Severe Hypoglycaemia and Cardiovascular Disease
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 (I=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.
Severe hypoglycaemia is a potential risk factor for cardiovascular disease in people with type 2 diabetes. Meta-analyses of recent clinical trials indicated that intensive glucose control was associated with a reduced risk of non-fatal myocardial infarction in people with type 2 diabetes. Individually, however, these recent clinical trials have failed to show a beneficial effect of intensive glucose control on overall cardiovascular disease events, despite earlier observational studies indicating a strong positive association between diabetes or hyperglycaemia and risk of cardiovascular disease. If severe hypoglycaemia induces cardiovascular disease events, it may also dilute the potential benefit of intensive glucose control on such events because intensive glucose control increases the risk of severe hypoglycaemia. This is biologically plausible because severe hypoglycaemia has acute effects on sympathoadrenal activation, inflammation, and endothelial function, all of which have potential adverse cardiovascular effects. In addition, cardiac ischaemia or fatal arrhythmia during hypoglycaemia may be responsible for the increased risk of cardiovascular disease among patients with severe hypoglycaemia.
Although observational studies have reported a positive association between severe hypoglycaemia and risk of cardiovascular disease, this association remains controversial. Some have suggested that severe hypoglycaemia may be a marker of vulnerability to cardiovascular disease events because the risk of hypoglycaemia is increased in patients with comorbid severe illnesses (for example, renal disease, liver disease, cognitive decline, and terminal cancer) that are risk factors for serious adverse health outcomes. Thus comorbid severe illnesses may confound the association between hypoglycaemia and cardiovascular disease. Randomisation of patients to hypoglycaemic and non-hypoglycaemic groups is not feasible; however, a bias analysis may help to elucidate the impact of a comorbid severe illness on the association between severe hypoglycaemia and cardiovascular disease.
We conducted a systematic review and meta-analysis to evaluate if severe hypoglycaemia is associated with risk of cardiovascular disease, and if confounding from an unmeasured comorbid severe illness accounts for the reported association between severe hypoglycaemia and cardiovascular disease, using a bias analysis.
Abstract and Introduction
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 (I=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.
Introduction
Severe hypoglycaemia is a potential risk factor for cardiovascular disease in people with type 2 diabetes. Meta-analyses of recent clinical trials indicated that intensive glucose control was associated with a reduced risk of non-fatal myocardial infarction in people with type 2 diabetes. Individually, however, these recent clinical trials have failed to show a beneficial effect of intensive glucose control on overall cardiovascular disease events, despite earlier observational studies indicating a strong positive association between diabetes or hyperglycaemia and risk of cardiovascular disease. If severe hypoglycaemia induces cardiovascular disease events, it may also dilute the potential benefit of intensive glucose control on such events because intensive glucose control increases the risk of severe hypoglycaemia. This is biologically plausible because severe hypoglycaemia has acute effects on sympathoadrenal activation, inflammation, and endothelial function, all of which have potential adverse cardiovascular effects. In addition, cardiac ischaemia or fatal arrhythmia during hypoglycaemia may be responsible for the increased risk of cardiovascular disease among patients with severe hypoglycaemia.
Although observational studies have reported a positive association between severe hypoglycaemia and risk of cardiovascular disease, this association remains controversial. Some have suggested that severe hypoglycaemia may be a marker of vulnerability to cardiovascular disease events because the risk of hypoglycaemia is increased in patients with comorbid severe illnesses (for example, renal disease, liver disease, cognitive decline, and terminal cancer) that are risk factors for serious adverse health outcomes. Thus comorbid severe illnesses may confound the association between hypoglycaemia and cardiovascular disease. Randomisation of patients to hypoglycaemic and non-hypoglycaemic groups is not feasible; however, a bias analysis may help to elucidate the impact of a comorbid severe illness on the association between severe hypoglycaemia and cardiovascular disease.
We conducted a systematic review and meta-analysis to evaluate if severe hypoglycaemia is associated with risk of cardiovascular disease, and if confounding from an unmeasured comorbid severe illness accounts for the reported association between severe hypoglycaemia and cardiovascular disease, using a bias analysis.
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