Acta Diabetologica

, Volume 53, Issue 3, pp 377–392 | Cite as

Hypoglycemia and risk of vascular events and mortality: a systematic review and meta-analysis

  • Jong Shiuan Yeh
  • Shih-Hsien Sung
  • Hui-Mei Huang
  • Huei-Ling Yang
  • Li-Kai You
  • Shao-Yuan Chuang
  • Po-Chieh Huang
  • Pai-Feng Hsu
  • Hao-Min Cheng
  • Chen-Huan Chen
Original Article



Hypoglycemia has been associated with adverse outcomes in patients with diabetes and critical illness. However, such associations in these populations have not been systematically examined.


We conducted a systematic review and meta-analysis of longitudinal follow-up cohort studies to investigate the associations between hypoglycemia and various adverse outcomes.


After removing duplicates and critically appraising all screened citations, a total of 19 eligible studies were included. As demonstrated by random-effects meta-analysis, hypoglycemia was strongly associated with a higher risk of adverse events (HR 1.90, 95 % CI 1.63–2.20; P < 0.001). Comparable risk ratios were shown in prespecified stratified analyses investigating above association for different study endpoints, in patients with or without critical illness, in patients with and without diabetes (from 1.47 to 3.31; p for interaction or heterogeneity >0.1). Additionally, a dose-dependent relationship between the severity of hypoglycemia and adverse vascular events and mortality (HR for mild hypoglycemia: 1.68, 95 % CI 1.25–2.26; P < 0.001 and HR for severe hypoglycemia: 2.33, 95 % CI 2.07–2.61; P < 0.001; p for trend 0.02) was observed. Suggested by a bias analysis, the above observations were unlikely to have resulted from unmeasured confounding parameters.


This is the first study demonstrating that hypoglycemia was associated with comparable risk ratios in different study populations and various study endpoints, and a trend of a dose-dependent relationship between hypoglycemia severity and adverse events. The findings of this systematic review support the speculation that hypoglycemia is a risk factor for adverse vascular events and mortality.


Hypoglycemia Vascular events Mortality Risk factor 



Hao-min Cheng is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Author contributions

Jong Shiuan Yeh: the literature search, data extraction, manuscript drafting, Shih-Hsien Sung: the literature search, data extraction, manuscript drafting, Hui-Mei Huang: the literature search, data extraction, Huei-Ling Yang: the literature search, data extraction, Li-Kai You: data analysis, Shao-Yuan Chuang: data analysis, Po-Chieh Huang: data analysis, Pai-Feng Hsu: the literature search, data extraction, Hao-Min Cheng: the literature search, data extraction, data analysis, manuscript drafting, Chen-Huan Chen: manuscript drafting.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standard

All included studies have been reviewed by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards.

Statement of human and animal rights

This article is based on the secondary analysis of primary studies published in the literature. Therefore it does not contain any data obtained directly from human or animal subjects performed by any of the authors.

Informed consent

All persons gave their informed consent prior to their inclusion in the studies.

Supplementary material

592_2015_803_MOESM1_ESM.docx (495 kb)
Supplementary material 1 (DOCX 494 kb)


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Copyright information

© Springer-Verlag Italia 2015

Authors and Affiliations

  • Jong Shiuan Yeh
    • 1
  • Shih-Hsien Sung
    • 2
    • 6
    • 7
  • Hui-Mei Huang
    • 5
  • Huei-Ling Yang
    • 5
  • Li-Kai You
    • 3
  • Shao-Yuan Chuang
    • 8
  • Po-Chieh Huang
    • 3
  • Pai-Feng Hsu
    • 4
    • 6
    • 7
  • Hao-Min Cheng
    • 3
    • 6
    • 7
  • Chen-Huan Chen
    • 3
    • 6
    • 7
  1. 1.Cardiology Division, Internal Medicine DepartmentTaipei Medical University Wan-Fang HospitalTaipeiTaiwan
  2. 2.Division of Cardiology, Department of Internal MedicineTaipei Veterans General HospitalTaipeiTaiwan
  3. 3.Department of Medical EducationTaipei Veterans General HospitalTaipeiTaiwan, Roc
  4. 4.Healthcare and Management CenterTaipei Veterans General HospitalTaipeiTaiwan
  5. 5.Nursing DepartmentTaipei Veterans General HospitalTaipeiTaiwan
  6. 6.Institute of Public Health and Community Medicine Research CenterNational Yang-Ming UniversityTaipeiTaiwan
  7. 7.Department of MedicineNational Yang-Ming UniversityTaipeiTaiwan
  8. 8.Division of Preventive Medicine and Health ServiceResearch Institute of Population Health Sciences, National Health Research InstitutesMiaoliTaiwan

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