J. M. Dekker

Ankle brachial index combined with Framingham risk score to predict cardiovascular events and mortality - A meta-analysis

CONTEXT Prediction models to identify healthy individuals at high risk of cardiovascular disease have limited accuracy. A low ankle brachial index (ABI) is an indicator of atherosclerosis and has the potential to improve prediction. OBJECTIVE To determine if the ABI provides information on the risk of cardiovascular events and mortality independently of the Framingham risk score (FRS) and can improve risk prediction. DATA SOURCES Relevant studies were identified. A search of MEDLINE (1950 to February 2008) and EMBASE (1980 to February 2008) was conducted using common text words for the term ankle brachial index combined with text words and Medical Subject Headings to capture prospective cohort designs. Review of reference lists and conference proceedings, and correspondence with experts was conducted to identify additional published and unpublished studies. STUDY SELECTION Studies were included if participants were derived from a general population, ABI was measured at baseline, and individuals were followed up to detect total and cardiovascular mortality. DATA EXTRACTION Prespecified data on individuals in each selected study were extracted into a combined data set and an individual participant data meta-analysis was conducted on individuals who had no previous history of coronary heart disease. RESULTS Sixteen population cohort studies fulfilling the inclusion criteria were included. During 480,325 person-years of follow-up of 24,955 men and 23,339 women, the risk of death by ABI had a reverse J-shaped distribution with a normal (low risk) ABI of 1.11 to 1.40. The 10-year cardiovascular mortality in men with a low ABI (< or = 0.90) was 18.7% (95% confidence interval [CI], 13.3%-24.1%) and with normal ABI (1.11-1.40) was 4.4% (95% CI, 3.2%-5.7%) (hazard ratio [HR], 4.2; 95% CI, 3.3-5.4). Corresponding mortalities in women were 12.6% (95% CI, 6.2%-19.0%) and 4.1% (95% CI, 2.2%-6.1%) (HR, 3.5; 95% CI, 2.4-5.1). The HRs remained elevated after adjusting for FRS (2.9 [95% CI, 2.3-3.7] for men vs 3.0 [95% CI, 2.0-4.4] for women). A low ABI (< or = 0.90) was associated with approximately twice the 10-year total mortality, cardiovascular mortality, and major coronary event rate compared with the overall rate in each FRS category. Inclusion of the ABI in cardiovascular risk stratification using the FRS would result in reclassification of the risk category and modification of treatment recommendations in approximately 19% of men and 36% of women. CONCLUSION Measurement of the ABI may improve the accuracy of cardiovascular risk prediction beyond the FRS.

Hyperglycaemia is associated with all-cause and cardiovascular mortality in the Hoorn population: the Hoorn Study

Aims/hypothesis. The degree of glycaemia has been shown to be associated with all-cause and cardiovascular mortality in diabetic subjects. Whether this association also exists in the general population is still controversial. We studied the predictive value of fasting plasma glucose, 2-hour post-load glucose and HbA1 c in a population-based cohort of 2363 older (50–75 years) subjects, without known diabetes. Methods. Relative risks (RR) of all-cause and cardiovascular mortality were estimated by Cox proportional hazards model, adjusting for age and sex, and additionally for known cardiovascular risk factors. Results. During 8 years of follow-up, 185 subjects died; 98 of cardiovascular causes. Fasting plasma glucose was only predictive in the diabetic range, although the risks started to increase at about 6.1 mmol/l. Post-load glucose and HbA1 c values were, even within the non-diabetic range, associated with an increased risk (p for linear trend < 0.05). These increased risks were mostly, but not completely, attributable to known cardiovascular risk factors. After exclusion of subjects with newly diagnosed diabetes or with pre-existent cardiovascular disease (n = 551), a 5.8 mmol/l increase of post-load glucose (corresponding to two standard deviations of the population distribution) was associated with a higher age-adjusted and sex-adjusted risk of all-cause (RR 2.24) and cardiovascular mortality (RR 3.40) (p < 0.05). After additional adjustment for known cardiovascular risk factors, these relative risks were still statistically significant, with values of 2.20 and 3.00 respectively (p < 0.05). Conclusion/interpretation. High glycaemic variables, especially 2-h post-load glucose concentrations and to a lesser extent HbA1 c values, indicate a risk of all-cause and cardiovascular mortality in a general population without known diabetes. [Diabetologia (1999) 42: 926–931]

