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BMJ. 2013 Jul 29;347:f4533. doi: 10.1136/bmj.f4533.

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

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Department of Diabetes Research, Diabetes Research Center, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.



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.


Meta-analysis of observational studies.


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


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.


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 (I(2)=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.


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.

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