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北京大学学报（医学版） ›› 2023, Vol. 55 ›› Issue (3): 456-464. doi: 10.19723/j.issn.1671-167X.2023.03.011

• 论著 • 上一篇    下一篇

2型糖尿病患者使用二甲双胍与缺血性脑卒中发病风险的队列研究

于欢,杨若彤,王斯悦,吴俊慧,王梦莹,秦雪英,吴涛,陈大方,武轶群*(),胡永华   

  1. 北京大学公共卫生学院流行病学与卫生统计学系，重大疾病流行病学教育部重点实验室(北京大学)，北京 100191
  • 收稿日期:2023-02-28 出版日期:2023-06-18 发布日期:2023-06-12
  • 通讯作者: 武轶群 E-mail:qywu118@163.com
  • 基金资助:
    国家自然科学基金(81703291)

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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摘要：

目的: 探索2型糖尿病患者中使用二甲双胍与缺血性脑卒中发生风险的关联。方法: 基于“北方农村地区居民常见慢性非传染性疾病家系队列”工作，采用队列研究设计，选取北京市房山区2 625例2型糖尿病患者，按照进入队列时是否使用二甲双胍，利用Cox比例风险回归模型比较不同组别随访过程中缺血性脑卒中的发生情况。使用二甲双胍的研究对象首先与所有未使用二甲双胍者进行比较，然后进一步分别与未使用降糖药者及使用其他降糖药者进行比较。结果: 纳入的2型糖尿病患者平均年龄为(59.5±8.7)岁，男性占41.9%。中位随访时间为4.5年，共发生84例缺血性脑卒中，粗发病率为6.4(95%CI: 5.0~7.7)/1 000人年。研究对象中有1 149例使用二甲双胍，1 476例未使用二甲双胍(其中593例使用其他降糖药物，883例未使用降糖药物)。与未使用二甲双胍者相比，使用二甲双胍者发生缺血型脑卒中的风险比(hazard ratio, HR)为0.58(95%CI: 0.36~0.93; P=0.024)。与使用其他降糖药组相比，HR为0.48(95%CI: 0.28~0.84; P < 0.01);与未使用降糖药组相比，HR为0.65(95%CI: 0.37~1.13; P=0.13)。在≥60岁患者中，与所有未使用二甲双胍者及使用其他降糖药者比较，二甲双胍与缺血性脑卒中的关联具有统计学意义(HR: 0.48, 95%CI: 0.25~0.92; P < 0.05)。在血糖控制良好的患者中，二甲双胍使用和较低的缺血性脑卒中发病率相关(HR: 0.32, 95%CI: 0.13~0.77; P < 0.05);在血糖控制不良的患者中，该关联均无统计学意义(HR: 0.97, 95%CI: 0.53~1.79; P>0.05);血糖控制与二甲双胍的使用对缺血性脑卒中的发生存在交互作用(P交互 < 0.05)。结论: 在我国北方农村2型糖尿病患者，尤其是在老年糖尿病患者中，二甲双胍的使用和较低的缺血性脑卒发病风险相关; 血糖控制水平和二甲双胍使用对缺血性脑卒中的发生可能存在交互作用。

关键词: 队列研究, 二甲双胍, 缺血性脑卒中, 2型糖尿病

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

中图分类号: 

  • R186.4

表1

研究对象基本特征"

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)

表2

研究对象缺血性脑卒中发生情况"

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)

表3

二甲双胍使用与缺血性脑卒中的关联性分析"

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

表4

二甲双胍使用组与缺血性脑卒中的关联性分析"

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

表5

血糖控制与使用二甲双胍对缺血性脑卒中发病风险的交互作用分析"

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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