Insulin and Risk of Cardiovascular Disease A Meta-Analysis

BACKGROUND Our purposes were to estimate the strength of the longitudinal relationship between hyperinsulinemia and cardiovascular diseases (CVD) from the available literature and to identify study characteristics that modify this relationship. METHODS AND RESULTS Articles were identified by means of a MEDLINE and Embase search and citation tracking. Eligible studies were prospective population-based cohort studies and nested case-control studies on the relationship between, on the one hand, fasting or nonfasting insulin levels and, on the other hand, myocardial infarction, death from coronary heart disease, and/or ECG abnormalities. Data were extracted pertaining to insulin measurements, type of outcome studied, adjustment for confounding, sex, mean age of the study population, follow-up period, insulin assay, and ethnic background (white or nonwhite). Associations of insulin and CVD were reexpressed in a uniform manner, an estimate of relative risk (RR) and 95% CI, to be used in meta-regression analyses. Twelve of 17 potentially eligible articles provided sufficient information. Overall, a weak positive association was found. The meta-analysis resulted in an estimated summary RR (95% CI) of 1.18 (1.08 to 1.29) for differences in insulin level, equivalent to the difference between the 75th and the 25th percentiles of the general population in The Netherlands. Ethnic background and type of insulin assay modified the relationship between insulin and CVD with borderline significance. CONCLUSIONS Hyperinsulinemia is a weak risk indicator for the occurrence of CVD. The relationship between hyperinsulinemia and CVD was modified by ethnic background and by the type of insulin assay involved.

Inflammation and endothelial dysfunction are associated with retinopathy: the Hoorn study

Aims/hypothesisThe exact pathogenesis of retinopathy in diabetic and non-diabetic individuals is incompletely understood, but may involve chronic low-grade inflammation and dysfunction of the vascular endothelium. The aim of this study was to investigate the association of inflammation and endothelial dysfunction with prevalent retinopathy in individuals with and without type 2 diabetes.MethodsAs part of a population-based cohort study, 625 individuals aged 50–74 years, stratified according to age, sex and glucose tolerance status, underwent an extensive physical examination. Retinopathy was assessed by an ophthalmological examination, including funduscopy and two-field 45° fundus photography with mydriasis in both eyes. Levels of C-reactive protein (CRP), soluble intercellular adhesion molecule-1 (sICAM-1), von Willebrand factor, and soluble vascular adhesion molecule-1 (sVCAM-1) were assessed, together with the urinary albumin : creatinine ratio, and the results were combined to obtain summarising z scores for inflammation and endothelial dysfunction.ResultsThe prevalence of retinopathy was positively associated with tertiles of CRP and sICAM-1. When compared with the lowest tertile, the highest tertile of the inflammatory z score was associated with retinopathy in all subjects (odds ratio [OR]=2.2, 95% CI 1.2–4.1, adjusted for age, sex and glucose tolerance status). The highest tertile of the endothelial dysfunction z score was associated with retinopathy among diabetic individuals (OR=4.4, 95% CI 1.2–15.9, adjusted for age and sex) but not in non-diabetic individuals. Additional adjustment for other risk factors, such as systolic and diastolic blood pressure, BMI, total cholesterol and triglycerides, or mutual adjustment of the inflammatory and endothelial dysfunction z scores did not change the results.Conclusions/interpretationIn this study, inflammatory activity and endothelial dysfunction were associated with retinopathy, which suggests their involvement in the pathogenesis of retinopathy.

