Robert Luben

Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of European Prospective Investigation of Cancer and Nutrition (EPIC-Norfolk)

Abstract Objective: To examine the value of glycated haemoglobin (HbA1c) concentration, a marker of blood glucose concentration, as a predictor of death from cardiovascular and all causes in men. Design: Prospective population study. Setting: Norfolk cohort of European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk). Subjects: 4662 men aged 45-79 years who had had glycated haemoglobin measured at the baseline survey in 1995-7 who were followed up to December 1999. Main outcome measures: Mortality from all causes, cardiovascular disease, ischaemic heart disease, and other causes. Results: Men with known diabetes had increased mortality from all causes, cardiovascular disease, and ischaemic disease (relative risks 2.2, 3.3, and 4.2, respectively, P <0.001 independent of age and other risk factors) compared with men without known diabetes. The increased risk of death among men with diabetes was largely explained by HbA1c concentration. HbA1c was continuously related to subsequent all cause, cardiovascular, and ischaemic heart disease mortality through the whole population distribution, with lowest rates in those with HbA1c concentrations below 5%. An increase of 1% in HbA1c was associated with a 28% (P<0.002) increase in risk of death independent of age, blood pressure, serum cholesterol, body mass index, and cigarette smoking habit; this effect remained (relative risk 1.46, P=0.05 adjusted for age and risk factors) after men with known diabetes, a HbA1c concentration ≥7%, or history of myocardial infarction or stroke were excluded. 18% of the population excess mortality risk associated with a HbA1c concentration ≥5% occurred in men with diabetes, but 82% occurred in men with concentrations of 5%-6.9% (the majority of the population). Conclusions: Glycated haemoglobin concentration seems to explain most of the excess mortality risk of diabetes in men and to be a continuous risk factor through the whole population distribution. Preventive efforts need to consider not just those with established diabetes but whether it is possible to reduce the population distribution of HbA1c through behavioural means.

Dietary fibre in food and protection against colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC): an observational study

BACKGROUND Dietary fibre is thought to protect against colorectal cancer but this view has been challenged by recent prospective and intervention studies that showed no protective effect. METHODS We prospectively examined the association between dietary fibre intake and incidence of colorectal cancer in 519978 individuals aged 25-70 years taking part in the EPIC study, recruited from ten European countries. Participants completed a dietary questionnaire in 1992-98 and were followed up for cancer incidence. Relative risk estimates were obtained from fibre intake, categorised by sex-specific, cohort-wide quintiles, and from linear models relating the hazard ratio to fibre intake expressed as a continuous variable. FINDINGS Follow-up consisted of 1939011 person-years, and data for 1065 reported cases of colorectal cancer were included in the analysis. Dietary fibre in foods was inversely related to incidence of large bowel cancer (adjusted relative risk 0.75 [95% CI 0.59-0.95] for the highest versus lowest quintile of intake), the protective effect being greatest for the left side of the colon, and least for the rectum. After calibration with more detailed dietary data, the adjusted relative risk for the highest versus lowest quintile of fibre from food intake was 0.58 (0.41-0.85). No food source of fibre was significantly more protective than others, and non-food supplement sources of fibre were not investigated. INTERPRETATION In populations with low average intake of dietary fibre, an approximate doubling of total fibre intake from foods could reduce the risk of colorectal cancer by 40%.

Association of Hemoglobin A1c with Cardiovascular Disease and Mortality in Adults: The European Prospective Investigation into Cancer in Norfolk

