入院前使用二甲双胍对糖尿病合并脓毒症患者临床结局的影响

doi:10.12114/j.issn.1007-9572.2023.0347

中国全科医学 ›› 2024, Vol. 27 ›› Issue (09): 1034-1041.DOI: 10.12114/j.issn.1007-9572.2023.0347

所属专题：内分泌代谢性疾病最新文章合辑

入院前使用二甲双胍对糖尿病合并脓毒症患者临床结局的影响

何宇福¹^,², 佟文英¹^,², 王芳¹^,², 李丽霞¹^,², 何俊冰³, 邵义明¹^,^*()

1．523940　广东省东莞市，广东医科大学附属东莞第一医院重症医学科
2．524000　广东省湛江市，广东医科大学研究生院
3．522000　广东省揭阳市人民医院揭阳市医学科研中心实验室

收稿日期:2023-06-13 修回日期:2023-08-22 出版日期:2024-03-20 发布日期:2023-12-19
通讯作者: 邵义明
作者贡献：何宇福负责研究的实施与可行性分析、文章的修订和审校；佟文英、王芳负责资料收集与整理分类；李丽霞负责监督管理和结果的分析与解释；何俊冰负责数据分析和统计学处理；邵义明负责文章的构思与设计、论文撰写，对文章整体负责，监督管理。
基金资助:
国家自然科学基金资助项目(82072151)

Effects of Pre-hospital Metformin Use on Clinical Outcomes in Patients with Diabetes and Sepsis

HE Yufu¹^,², TONG Wenying¹^,², WANG Fang¹^,², LI Lixia¹^,², HE Junbing³, SHAO Yiming¹^,^*()

1. The Intensive Care Unit, the First Affiliated Dongguan Hospital of Guangdong Medical University, Dongguan 523940, China
2. Graduate School of Guangdong Medical University, Zhanjiang 524000, China
3. Jieyang Medical Research Center, Jieyang People's Hospital, Jieyang 522000, China

Received:2023-06-13 Revised:2023-08-22 Published:2024-03-20 Online:2023-12-19
Contact: SHAO Yiming

分享到

摘要/Abstract

摘要： 背景越来越多的证据表明，入院前使用二甲双胍可降低糖尿病合并脓毒症患者的死亡率，然而，二甲双胍对糖尿病合并脓毒症患者临床结局的影响仍存在争议，因此，有必要对现有研究进行系统回顾和荟萃分析，进一步评估二甲双胍是否有利于改善糖尿病合并脓毒症患者死亡率等临床结局。目的系统评价入院前使用二甲双胍对糖尿病合并脓毒症患者死亡率、初始血浆乳酸水平和器官功能障碍等的影响。方法计算机检索PubMed、Embase、Cochrane Library、Web of Science、Scopus、中国生物医学文献服务系统、万方数据知识服务平台、中国知网以及其他数据库中二甲双胍对糖尿病合并脓毒症患者临床结局影响的相关中、英文文献，试验组（MET组）为入院前使用二甲双胍的糖尿病合并脓毒症的成年患者，对照组（NM组）为入院前未使用二甲双胍的糖尿病合并脓毒症的成年患者，检索时限为数据库建立至2023-03-15。由2名研究人员筛选、提取数据及评价文献质量后，采用RevMan 5.3软件进行Meta分析。结果本研究共纳入12篇文献，共12 320例糖尿病合并脓毒症患者，纳入文献的纽卡斯尔-渥太华量表（NOS）评分为7~8分。Meta分析结果显示：MET组患者死亡率（OR=0.61，95%CI=0.46~0.80，P<0.001）、血管升压药的使用率（OR=0.83，95%CI=0.69~0.98，P=0.03）低于NM组；MET组与NM组患者初始血浆乳酸水平（MD=0.31，95%CI=-0.12~0.75，P=0.16）、血清肌酐水平（MD=-0.81，95%CI=-0.48~0.13，P=0.25）、初始血糖水平（MD=32.94，95%CI=-10.12~76.01，P=0.13）、机械通气（OR=0.90，95%CI=0.77~1.06，P=0.23）比较，差异无统计学意义。结论入院前使用二甲双胍可以降低糖尿病合并脓毒症患者的死亡率，并可减少相应患者血管升压药的使用率，为二甲双胍可降低糖尿病合并脓毒症患者死亡率提供了全新的证据。但对于糖尿病合并脓毒症患者能否降低脓毒症严重程度评分以及减少去甲肾上腺素最大剂量仍有待进一步的研究。