Beyond postprandial hyperglycaemia: metabolic factors associated with cardiovascular disease

Type II (non-insulin-dependent) diabetes mellitus is associated with a considerably enhanced risk of cardiovascular disease morbidity and mortality. Several epidemiological studies have shown an association between the 2-h glucose value after a 75 gm glucose load (2hPG) and mortality from all causes and from cardiovascular disease. The key question is whether postprandial glucose is related causally to the adverse outcomes (risk factors) or just a marker of risk. Since insulin resistance is one of the determinants of the 2hPG, factors associated with the insulin resistance syndrome, in particular postprandial hypertriglyceridaemia, also need to be considered. Glycaemic excursions could contribute to oxidative stress, endothelial dysfunction, formation of advanced glycation end-products and prolongation of the QTc interval. However, high postprandial concentrations of triglyceride rich lipoproteins, which can be partly attributed to obesity and insulin resistance, have now been recognised to affect endothelial function, to promote atherogenesis, and to be associated with coronary artery disease. On the basis of present evidence Type II diabetic patients require good overall glycaemic control, as reflected by target values of HbA1 c. However, postprandial hyperglycaemia should be considered as a marker of underlying metabolic abnormalities. Therefore, at present there is no evidence to support the recommendation to consider postprandial hyperglycaemia as a treatment target in itself and would thus require intervention studies showing added benefit of selectively targeting at meal-related glucose excursions in patients with an adequate HbA1 c. Drugs aiming at improving only postprandial glucose values are not likely to lower the excess mortality associated with Type II diabetes. [Diabetologia (2002) 45: ▪–▪]

The 1997 American Diabetes Association Criteria Versus the 1985 World Health Organization Criteria for the Diagnosis of Abnormal Glucose Tolerance: Poor agreement in the Hoorn Study

OBJECTIVE Recently, the American Diabetes Association (ADA) introduced new diagnostic criteria. These new criteria are based on fasting plasma glucose levels, avoiding the burdensome oral glucose tolerance test (OGTT). We compared the 1997 ADA criteria with the 1985 World Health Organization (WHO) criteria with respect to the prevalence of diabetes and the cardiovascular risk profile in the population of the Hoorn Study. RESEARCH DESIGN AND METHODS The Hoorn Study is a population-based survey of 2,484 men and women, aged 50–75 years. An OGTT was performed and cardiovascular risk factors were determined in 2,378 subjects without known diabetes. Subjects were categorized according to both sets of diagnostic criteria. RESULTS Although the prevalence of diabetes was similar for both sets of criteria, 47 of 120 (39.2%) subjects who were diagnosed with diabetes according to the 1997 ADA criteria were not classified as having diabetes when using the 1985 WHO criteria. Similarly, of 285 subjects diagnosed with impaired fasting glucose by the 1997 ADA criteria, 195 (68.4%) were classified as having normal glucose tolerance by the 1985 WHO criteria. The overall agreement was poor (K 0.33; 95% CI 0.28−0.38). Subjects who were diagnosed as having diabetes by either set of criteria had an adverse cardiovascular risk profile, which was between the cardiovascular risk profiles of concordant normal and concordant diabetic subjects. CONCLUSIONS In this study, both sets of criteria diagnosed a similar number of diabetic subjects, but many of the subjects shifted between glucose intolerance categories. With either set of criteria, a considerable number of subjects at risk of developing diabetes and subjects carrying an increased risk of cardiovascular disease, as reflected by an adverse cardiovascular risk profile, will be missed.

Plasma insulin and cardiovascular mortality in non-diabetic European men and women: a meta-analysis of data from eleven prospective studies

