Severe Hypoglycaemia and Cardiovascular Disease
Severe Hypoglycaemia and Cardiovascular Disease
Our initial search identified 3443 citations. Based on the titles and abstracts, 56 citations were considered potentially eligible and we evaluated the full texts of these 56 citations. A total of 50 studies were subsequently excluded; three were performed in acute hospital settings, one was a design paper, 34 did not report an association between hypoglycaemia and cardiovascular disease, and 12 were reviews or abstracts from meetings. Of the three excluded studies performed in acute hospital settings, the Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction 2 (DIGAMI-2) study showed an association between hypoglycaemia and cardiovascular disease, but its study participants were patients admitted to participating coronary care units for suspected acute myocardial infarction. Thus, the DIGAMI-2 study was not included in this meta-analysis. We did not include the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial or the study by McCoy et al; these studies provided relative risks for mortality associated with hypoglycaemia, but the relative risk for cardiovascular disease associated with severe hypoglycaemia was not available. Of the meeting abstracts identified through our search, two satisfied our eligibility criteria; the full text articles were retrieved and included in our meta-analysis. Therefore, six studies were eventually included in the meta-analysis (Figure 1).
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Figure 1.
Flow of studies through review.
Table 1 and Table 2 show the characteristics of the studies included in the meta-analysis. Two studies (the ADVANCE study and the Veterans Affairs Diabetes Trial [VADT]) were secondary analyses of randomised clinical trials, and the other four studies (Johnston et al, Zhao et al, Rathmann et al, and Hsu et al) were based on administrative databases. The number of participants ranged from 1522 to 860 845, with a mean age range of 60-67 years and a mean duration of diabetes of 3.2-11.5 years; the follow-up period ranged from 1 to 5.6 years. The VADT, Johnston et al, and Zhao et al studies were conducted in the United States; the ADVANCE study was done in Europe, Asia, Australia/New Zealand, and Canada; Rathmann et al in Germany; and Hsu et al in Taiwan. The quality of the secondary analyses of randomised controlled trials (the ADVANCE study and VADT) was generally high. The detailed quality assessment is described in Supplementary Text B and Supplementary Table A ). All of the included studies adjusted for age, sex, history of cardiovascular disease, history of microvascular complications or its surrogate, baseline health status, and use of antihyperglycaemic agents. Other factors, such as race, dyslipidaemia, smoking status, and body mass index, were less consistently adjusted ( Table 2 and Supplementary Text A and Supplementary Text B ). The impact of unmeasured comorbid severe illness was not assessed in these studies.
The six studies included 903,510 participants, with 1 to 5.6 years of follow-up. During the follow-up period, 0.6% to 5.8% experienced severe hypoglycaemia. The conventional random effects meta-analysis, which ignores unmeasured confounding, indicated that 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) ( Table 3 and Figure 2). Moderate heterogeneity among these studies was indicated (I=73.1%; P=0.002 for heterogeneity). There was little evidence of publication bias. The funnel plot did not indicate asymmetry; Begg's P value was 0.71 and Egger's bias coefficient was 1.49 (95% confidence interval -1.50 to 4.47; P=0.24) (see Supplementary Figure A). We also estimated the population attributable fraction for cardiovascular disease associated with severe hypoglycaemia, assuming that the observed association between severe hypoglycaemia and cardiovascular disease reflected a causal effect of severe hypoglycaemia on risk of cardiovascular disease in people with type 2 diabetes. The excess fraction of cardiovascular disease incidence attributable to severe hypoglycaemia was 1.56% (95% confidence interval 1.32% to 1.81%; P<0.001).
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Figure 2.
Conventional random effects meta-analysis according to study design. ADVANCE=Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; VADT=Veterans Affairs Diabetes Trial. Dots indicate relative risks for severe hypoglycaemia and cardiovascular events in people with type 2 diabetes. Horizontal lines indicate 95% confidence intervals for relative risks. Diamonds represent pooled relative risk estimates with 95% confidence intervals.
(Enlarge Image)
Supplementary Figure A.
Assessment of publication bias by funnel plot.
