
Met users vs. NHA < 0.01
  Under control 0.34 (0.13-0.87) 0.02
  Lose control 1.27 (0.57-2.85) 0.56
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