关键词: 糖尿病, 脓毒症, 二甲双胍, 临床结局, 死亡率, 器官功能障碍, Meta分析

Abstract:

Background

There is growing evidence that pre-hospital use of metformin reduces mortality in patients with diabetes and sepsis; however, the effect of metformin on clinical outcomes in patients with diabetes and sepsis remains controversial. Therefore, there is a need for a systematic review and Meta-analysis of existing studies to further evaluate whether metformin can improve mortality and other clinical outcomes in patients with diabetes and sepsis.

Objective

To systematically evaluate the effects of pre-hospital metformin use on mortality, initial plasma lactate level and organ dysfunction in patients with diabetes and sepsis.

Methods

PubMed, Embase, Cochrane Library, Web of Science, Scopus, China Biomedical Literature Service System, Wanfang Data, CNKI and other databases were searched by computer for Chinese and English literature on the effects of pre-hospital metformin use on clinical outcomes in patients with sepsis and diabetes from inception to March 15, 2023. The test group (MET group) involved adult patients with diabetes and sepsis received pre-hospital metformin use, and the control group (NM group) involved adult patients with diabetes and sepsis who did not receive pre-hospital metformin use. After screening, data extraction and literature quality evaluation were conducted by two researchers, Meta-analysis was performed using RevMan 5.3 software.

Results

A total of 12 papers were included in this study, involving 12 320 patients with diabetes and sepsis, with Newcastle-Ottawa Scale (NOS) scores of 7-8. The results of Meta-analysis showed that the mortality rate (OR=0.61, 95%CI=0.46 to 0.80, P<0.001) and the use rate of vasopressors (OR=0.83, 95%CI=0.69 to 0.98, P=0.03) in MET group were lower than those in NM group; there was no significant difference in initial plasma lactate level (MD=0.31, 95%CI=-0.12 to 0.75, P=0.16) , serum creatinine level (MD=-0.81, 95%CI=-0.48 to 0.13, P=0.25) , initial blood glucose level (MD=32.94, 95%CI=-10.12 to 76.01, P=0.13) and mechanical ventilation (OR=0.90, 95%CI=0.77 to 1.06, P=0.23) between the MET group and NM group.

Conclusion

The pre-hospital use of metformin can reduce the mortality of patients with diabetes and sepsis, and reduce the use rate of vasoppressors in corresponding patients, providing updated evidence that metformin can reduce the mortality of patients with diabetes and sepsis. However, whether it can reduce the sepsis severity score and reduce the maximum dose of norepinephrine in patients with diabetes and sepsis remains to be further studied.

Key words: Diabetes mellitus, Sepsis, Metformin, Clinical outcomes, Mortality rate, Organ dysfunction, Meta-analysis

何宇福,佟文英,王芳,等. 入院前使用二甲双胍对糖尿病合并脓毒症患者临床结局的影响[J]. 中国全科医学, 2024, 27(09): 1034-1041. DOI: 10.12114/j.issn.1007-9572.2023.0347.
HE Yufu,TONG Wenying,WANG Fang, et al. Effects of Pre-hospital Metformin Use on Clinical Outcomes in Patients with Diabetes and Sepsis[J]. Chinese General Practice, 2024, 27(09): 1034-1041. DOI: 10.12114/j.issn.1007-9572.2023.0347.

