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北京大学学报（医学版） ›› 2024, Vol. 56 ›› Issue (3): 424-430. doi: 10.19723/j.issn.1671-167X.2024.03.008

• 论著 • 上一篇    下一篇

真实世界中2型糖尿病患者二甲双胍联用西格列汀的心血管安全性

刘佐相1,2,陈晓薇1,2,赵厚宇1,2,詹思延1,2,3,*(),孙凤1,2,4,*()   

  1. 1. 北京大学公共卫生学院流行病与卫生统计学系，北京 100191
    2. 重大疾病流行病学教育部重点实验室(北京大学)，北京 100191
    3. 北京大学第三医院临床流行病学研究中心，北京 100191
    4. 海南省真实世界数据研究院，海南琼海 571437
  • 收稿日期:2024-02-15 出版日期:2024-06-18 发布日期:2024-06-12
  • 通讯作者: 詹思延,孙凤 E-mail:siyan-zhan@bjmu.edu.cn;sunfeng@bjmu.edu.cn
  • 基金资助:
    国家自然科学基金(72074011);中国药品监管科学行动计划第二批重点项目([2021]37-10);海南省博鳌乐城国际医疗旅游先行区管理局真实世界研究专项计划项目(HNLC2022RWS012)

Cardiovascular safety of sitagliptin added to metformin in real world patients with type 2 diabetes

Zuoxiang LIU1,2,Xiaowei CHEN1,2,Houyu ZHAO1,2,Siyan ZHAN1,2,3,*(),Feng SUN1,2,4,*()   

  1. 1. Department of Epidemiology and Biostatistics, Peking University School of Public Health, Beijing 100191, China
    2. Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing 100191, China
    3. Clinical Epidemiology Research Center, Peking University Third Hospital, Beijing 100191, China
    4. Hainan Institute of Real World Data, Qionghai 571437, Hainan, China
  • Received:2024-02-15 Online:2024-06-18 Published:2024-06-12
  • Contact: Siyan ZHAN,Feng SUN E-mail:siyan-zhan@bjmu.edu.cn;sunfeng@bjmu.edu.cn
  • Supported by:
    the National Natural Science Foundation of China(72074011);The Second Batch of Key Projects of China Drug Regulatory Scientific Action Plan([2021]37-10);Real World Research Project of Boao Lecheng International Medical Tourism Pilot Zone Administration of Hainan Province(HNLC2022RWS012)

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摘要：

目的: 评估真实世界中2型糖尿病(type 2 diabetes mellitus，T2DM)患者在二甲双胍治疗基础上联用西格列汀对心血管不良事件的发生风险的影响。方法: 使用来自宁波市鄞州区域健康信息平台的真实世界数据，选取2017年1月1日至2022年12月31日期间，在平台中具有诊疗记录的T2DM患者。根据其用药情况，将其分二甲双胍联用西格列汀组(联用组)以及二甲双胍单用药组(单用组)。根据用药索引日期构建一系列回顾性队列，并使用倾向性评分匹配，将可能与结局有关的基线协变量纳入模型，用单用组研究对象匹配联用组研究对象，以增加组间基线特征的可比性，构建最终的回顾性队列。随访终止时间为结局发生、死亡或者是研究结束时间(2022年12月31日)，以先发生者为准。观察结束后使用Cox比例风险模型估算两组间三点主要心血管不良事件(3-point major adverse cardiovascular events，3P-MACE)复合结局(心血管死亡、心肌梗死、卒中)以及各次要结局发生的风险比(hazard ratio，HR)及其95%置信区间(confidence interval，CI)。结果: 倾向性评分匹配前，联用组基线使用胰岛素、α糖苷酶抑制剂、钠-葡萄糖转运体2抑制剂(sodium-glucose transporter 2 inhibitors，SGLT-2I)、格列奈类降糖药的患者比例大于单用组，且联用组基线空腹血糖(fasting blood glucose，FBG)与糖化血红蛋白(hemoglobin A1c，HbA1c)水平高于单用组。在倾向性评分匹配后，联用组和单用组各纳入5 416例研究对象，组间基线特征均得到有效平衡。两组3P-MACE的发病密度分别为6.41/100人年和6.35/100人年。与单用组相比，联用组3P-MACE发生风险不增加也不降低(HR=1.00，95% CI：0.91~1.10)。次要结局比较，联用组患者心血管死亡发生率低于单用组(HR=0.59，95% CI：0.41~0.85)，未发现二甲双胍联用西格列汀与心肌梗死和卒中发生风险的关联(HR=1.12，95% CI：0.89~1.41；HR=0.99，95% CI：0.91~1.12)。结论: 在我国宁波市鄞州区T2DM患者中，与单用二甲双胍相比，二甲双胍联用西格列汀治疗可能降低心血管死亡的发生风险，且不增加或减少总体心血管事件发生风险，研究结果可为西格列汀的心血管安全性评价提供真实世界证据。

