Intended for healthcare professionals

  1. Research
  2. Severe hypoglycaemia...
  3. Severe hypoglycaemia and cardiovascular disease: systematic review and meta-analysis with bias analysis
CCBYNC Open access
Research

Severe hypoglycaemia and cardiovascular disease: systematic review and meta-analysis with bias analysis

BMJ 2013; 347 doi: https://doi.org/10.1136/bmj.f4533 (Published 30 July 2013) Cite this as: BMJ 2013;347:f4533
  1. Atsushi Goto, senior researcher12,
  2. Onyebuchi A Arah, professor34,
  3. Maki Goto, researcher12,
  4. Yasuo Terauchi, professor2,
  5. Mitsuhiko Noda, director1
  1. 1Department of Diabetes Research, Diabetes Research Center, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan
  2. 2Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, Yokohama, Japan
  3. 3Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA, USA
  4. 4Department of Public Health, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
  1. Correspondence to: M Noda mnoda{at}hosp.ncgm.go.jp
  • Accepted 9 July 2013

Abstract

Objectives To provide a systematic and quantitative summary of the association between severe hypoglycaemia and risk of cardiovascular disease in people with type 2 diabetes and to examine the sensitivity of the association to possible uncontrolled confounding by unmeasured comorbid severe illness using a bias analysis.

Design Meta-analysis of observational studies.

Data sources Medline, Embase, the Cochrane Library, and Web of Science databases were searched to February 2013, without any language restrictions.

Eligibility criteria Two independent reviewers selected cohort studies that evaluated the association of severe hypoglycaemia with cardiovascular events in people with type 2 diabetes; we excluded studies from acute hospital settings. We extracted descriptive and quantitative data.

Results Of 3443 citations screened, six eligible studies with 903 510 participants were identified. In the conventional random effects meta-analysis, severe hypoglycaemia was strongly associated with a higher risk of cardiovascular disease (relative risk 2.05, 95% confidence interval 1.74 to 2.42; P<0.001). The excess fraction of cardiovascular disease incidence that was attributable to severe hypoglycaemia (the population attributable fraction) was 1.56% (95% confidence interval 1.32% to 1.81%; P<0.001). Although moderate heterogeneity across the studies was suggested (I2=73.1%; P=0.002 for heterogeneity), most subgroups showed similar results in stratified analyses. The bias analysis indicated that comorbid severe illness alone may not explain the association between hypoglycaemia and cardiovascular disease; to explain this association, comorbid severe illness would have had to be extremely strongly associated with both severe hypoglycaemia and cardiovascular disease.

Conclusion Our findings suggest that severe hypoglycaemia is associated with a higher risk of cardiovascular disease; they also support the notion that avoiding severe hypoglycaemia may be important to prevent cardiovascular disease in people with type 2 diabetes.

Footnotes

  • We thank Shao-Yuan Chuang, Wolfgang Rathmann, Yingnan Zhao, and Stephen Johnston for providing the data and the information for this meta-analysis.

  • Contributors: AG and MN designed the study. AG and MG independently searched the literature, selected the studies, and extracted the data. AG and OAA analysed and interpreted the data. AG and MG drafted the manuscript. OAA, YT, and MN contributed to the critical revision of the manuscript for important intellectual content. AG and NM are guarantors.

  • Funding: This work was funded by health sciences research grants (comprehensive research on life-style related diseases including cardiovascular diseases and diabetes mellitus H22-019 and H25-016) from the Ministry of Health, Labour and Welfare of Japan. OAA has been supported by Veni career grant No 916.96.059 awarded by the Netherlands Organization for Scientific Research. The funders had no role in the study design, data collection, data analysis, data interpretation, writing of the report, or decision to submit the results.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: Not required.

  • Data sharing: No additional data available.

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/.

View Full Text
Back to top