图/表 11

图1 文献筛选流程图

Figure 1 Literature screening flow chart

表1 纳入文献基本特征

Table 1 Basic characteristics of included literature

第一作者	发表时间（年）	研究类型	国家	多中心/单中心	诊断	样本量（例）		研究周期（月）	主要观察指标	次要观察指标	NOS评分（分）
第一作者	发表时间（年）	研究类型	国家	多中心/单中心	诊断	MET组	NM组	研究周期（月）	主要观察指标	次要观察指标	NOS评分（分）
SCALE^[24]	2011	RC	英国	单中心	脓毒症	12	53	43	LA发生率、死亡率	②	7
GREEN^[20]	2012	RC	美国	单中心	脓毒症	192	1 755	20	28 d死亡率	①②③⑧	8
HLOCH^[25]	2012	RC	捷克共和国	单中心	感染性休克	4	21	31	死亡率	②	7
CHRISTIANSEN^[26]	2013	RC	丹麦	多中心	糖尿病；脓毒症	73	182	84	30 d死亡率	⑧	8
VAN VUGHT^[21]	2016	PO	荷兰	多中心	脓毒症	114	127	31	住院死亡率	①②⑤⑥⑦⑧	7
DOENYAS-BARAK^[27]	2016	RC	以色列	单中心	感染性休克	44	118	30	住院死亡率	①②③④⑤	8
PARK^[28]	2017	RC	韩国	单中心	严重脓毒症；感染性休克	71	1 247	73	28 d死亡率	①②③⑥⑦⑧	8
JOCHMANS^[29]	2017	RC	法国	单中心	感染性休克	52	79	38	住院死亡率	①②③④⑤⑥⑦	8
CHEN^[22]	2019	RC	中国	单中心	脓毒症；菌血症	198	392	84	28 d死亡率	②③	8
OH^[30]	2020	RC	韩国	单中心	脓毒症	1 045	1 467	48	30 d死亡率		8
YANG^[19]	2021	RC	中国	多中心	脓毒症	476	1 907	132	30 d死亡率	①②④⑥⑦⑧	7
GÓMEZ^[31]	2022	RC	美国	多中心	脓毒症	599	2 092	74	90 d死亡率	⑤	8

图2 纳入研究偏倚风险图

Figure 2 Risk of bias graph for included studies

图3 纳入研究偏倚风险汇总图注：+表示达标，-表示未达标，？表示不清楚。

Figure 3 Risk of bias summary for included studies

图4 MET组与NM组患者死亡率比较森林图

Figure 4 Forest plot comparing mortality between MET and NM patients

图5 MET组与NM组患者初始血浆乳酸水平比较森林图

Figure 5 Forest plot comparing initial plasma lactate levels between MET group and NM group

图6 MET组与NM组患者血清肌酐水平比较森林图

Figure 6 Forest plot comparing serum creatinine levels in MET group and NM group

图7 MET组与NM组患者初始血糖水平比较森林图

Figure 7 Forest plot comparing initial blood glucose levels between MET group and NM group

图8 MET组与NM组患者机械通气比较森林图

Figure 8 Forest plot comparing mechanical ventilation between MET group and NM group

图9 MET组与NM组患者血管升压药的使用率比较森林图

Figure 9 Forest plot comparing use of vasopressors between MET group and NM group

图10 二甲双胍对糖尿病合并脓毒症患者死亡率影响的漏斗图

Figure 10 Funnel plot of the effect of metformin on mortality in patients with diabetes and sepsis