关键词: 真实世界研究, 心血管安全性, Cox比例风险模型, 西格列汀

Abstract:

Objective: To assess the safety of sitagliptin added to metformin on cardiovascular adverse events in real world patients with type 2 diabetes mellitus (T2DM). Methods: Real world data from Yinzhou Regional Health Care Database were used to select T2DM patients with diagnosis and treatment records in the platform from January 1, 2017 to December 31, 2022. According to drug prescription records, the patients were divided into metformin plus sitagliptin group (combination group) and metformin monotherapy group(monotherapy group). A series of retrospective cohorts were constructed according to the index date.Finally, full retrospective cohorts were constructed according to propensity score model, including baseline covariates that might be related to outcomes, to match the subjects in the combination group and monotherapy group for the purpose of increasing the comparability of baseline characteristics. The participants were followed up from the index date until the first occurrence of the following events: Diagnosis of outcomes, death, or the end of the study period (December 31, 2022). Cox proportional risk model was used to estimate the hazard ratio(HR)and 95% confidence interval (CI) of sitagliptin added to metformin on 3-point major adverse cardiovascular events (3P-MACE) combination outcome and secondary cardiovascular outcomes. Results: Before propensity score matching, the proportion of the patients in combination group using insulin, α glucosidase inhibitors, sodium-glucose transporter 2 inhibitors (SGLT-2I) and glienides at baseline was higher than that in monotherapy group, and the baseline fasting blood glucose (FBG) and hemoglobin A1c (HbA1c) levels in combination group were higher than those in monotherapy group. After propensity score matching, 5 416 subjects were included in the combination group and the monotherapy group, and baseline characteristics were effectively balanced between the groups. The incidence densities of 3P-MACE were 6.41/100 person years and 6.35/100 person years, respectively. Sitagliptin added to metformin did not increase or decrease the risk of 3P-MACE compared with the metformin monotherapy (HR=1.00, 95% CI: 0.91-1.10). In secondary outcomes analysis, the incidence of cardiovascular death was lower in the combination group than in the monotherapy group (HR=0.59, 95% CI: 0.41-0.85), and no association was found between sitagliptin and the risk of myocardial infarction and stroke (HR=1.12, 95% CI: 0.89-1.41; HR=0.99, 95% CI: 0.91-1.12). Conclusion: In T2DM patients in Yinzhou district of Ningbo, compared with metformin alone, sitagliptin added to metformin may reduce the risk of cardiovascular death, and do not increase the incidence of overall cardiovascular events. The results of this study can provide real-world evidence for post-marketing cardiovascular safety evaluation of sitagliptin.

Key words: Real world study, Cardiovascular safety, Cox proportional risk model, Sitagliptin

中图分类号: 

  • R195.4

图1

研究人群纳入、排除流程图"

表1

单用组和联用组组间基线特征"