To examine possible sources of heterogeneity across studies, we carried out stratified analyses according to study design, study location, sex, duration of follow-up, insulin use, adjustment for race and dyslipidaemia, adjustment for smoking status, and adjustment for body mass index ( Table 3 ). Stratified analysis according to study design did not indicate apparent heterogeneity. Subgroups by duration of follow-up and by adjustment for race and dyslipidaemia seemed to differ in the magnitude of relative risk estimates. In a stratified analysis according to duration of follow-up, the pooled relative risk from studies with a duration of follow-up of more than one year (that is, the pooled relative risk excluding the study by Johnston et al) was larger than the relative risk from the study by Johnston et al (2.16, 95% confidence interval 1.77 to 2.64 v 1.79, 1.69 to 1.89; P=0.07 for interaction). In addition, the ADVANCE study did not adjust for race and dyslipidaemia, and it had larger a relative risk than the pooled relative risk from the other studies (3.45, 2.34 to 5.08 v 1.93, 1.70 to 2.18; P=0.005 for interaction). However, stratification by these factors did not explain much of the heterogeneity in results, with I statistics moderate to high within each stratum.
All studies showed a strong positive association between hypoglycaemia and cardiovascular disease (with point estimates of the relative risk ranging from 1.60 to 3.45). We performed a bias analysis to provide quantitative estimates, externally adjusted for comorbid severe illness (Figure 3 and Supplementary Table B ). The bias analysis indicated that comorbid severe illness, alone, may not explain the observed association between severe hypoglycaemia and cardiovascular disease. To explain the association, comorbid severe illness would have had to be extremely strongly associated with both severe hypoglycaemia and cardiovascular disease. For example, to account for the association, comorbid severe illness would have needed to be 10 times more prevalent in patients with severe hypoglycaemia than in those without severe hypoglycaemia, and would have to have had a relative risk of 10.
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Figure 3.
Random effects meta-analysis with bias analysis. Bias adjusted relative risks of severe hypoglycaemia and cardiovascular disease were computed to examine the sensitivity of the association to possible confounding by comorbid severe illness. The prevalence of comorbid severe illness in patients without severe hypoglycaemia was assumed to be 0.5%. CVD=cardiovascular disease.
Results
Our initial search identified 3443 citations. Based on the titles and abstracts, 56 citations were considered potentially eligible and we evaluated the full texts of these 56 citations. A total of 50 studies were subsequently excluded; three were performed in acute hospital settings, one was a design paper, 34 did not report an association between hypoglycaemia and cardiovascular disease, and 12 were reviews or abstracts from meetings. Of the three excluded studies performed in acute hospital settings, the Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction 2 (DIGAMI-2) study showed an association between hypoglycaemia and cardiovascular disease, but its study participants were patients admitted to participating coronary care units for suspected acute myocardial infarction. Thus, the DIGAMI-2 study was not included in this meta-analysis. We did not include the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial or the study by McCoy et al; these studies provided relative risks for mortality associated with hypoglycaemia, but the relative risk for cardiovascular disease associated with severe hypoglycaemia was not available. Of the meeting abstracts identified through our search, two satisfied our eligibility criteria; the full text articles were retrieved and included in our meta-analysis. Therefore, six studies were eventually included in the meta-analysis (Figure 1).
(Enlarge Image)
Figure 1.
Flow of studies through review.
Study Characteristics and Quality Assessment
Table 1 and Table 2 show the characteristics of the studies included in the meta-analysis. Two studies (the ADVANCE study and the Veterans Affairs Diabetes Trial [VADT]) were secondary analyses of randomised clinical trials, and the other four studies (Johnston et al, Zhao et al, Rathmann et al, and Hsu et al) were based on administrative databases. The number of participants ranged from 1522 to 860 845, with a mean age range of 60-67 years and a mean duration of diabetes of 3.2-11.5 years; the follow-up period ranged from 1 to 5.6 years. The VADT, Johnston et al, and Zhao et al studies were conducted in the United States; the ADVANCE study was done in Europe, Asia, Australia/New Zealand, and Canada; Rathmann et al in Germany; and Hsu et al in Taiwan. The quality of the secondary analyses of randomised controlled trials (the ADVANCE study and VADT) was generally high. The detailed quality assessment is described in Supplementary Text B and Supplementary Table A ). All of the included studies adjusted for age, sex, history of cardiovascular disease, history of microvascular complications or its surrogate, baseline health status, and use of antihyperglycaemic agents. Other factors, such as race, dyslipidaemia, smoking status, and body mass index, were less consistently adjusted ( Table 2 and Supplementary Text A and Supplementary Text B ). The impact of unmeasured comorbid severe illness was not assessed in these studies.