参考文献 35

[1]	SINGER M, DEUTSCHMAN C S, SEYMOUR C W，et al. The third international consensus definitions for sepsis and septic shock（sepsis-3）[J]. JAMA，2016,315(8):801-810. DOI：10.1001/jama.2016.0287.
[2]	BELTRÁN-GARCÍA J, OSCA-VERDEGAL R, JÁVEGA B，et al. Characterization of early peripheral immune responses in patients with sepsis and septic shock[J]. Biomedicines，2022,10(3):525. DOI：10.3390/biomedicines10030525.
[3]	RITTIRSCH D, FLIERL M A, WARD P A. Harmful molecular mechanisms in sepsis[J]. Nat Rev Immunol，2008,8(10):776-787. DOI：10.1038/nri2402.
[4]	DAVIAUD F, GRIMALDI D, DECHARTRES A，et al. Timing and causes of death in septic shock[J]. Ann Intensive Care，2015,5(1):16. DOI：10.1186/s13613-015-0058-8.
[5]	冒秀宏，孙卫和，汪涛，等. 血清发育内皮细胞基因-1、组织激肽释放酶结合蛋白对脓毒症患者病情严重程度及预后评估研究[J]. 创伤与急危重病医学，2020,8(4):263-266. DOI：10.16048/j.issn.2095-5561.2020.04.12.
[6]	RAIA L, ZAFRANI L. Endothelial activation and microcirculatory disorders in sepsis[J]. Front Med，2022,9:907992. DOI：10.3389/fmed.2022.907992.
[7]	LIU J L, LIU M, CHAI Z L，et al. Projected rapid growth in diabetes disease burden and economic burden in China：a spatio-temporal study from 2020 to 2030[J]. Lancet Reg Heath West Pac，2023,33:100700. DOI：10.1016/j.lanwpc.2023.100700.
[8]	KOH G C K W, PEACOCK S J, VAN DER POLL T，et al. The impact of diabetes on the pathogenesis of sepsis[J]. Eur J Clin Microbiol Infect Dis，2012,31(4):379-388. DOI：10.1007/s10096-011-1337-4.
[9]	SCHUETZ P, JONES A E, HOWELL M D，et al. Diabetes is not associated with increased mortality in emergency department patients with sepsis[J]. Ann Emerg Med，2011,58(5):438-444. DOI：10.1016/j.annemergmed.2011.03.052.
[10]	GRAHAM G G, PUNT J, ARORA M，et al. Clinical pharmacokinetics of metformin[J]. Clin Pharmacokinet，2011,50(2):81-98. DOI：10.2165/11534750-000000000-00000.
[11]	DI FUSCO D, DINALLO V, MONTELEONE I，et al. Metformin inhibits inflammatory signals in the gut by controlling AMPK and p38 MAP kinase activation[J]. Clin Sci，2018,132(11):1155-1168. DOI：10.1042/CS20180167.
[12]	FEI Q, MA H, ZOU J，et al. Metformin protects against ischaemic myocardial injury by alleviating autophagy-ROS-NLRP3-mediated inflammatory response in macrophages[J]. J Mol Cell Cardiol，2020,145:1-13. DOI：10.1016/j.yjmcc.2020.05.016.
[13]	JIA Y F, CUI R X, WANG C，et al. Metformin protects against intestinal ischemia-reperfusion injury and cell pyroptosis via TXNIP-NLRP3-GSDMD pathway[J]. Redox Biol，2020,32:101534. DOI：10.1016/j.redox.2020.101534.
[14]	CAMERON A R, MORRISON V L, LEVIN D，et al. Anti-inflammatory effects of metformin irrespective of diabetes status[J]. Circ Res，2016,119(5):652-665. DOI：10.1161/CIRCRESAHA.116.308445.
[15]	LIU P, LI M, WU W，et al. Protective effect of omega-3 polyunsaturated fatty acids on sepsis via the AMPK/mTOR pathway[J]. Pharm Biol，2023,61(1):306-315. DOI：10.1080/13880209.2023.2168018.
[16]	ZHAO H D, CHEN Y, QIAN L，et al. Lycorine protects against septic myocardial injury by activating AMPK-related pathways[J]. Free Radic Biol Med，2023,197:1-14. DOI：10.1016/j.freeradbiomed.2023.01.010.
[17]	LIU B, SU H L. Luteolin improves vasoconstriction function and survival of septic mice via AMPK/NF-κB pathway[J]. Heliyon，2023,9(2):e13330. DOI：10.1016/j.heliyon.2023.e13330.
[18]	PEDROSA A R, MARTINS D C, RIZZO M，et al. Metformin in SARS-CoV-2 infection：a hidden path - from altered inflammation to reduced mortality. A review from the literature[J]. J Diabetes Complications，2023,37(2):108391. DOI：10.1016/j.jdiacomp.2022.108391.