Context Several studies suggest that blood glucose levels are associated with cardiovascular disease, even at blood glucose values that do not meet diagnostic criteria for diabetes. Contribution Among adult residents of Norfolk, United Kingdom, there was a continuous relationship between hemoglobin A1c levels and cardiovascular disease and total mortality. This relationship was apparent even among persons without diabetes. Implications These observations justify the need for studies that address whether improvements in glycemic control might improve health outcomes in persons who do not have diabetes. The Editors Diabetes mellitus is of major and increasing global public health importance (1). Persons with diabetes are at increased risk for premature disability and death associated with vascular, renal, retinal, and neuropathic complications. Raised fasting and postchallenge blood glucose levels in an oral glucose tolerance test are used to diagnose diabetes. The diagnostic threshold is based on the shape of the risk curve between glucose levels and specific microvascular complications of diabetes (2-6). Diabetes also increases the risk for macrovascular diseases, such as coronary heart disease and stroke (7). In contrast to microvascular disease, increasing evidence suggests that the relationship between blood glucose level and macrovascular disease is continuous and does not have an obvious threshold (2, 8, 9). Hemoglobin A1c concentration is an indicator of average blood glucose concentrations over the preceding 3 months; it is useful for characterizing dysglycemia in population studies because it is simpler to perform than the oral glucose tolerance test (10). In a 3-year follow-up of men in a prospective study, we previously reported that hemoglobin A1c concentrations were related to cardiovascular disease and all-cause mortality (11). However, we had insufficient power to examine risk relationships at concentrations close to the diagnostic threshold of 7% or to examine the relationship in women. We report the relation between hemoglobin A1c concentrations and fatal and nonfatal coronary heart disease, cardiovascular disease events, and all-cause mortality in men and women after an average of 6 years of follow-up. Methods The European Prospective Investigation into Cancer in Norfolk (EPICNorfolk) is a prospective population study of 25 623 men and women who were between 40 and 79 years of age and who resided in Norfolk, United Kingdom. Participants were recruited from general practice registers. Information on the recruitment process is available elsewhere (12). Between 1993 and 1997, participants completed a health and lifestyle questionnaire. Participants were asked whether a doctor had ever told them that they have any of the conditions contained in a list that included diabetes, heart attack, and stroke. People with known diabetes were defined as those who responded yes to the diabetes option of this question. Smoking history was derived from responses (yes or no) to the questions: Have you ever smoked as much as 1 cigarette a day for as long as a year? and Do you smoke cigarettes now? At a clinic, trained nurses performed a health examination for each participant. Body mass index was estimated as weight (kg)/height (m2), and waist-to-hip ratio was determined by measurements of the circumference of the waist and hips. Blood pressure was measured by using an Accutorr (Datascope, Mahwah, New Jersey) noninvasive blood pressure monitor after the participant had been seated for 5 minutes. The mean of 2 readings was used for analysis. Nonfasting blood samples were taken; samples for assay were stored in a refrigerator at 4 C until transport within 1 week of sampling to the Department of Clinical Biochemistry, University of Cambridge. Starting in 1995, hemoglobin A1c was measured on fresh EDTA blood samples by using high-performance liquid chromatography (BioRad Diamat Automated Glycosylated Haemoglobin Analyser, Hemel Hempstead, United Kingdom). We report results for follow-up to January 2003, an average of about 6 years. All participants were flagged for death certification at the Office of National Statistics; vital status was obtained for the entire cohort. Trained nosologists coded death certificates according to the International Classification of Diseases, Ninth or Tenth Revisions (ICD-9 or ICD-10). Cardiovascular death (stroke, coronary heart disease, and other vascular causes) was defined as those whose underlying cause of death was coded as ICD-9 400448 or ICD-10 I10I79. Death from coronary heart disease was defined as those whose cause of death was coded as ICD-9 410414 or ICD-10 I22I25. Participants admitted to a hospital were identified by their National Health Service number. Hospitals were linked to the East Norfolk Health Authority database, which identifies all hospital contacts throughout England and Wales for Norfolk residents. We used the same ICD diagnostic codes described in the preceding paragraphs to ascertain hospital episodes of cardiovascular disease and coronary heart disease in our cohort. Participants were identified as having a coronary heart disease event during follow-up if they had a hospital admission or died with coronary heart disease as the cause of death. Of the coronary heart disease events identified, 21% (112 of 529) were fatal; of the cardiovascular disease events, 23% (197 of 806) were fatal. In men, 24% (76 of 321) of deaths were attributed to heart disease and 29% (117 of 321) were attributed to cardiovascular disease. In women, 18% (36 of 200) of deaths were attributed to heart disease and 35% (70 of 200) were attributed to cardiovascular causes. The Norwich Ethics Committee approved the study, and participants gave signed informed consent. Statistical Analysis These analyses, undertaken by using SPSS software, version 10.0 (SPSS, Inc., Chicago, Illinois), included 10 232 men and women age 45 to 79 years who completed the health and lifestyle questionnaire and had available hemoglobin A1c measurements. We divided the cohort into 7 categories on the basis of baseline data: known diabetes, high likelihood of previously undiagnosed diabetes (no personal history of diabetes but a hemoglobin A1c concentration 7%), and hemoglobin A1c concentrations in 0.5percentage point intervals (<5%, 5% to 5.4%, 5.5% to 5.9%, 6.0% to 6.4%, and 6.5% to 6.9%). We examined risk factor distributions and then coronary heart disease, cardiovascular disease, and all-cause mortality rates by hemoglobin A1c and diabetes category. Age-adjusted odds ratios were calculated by using logistic regression models. We used a Cox proportional hazards model to determine the independent contribution of hemoglobin A1c to total mortality and cardiovascular and coronary heart disease after adjustment for age, body mass index, waist-to-hip ratio, systolic blood pressure, blood cholesterol concentrations, cigarette smoking, and history of heart attack or stroke. Participants with missing baseline data for 1 or more risk factors (130 men and 186 women) were excluded from the multivariate analyses. Role of the Funding Sources The funding sources had no role in the design, conduct, and reporting of the study or in the decision to submit the manuscript for publication. Results Table 1 presents characteristics of the participants according to hemoglobin A1c concentration and self-reported diabetes. Those with known diabetes had higher mean (SD) hemoglobin A1c concentrations (8.0% 1.9%) than the rest of the study sample (5.3% 0.7%). They were older and had a higher body mass index, waist-to-hip ratio, and systolic blood pressure; they were also more likely to report having had a previous heart attack or stroke. Participants with probable but previously undiagnosed diabetes (hemoglobin A1c 7%) shared these characteristics. Mean risk factor levels rose with increasing concentration of hemoglobin A1c less than 7%. Table 1. Distribution of Variables by Hemoglobin A1c Concentration and Known Diabetes in 4662 Men and 5570 Women Age 45 to 79 Years (European Prospective Investigation into Cancer in Norfolk, 1995 to 1997) Table 2 shows adjusted odds ratios for hemoglobin A1c concentrations, diabetes status, and outcomes. Persons with known or undiagnosed diabetes had a greater risk for all-cause mortality and cardiovascular or coronary heart disease than those without diabetes. Risk for coronary heart or cardiovascular disease and total mortality increased throughout the whole range of hemoglobin A1c concentrations; those with hemoglobin A1c concentrations less than 5% had the lowest rates. For men, a gradient of increasing rates through the distribution was apparent for all end points. For women, odds ratios for cardiovascular or coronary heart disease did not increase significantly until the hemoglobin A1c concentration reached 6%; odds ratios were very high in women with concentrations greater than 7%. Table 2. Rates and Age-Adjusted Relative Risks for Total Coronary Heart Disease Events, Cardiovascular Disease Events, and All-cause Mortality by Category of Hemoglobin A1c Concentration and Known Diabetes in 4462 Men and 5570 Women Age 45 to 79 Years (European Prospective Investigation into Cancer in Norfolk, 1995 to 2003) Table 3 shows outcomes after adjustment for age alone and then after adjustment for age and other risk factors. In men, known diabetes predicted coronary heart and cardiovascular disease events and total mortality with approximate 2-fold relative risks. These relative risks were only slightly attenuated after adjustment for known risk factors. In women, known diabetes status predicted an approximate 5-fold increase in risk for coronary heart and 3-fold increase in risk for cardiovascular disease events; these increases were attenuated after adjustment for known risk factors to 3-fold and 2-fold risk, respectively. In men and women, hemoglobin A1c concentrations predicted an increased risk for coronar