Characteristics Pre-PS matching Post-PS matching
Monotherapy group (n=118 854) Combination group (n=5 416) SMD Monotherapy group (n=5 416) Combination group (n=5 416) SMD
Male 57 587 (48.5) 2 834 (52.3) 0.083 2 818 (52.0) 2 834 (52.3) 0.006
Age/years 67.18±10.65 66.19±10.20 0.095 65.91±10.88 66.19±10.20 0.026
Smoke 18 120 (15.2) 971 (17.9) 0.071 964 (17.8) 971 (17.9) 0.003
Alcohol 20 632 (17.4) 1 046 (19.3) 0.057 1 072 (19.8) 1 046 (19.3) 0.012
T2DM duration/years 5.86±3.72 5.37±3.90 0.129 5.22±3.77 5.37±3.90 0.039
Insulin 14 556 (12.2) 1 112 (20.5) 0.231 1 104 (20.4) 1 112 (20.5) 0.004
Sulfonylurea 58 358 (49.1) 2 676 (49.4) 0.006 2 655 (49.0) 2 676 (49.4) 0.008
α-glucosidase inhibitor 30 697 (25.8) 1 943 (35.9) 0.205 1 979 (36.5) 1 943 (35.9) 0.014
Thiazolidinedione 10 259 (8.6) 525 (9.7) 0.039 525 (9.7) 525 (9.7) < 0.001
SGLT-2I 4 763 (4.0) 715 (13.2) 0.197 699 (12.9) 715 (13.2) 0.008
Glienide 9 526 (8.0) 611 (11.3) 0.107 597 (11.0) 611 (11.3) 0.008
NSAID 45 966 (38.7) 2 310 (42.7) 0.086 2 307 (42.6) 2 310 (42.7) 0.001
Lipid-lowering drug 50 435 (42.4) 2 870 (53.0) 0.223 2 934 (54.2) 2 870 (53.0) 0.024
ACEI 45 523 (38.3) 2 085 (38.5) 0.004 2 060 (38.0) 2 085 (38.5) 0.009
ARB 6 402 (5.4) 275 (5.1) 0.010 302 (5.6) 275 (5.1) 0.022
CCB 59 597 (50.1) 2 923 (54.0) 0.082 2 927 (54.0) 2 923 (54.0) 0.001
β-blocker 26 848 (22.6) 1 481 (27.3) 0.097 1 536 (28.4) 1 481 (27.3) 0.023
Diuretic 26 238 (22.1) 1 507 (27.8) 0.102 1 466 (27.1) 1 507 (27.8) 0.017
PPI 21 000 (17.7) 1 286 (23.7) 0.104 1 316 (24.3) 1 286 (23.7) 0.013
Antipsychotic drug 3 919 (3.3) 229 (4.2) 0.050 230 (4.2) 229 (4.2) 0.001
Sedative-hypnotic drug 22 853 (19.2) 1 104 (20.4) 0.031 1 118 (20.6) 1 104 (20.4) 0.006
Antidepressant 1 178 (1.0) 85 (1.6) 0.048 93 (1.7) 85 (1.6) 0.012
Antitumor and immune agent 1 045 (0.9) 54 (1.0) 0.012 56 (1.0) 54 (1.0) 0.004
BMI/(kg/m2) 24.86±3.50 24.83±3.48 0.009 24.79±3.45 24.83±3.48 0.011
FBG/(mmol/L) 6.82±1.64 7.59±2.50 0.364 7.44±2.54 7.59±2.50 0.058
HbA1c/% 7.27±1.69 7.99±1.98 0.390 7.99±2.15 7.99±1.98 0.003
SBP/mmHg 132.36±12.84 132.16±13.31 0.016 132.12±12.66 132.16±13.31 0.002
DBP/mmHg 77.33±6.80 77.08±6.83 0.038 77.15±6.70 77.08±6.83 0.011
CCI score 0.050 0.022
   < 5 71 770 (60.4) 3 141 (58.0) 3 089 (57.0) 3 141 (58.0)
  5-10 45 584 (38.4) 2 194 (40.5) 2 251 (41.6) 2 194 (40.5)
  >10 1 500 (1.3) 81 (1.5) 76 (1.4) 81 (1.5)

表2

联用组与单用组心血管结局比较"

Outcomes Combination group Monotherapy group HR(95% CI) P value
Follow-up/person years Cases/(incidence density/100 person years) Follow-up/person years Cases/(incidence density/100 person years)
3P-MACE 12 562 805 (6.41) 13 061 830 (6.35) 1.00 (0.91, 1.10) 0.98
Cardiovascular death 14 008 46 (0.33) 14 469 80 (0.55) 0.59 (0.41, 0.85) < 0.01
MI 13 724 156 (1.14) 14 232 140 (0.98) 1.12 (0.89, 1.41) 0.34
Stroke 12 794 668 (5.22) 13 260 680 (5.13) 0.99 (0.91，1.12) 0.86

图2

联用组和单用组3P-MACE结局Kaplan-Meier生存曲线"

图3

联用组和单用组心血管死亡结局Kaplan-Meier生存曲线"

图4

联用组和单用组MI结局Kaplan-Meier生存曲线"

图5

联用组和单用组卒中结局Kaplan-Meier生存曲线"

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ISSN 1671-167X
CN 11-4691/R
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