[19]	YANG Q L, ZHENG J Z, CHEN W Y，et al. Association between preadmission metformin use and outcomes in intensive care unit patients with sepsis and type 2 diabetes：a cohort study[J]. Front Med，2021,8:640785. DOI：10.3389/fmed.2021.640785.
[20]	GREEN J P, BERGER T, GARG N，et al. Impact of metformin use on the prognostic value of lactate in sepsis[J]. Am J Emerg Med，2012,30(9):1667-1673. DOI：10.1016/j.ajem.2012.01.014.
[21]	VAN VUGHT L A, SCICLUNA B P, HOOGENDIJK A J，et al. Association of diabetes and diabetes treatment with the host response in critically ill sepsis patients[J]. Crit Care，2016,20(1):1-15. DOI：10.1186/s13054-016-1429-8.
[22]	CHEN F C, KUNG C T, CHENG H H，et al. Metformin affects serum lactate levels in predicting mortality of patients with sepsis and bacteremia[J]. J Clin Med，2019,8(3):318. DOI：10.3390/jcm8030318.
[23]	STANG A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses[J]. Eur J Epidemiol，2010,25(9):603-605. DOI：10.1007/s10654-010-9491-z.
[24]	SCALE T, HARVEY J N. Diabetes，metformin and lactic acidosis[J]. Clin Endocrinol，2011,74(2):191-196. DOI：10.1111/j.1365-2265.2010.03891.x.
[25]	HLOCH O, CHARVAT J, MASOPUST J，et al. Lactic acidosis in medical ICU - the role of diabetes mellitus and metformin[J]. Neuro Endocrinol Lett，2012,33(8):792-795.
[26]	CHRISTIANSEN C, JOHANSEN M, CHRISTENSEN S，et al. Preadmission metformin use and mortality among intensive care patients with diabetes：a cohort study[J]. Crit Care Lond Engl，2013,17(5):R192. DOI：10.1186/cc12886.
[27]	DOENYAS-BARAK K, BEBERASHVILI I, MARCUS R，et al. Lactic acidosis and severe septic shock in metformin users：a cohort study[J]. Crit Care，2016,20:10. DOI：10.1186/s13054-015-1180-6.
[28]	PARK J, HWANG S Y, JO I J，et al. Impact of metformin use on lactate kinetics in patients with severe sepsis and septic shock[J]. Shock，2017,47(5):582-587. DOI：10.1097/shk.0000000000000782.
[29]	JOCHMANS S, ALPHONSINE J E, CHELLY J，et al. Does metformin exposure before ICU stay have any impact on patients' outcome? A retrospective cohort study of diabetic patients[J]. Ann Intensive Care，2017,7(1):116. DOI：10.1186/s13613-017-0336-8.
[30]	OH T K, SONG I A. Association between prior metformin therapy and sepsis in diabetes patients：a nationwide sample cohort study[J]. J Anesth，2020,34(3):358-366. DOI：10.1007/s00540-020-02753-3.
[31]	GÓMEZ H, DEL RIO-PERTUZ G, PRIYANKA P，et al. Association of metformin use during hospitalization and mortality in critically ill adults with type 2 diabetes mellitus and sepsis[J]. Crit Care Med，2022,50(6):935-944. DOI：10.1097/CCM.0000000000005468.
[32]	MALÍNSKÁ H, OLIYARNYK O, ŠKOP V，et al. Effects of metformin on tissue oxidative and dicarbonyl stress in transgenic spontaneously hypertensive rats expressing human C-reactive protein[J]. PLoS One，2016,11(3):e0150924. DOI：10.1371/journal.pone.0150924.
[33]	JING Y Y, WU F, LI D，et al. Metformin improves obesity-associated inflammation by altering macrophages polarization[J]. Mol Cell Endocrinol，2018,461:256-264. DOI：10.1016/j.mce.2017.09.025.
[34]	RENA G, HARDIE D G, PEARSON E R. The mechanisms of action of metformin[J]. Diabetologia，2017,60(9):1577-1585. DOI：10.1007/s00125-017-4342-z.
[35]	MALIK F, MEHDI S F, ALI H，et al. Is metformin poised for a second career as an antimicrobial?[J]. Diabetes/Metabolism Res Rev，2018,34(4):e2975. DOI：10.1002/dmrr.2975.