Conventional Random Effects Meta-analysis
The six studies included 903,510 participants, with 1 to 5.6 years of follow-up. During the follow-up period, 0.6% to 5.8% experienced severe hypoglycaemia. The conventional random effects meta-analysis, which ignores unmeasured confounding, indicated that 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) ( Table 3 and Figure 2). Moderate heterogeneity among these studies was indicated (I=73.1%; P=0.002 for heterogeneity). There was little evidence of publication bias. The funnel plot did not indicate asymmetry; Begg's P value was 0.71 and Egger's bias coefficient was 1.49 (95% confidence interval -1.50 to 4.47; P=0.24) (see Supplementary Figure A). We also estimated the population attributable fraction for cardiovascular disease associated with severe hypoglycaemia, assuming that the observed association between severe hypoglycaemia and cardiovascular disease reflected a causal effect of severe hypoglycaemia on risk of cardiovascular disease in people with type 2 diabetes. The excess fraction of cardiovascular disease incidence attributable to severe hypoglycaemia was 1.56% (95% confidence interval 1.32% to 1.81%; P<0.001).
(Enlarge Image)
Figure 2.
Conventional random effects meta-analysis according to study design. ADVANCE=Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; VADT=Veterans Affairs Diabetes Trial. Dots indicate relative risks for severe hypoglycaemia and cardiovascular events in people with type 2 diabetes. Horizontal lines indicate 95% confidence intervals for relative risks. Diamonds represent pooled relative risk estimates with 95% confidence intervals.
(Enlarge Image)
Supplementary Figure A.
Assessment of publication bias by funnel plot.
Stratified Analysis
To examine possible sources of heterogeneity across studies, we carried out stratified analyses according to study design, study location, sex, duration of follow-up, insulin use, adjustment for race and dyslipidaemia, adjustment for smoking status, and adjustment for body mass index ( Table 3 ). Stratified analysis according to study design did not indicate apparent heterogeneity. Subgroups by duration of follow-up and by adjustment for race and dyslipidaemia seemed to differ in the magnitude of relative risk estimates. In a stratified analysis according to duration of follow-up, the pooled relative risk from studies with a duration of follow-up of more than one year (that is, the pooled relative risk excluding the study by Johnston et al) was larger than the relative risk from the study by Johnston et al (2.16, 95% confidence interval 1.77 to 2.64 v 1.79, 1.69 to 1.89; P=0.07 for interaction). In addition, the ADVANCE study did not adjust for race and dyslipidaemia, and it had larger a relative risk than the pooled relative risk from the other studies (3.45, 2.34 to 5.08 v 1.93, 1.70 to 2.18; P=0.005 for interaction). However, stratification by these factors did not explain much of the heterogeneity in results, with I statistics moderate to high within each stratum.
Random Effects Meta-analysis With Bias Analysis
All studies showed a strong positive association between hypoglycaemia and cardiovascular disease (with point estimates of the relative risk ranging from 1.60 to 3.45). We performed a bias analysis to provide quantitative estimates, externally adjusted for comorbid severe illness (Figure 3 and Supplementary Table B ). The bias analysis indicated that comorbid severe illness, alone, may not explain the observed association between severe hypoglycaemia and cardiovascular disease. To explain the association, comorbid severe illness would have had to be extremely strongly associated with both severe hypoglycaemia and cardiovascular disease. For example, to account for the association, comorbid severe illness would have needed to be 10 times more prevalent in patients with severe hypoglycaemia than in those without severe hypoglycaemia, and would have to have had a relative risk of 10.
(Enlarge Image)
Figure 3.
Random effects meta-analysis with bias analysis. Bias adjusted relative risks of severe hypoglycaemia and cardiovascular disease were computed to examine the sensitivity of the association to possible confounding by comorbid severe illness. The prevalence of comorbid severe illness in patients without severe hypoglycaemia was assumed to be 0.5%. CVD=cardiovascular disease.