Aims/hypothesisWe examined the association between plasma insulin and cardiovascular mortality in non-diabetic European men and women based on data from eleven prospective studies.MethodsThe study population comprised 6156 men and 5351 women aged 30–89 years. Baseline measurements included oral glucose tolerance test, fasting and 2-h plasma insulin, and conventional risk factors. Cox models were used to calculate hazard ratios (HRs) and their 95% confidence intervals, and overall HRs were assessed by meta-analyses.ResultsDuring the 8.8-year follow-up, 362 men and 70 women died from cardiovascular disease. The age- and smoking-adjusted overall HR of cardiovascular mortality for the highest vs the lower quartiles of fasting insulin was 1.58 (95% CI: 1.26–1.97) in men and 2.64 (1.54–4.51) in women. Adjusting for other risk factors in addition, the HR was 1.54 (1.16–2.03) in men and 2.66 (1.45–4.90) in women. For 2-h insulin these HRs were 1.28 (0.99–1.66), 1.87 (0.87–4.02), and 0.85 (0.60–1.21), 1.36 (0.53–3.45). The overall HRs for interquartile ranges for fasting and 2-h insulin, with full adjustment, were 1.13 (1.05–1.22) and 1.11 (1.01–1.23) in men, and 1.25 (1.08–1.45) and 1.11 (0.91–1.36) in women.Conclusions/interpretationHyperinsulinaemia, defined by the highest quartile cut-off for fasting insulin, was significantly associated with cardiovascular mortality in both men and women independently of other risk factors. Associations between high 2-h insulin and cardiovascular mortality were weaker and non-significant. Weak positive associations of fasting and 2-h insulin with cardiovascular mortality over interquartile ranges were, however, more similar.We examined the association between plasma insulin and cardiovascular mortality in non-diabetic European men and women based on data from eleven prospective studies. The study population comprised 6156 men and 5351 women aged 30–89 years. Baseline measurements included oral glucose tolerance test, fasting and 2-h plasma insulin, and conventional risk factors. Cox models were used to calculate hazard ratios (HRs) and their 95% confidence intervals, and overall HRs were assessed by meta-analyses. During the 8.8-year follow-up, 362 men and 70 women died from cardiovascular disease. The age- and smoking-adjusted overall HR of cardiovascular mortality for the highest vs the lower quartiles of fasting insulin was 1.58 (95% CI: 1.26–1.97) in men and 2.64 (1.54–4.51) in women. Adjusting for other risk factors in addition, the HR was 1.54 (1.16–2.03) in men and 2.66 (1.45–4.90) in women. For 2-h insulin these HRs were 1.28 (0.99–1.66), 1.87 (0.87–4.02), and 0.85 (0.60–1.21), 1.36 (0.53–3.45). The overall HRs for interquartile ranges for fasting and 2-h insulin, with full adjustment, were 1.13 (1.05–1.22) and 1.11 (1.01–1.23) in men, and 1.25 (1.08–1.45) and 1.11 (0.91–1.36) in women. Hyperinsulinaemia, defined by the highest quartile cut-off for fasting insulin, was significantly associated with cardiovascular mortality in both men and women independently of other risk factors. Associations between high 2-h insulin and cardiovascular mortality were weaker and non-significant. Weak positive associations of fasting and 2-h insulin with cardiovascular mortality over interquartile ranges were, however, more similar.

Coffee consumption and incidence of impaired fasting glucose, impaired glucose tolerance, and type 2 diabetes: the Hoorn Study

Aims/hypothesisCoffee contains several substances that may affect glucose metabolism. The aim of this study was to evaluate the relationship between habitual coffee consumption and the incidence of IFG, IGT and type 2 diabetes.MethodsWe used cross-sectional and prospective data from the population-based Hoorn Study, which included Dutch men and women aged 50–74 years. An OGTT was performed at baseline and after a mean follow-up period of 6.4 years. Associations were adjusted for potential confounders including BMI, cigarette smoking, physical activity, alcohol consumption and dietary factors.ResultsAt baseline, a 5 cup per day higher coffee consumption was significantly associated with lower fasting insulin concentrations (−5.6%, 95% CI −9.3 to −1.6%) and 2-h glucose concentrations (−8.8%, 95% CI −11.8 to −5.6%), but was not associated with lower fasting glucose concentrations (−0.8%, 95% CI −2.1 to 0.6%). In the prospective analyses, the odds ratio (OR) for IGT was 0.59 (95% CI 0.36–0.97) for 3–4 cups per day, 0.46 (95% CI 0.26–0.81) for 5–6 cups per day, and 0.37 (95% CI 0.16–0.84) for 7 or more cups per day, as compared with the corresponding values for the consumption of 2 or fewer cups of coffee per day (p=0.001 for trend). Higher coffee consumption also tended to be associated with a lower incidence of type 2 diabetes (OR 0.69, CI 0.31–1.51 for ≥7 vs ≤2 cups per day, p=0.09 for trend), but was not associated with the incidence of IFG (OR 1.35, CI 0.80–2.27 for ≥7 vs ≤2 cups per day, p=0.49 for trend).Conclusions/interpretationOur findings indicate that habitual coffee consumption can reduce the risk of IGT, and affects post-load rather than fasting glucose metabolism.