入院前使用二甲双胍对糖尿病合并脓毒症患者临床结局的影响

Effects of Pre-hospital Metformin Use on Clinical Outcomes in Patients with Diabetes and Sepsis

RichHTML

PDF

可视化

摘要/Abstract

引用本文

使用本文

图/表 11

参考文献 35

相关文章 15

编辑推荐

Metrics

留言

[1]	许佳兰, 阎红, 文君, 周紫彤, 王思宇. 老年癌症患者潜在不适当用药发生率的Meta分析[J]. 中国全科医学, 2025, 28(30): 3815-3822.
[2]	张可兴, 张博, 吴琼, 朱珊珊, 王迪, 张春男. 基于代谢组学四妙勇安汤治疗糖尿病足的作用机制研究[J]. 中国全科医学, 2025, 28(30): 3796-3805.
[3]	卢冬磊, 杨风英, 冯展鹏, 曹立全, 谭思洁. 同期训练可改善伴有超重或肥胖2型糖尿病患者的健康效应：一项Meta分析[J]. 中国全科医学, 2025, 28(27): 3410-3421.
[4]	张天宇, 于海搏, 陈飞, 李新, 张佳佳, 詹晓凯, 申曼, 汤然, 范斯斌, 赵凤仪, 黄仲夏. POEMS综合征全身系统性治疗疗效和安全性的Meta分析[J]. 中国全科医学, 2025, 28(27): 3447-3455.
[5]	全家霖, 朱琳, 苏煜, 陈泽恺, 陈梓淇, 张卓凡. 运动方式对超重或肥胖儿童青少年执行功能改善效果的网状Meta分析[J]. 中国全科医学, 2025, 28(27): 3422-3431.
[6]	张宇诺, 李瑞斌, 王玮. 血清Nesfatin-1和Ghrelin水平与糖脂代谢及2型糖尿病的关系研究[J]. 中国全科医学, 2025, 28(26): 3264-3270.
[7]	张睿敏, 董哲毅, 李爽, 王倩, 陈香美. 基于肾活检病理诊断的糖尿病肾病中医相关因素研究[J]. 中国全科医学, 2025, 28(26): 3307-3313.
[8]	尚忠华, 蒋芝月, 黄朝晖, 杨星, 刘海燕, 张丽. 1990—2021年中国宫颈癌疾病负担趋势分析及2022—2035年预测研究[J]. 中国全科医学, 2025, 28(26): 3314-3320.
[9]	罗新宇, 刘瑾, 陈海龙. 1990—2021年中国和全球胰腺炎疾病负担趋势分析及2022—2031年预测研究[J]. 中国全科医学, 2025, 28(26): 3321-3327.
[10]	唐尚锋, 黄阳珍, 郑妍惜, 潘阳阳, 熊忠宝, 卿华, 宋佳, 魏艺琳, 董衡, 王春盈, 陈蔓维, 张康康. 糖尿病基层医防融合服务规范[J]. 中国全科医学, 2025, 28(25): 3096-3103.
[11]	杨晨, 陈瞳, 张利方, 张洪旭, 李鹏飞, 张雪娟. 达格列净对老年乳腺癌幸存者射血分数保留的心力衰竭合并2型糖尿病患者的预后影响研究[J]. 中国全科医学, 2025, 28(24): 3053-3058.
[12]	王汝朋, 南京, 胡奕然, 杨升华, 金泽宁. 三酰甘油-葡萄糖体质量指数对2型糖尿病合并急性心肌梗死行急诊经皮冠状动脉介入治疗术后患者慢血流/无复流的预测价值研究[J]. 中国全科医学, 2025, 28(24): 2985-2992.
[13]	蒋世华, 朱政, 任盈盈, 朱垚磊, 王越, 高希彬. 中国儿童青少年近视患病率及影响因素的Meta分析[J]. 中国全科医学, 2025, 28(24): 3043-3052.
[14]	李浩, 李江涛, 刘丹, 王建军. 贝利尤单抗和阿尼鲁单抗及泰它西普治疗系统性红斑狼疮疗效和安全性的网状Meta分析[J]. 中国全科医学, 2025, 28(23): 2924-2933.
[15]	王笑林, 李秋月, 周彦君, 张金辉, 梁涛. 转移性结直肠癌患者呋喹替尼治疗相关心血管毒性发生率和风险的Meta分析[J]. 中国全科医学, 2025, 28(23): 2934-2940.