Glucose tolerance and other determinants of cardiovascular autonomic function: the Hoorn Study

Aims/hypothesis. Currently, three categories of measures are used to assess cardiovascular autonomic dysfunction: measures of the Ewing-test, measures of heart-rate variability, and measures of baroreflex sensitivity. We studied the determinants of these measures obtained from cardiovascular autonomic function tests in the Hoorn Study. Methods. The study group (n = 631) consisted of a glucose-tolerance-stratified sample from a 50- to 75-year-old group of people. Cardiac cycle duration (RR interval) and continuous finger arterial pressure were measured under three conditions: during (a) spontaneous breathing, (b) six deep breaths over one minute, and (c) an active change in position from lying to standing. From these readings, ten measures of autonomic function were assessed (three Ewing, six heart-rate variability and one baroreflex sensitivity). As possible determinants we considered age, sex, glucose tolerance, cardiovascular disease, use of anti-hypertensive drugs, anthropometric factors, metabolic factors and lifestyle factors. Results. Multivariate analysis showed that eight of ten cardiovascular autonomic function measures were most strongly associated with glucose tolerance. Furthermore, measures were moderately associated with age, sex, waist-to-hip ratio, use of anti-hypertensive drugs, and insulin. The measures were weakly associated with coronary artery disease but not with lipids. The strongest determinants seemed to differ between subjects with and without diabetes: in the non-diabetic subjects the most strongly associated were age and use of anti-hypertensive drugs and in subjects with diabetes, insulin. No consistent differences in association between the three categories of measures were observed. Conclusion/interpretation. The strongest determinants of autonomic function were age, presence of diabetes and use of anti-hypertensive drugs. [Diabetologia (2000) 43: 561–570]

Variants in the sulphonylurea receptor gene: association of the exon 16-3t variant with type II diabetes mellitus in Dutch caucasians

Aims/hypothesis. We have analysed to what extent two previously reported single nucleotide polymorphisms in the sulphonylurea receptor gene (SUR1) are associated with Type II (non-insulin-dependent) diabetes mellitus in The Netherlands. Furthermore, we estimated haplotype frequencies in control and diabetic populations, including data extracted from three other studies. Methods. Subjects with Type II diabetes (n = 388) and normoglycaemic subjects (n = 336) were randomly selected from two population-based studies, the Hoorn and Rotterdam studies. DNA was typed for variants in exon 16 (-3c→t variant in the splice acceptor site) and exon 18 (Thr759Thr, ACC→ACT). Results. The genotype frequencies in both populations were similar. We observed an association of the exon 16–3t variant with Type II diabetes (allele frequencies 0.41 % vs 0.48 % in NGT and Type II diabetes, respectively, p = 0.01). There was no association between Type II diabetes and the variant in exon 18 or the combination of both variants (p > 0.5). A strong linkage disequilibrium between the exon 16 and exon 18 variants was observed in the diabetic groups but not, or less pronounced, in the control groups from the different studies. Haplotype estimation shows that several different risk haplotypes exist in different Caucasian populations. Conclusion/interpretation. The exon 16–3t allele of the SUR1 gene is associated with Type II diabetes in the Netherlands. Based on estimated haplotype frequencies in different Caucasian populations we conclude that multiple haplotypes on the SUR1 gene seem to confer a risk for developing Type II diabetes in Caucasians. [Diabetologia (1999) 42: 617–620]