Endogenous Testosterone and Mortality Due to All Causes, Cardiovascular Disease, and Cancer in Men European Prospective Investigation Into Cancer in Norfolk (EPIC-Norfolk) Prospective Population Study

Background— The relation between endogenous testosterone concentrations and health in men is controversial. Methods and Results— We examined the prospective relationship between endogenous testosterone concentrations and mortality due to all causes, cardiovascular disease, and cancer in a nested case-control study based on 11 606 men aged 40 to 79 years surveyed in 1993 to 1997 and followed up to 2003. Among those without prevalent cancer or cardiovascular disease, 825 men who subsequently died were compared with a control group of 1489 men still alive, matched for age and date of baseline visit. Endogenous testosterone concentrations at baseline were inversely related to mortality due to all causes (825 deaths), cardiovascular disease (369 deaths), and cancer (304 deaths). Odds ratios (95% confidence intervals) for mortality for increasing quartiles of endogenous testosterone compared with the lowest quartile were 0.75 (0.55 to 1.00), 0.62 (0.45 to 0.84), and 0.59 (0.42 to 0.85), respectively (P<0.001 for trend after adjustment for age, date of visit, body mass index, systolic blood pressure, blood cholesterol, cigarette smoking, diabetes mellitus, alcohol intake, physical activity, social class, education, dehydroepiandrosterone sulfate, androstanediol glucuronide, and sex hormone binding globulin). An increase of 6 nmol/L serum testosterone (≈1 SD) was associated with a 0.81 (95% confidence interval 0.71 to 0.92, P<0.01) multivariable-adjusted odds ratio for mortality. Inverse relationships were also observed for deaths due to cardiovascular causes and cancer and after the exclusion of deaths that occurred in the first 2 years. Conclusions— In men, endogenous testosterone concentrations are inversely related to mortality due to cardiovascular disease and all causes. Low testosterone may be a predictive marker for those at high risk of cardiovascular disease.

Relation between plasma ascorbic acid and mortality in men and women in EPIC-Norfolk prospective study: a prospective population study

BACKGROUND Ascorbic acid (vitamin C) might be protective for several chronic diseases. However, findings from prospective studies that relate ascorbic acid to cardiovascular disease or cancer are not consistent. We aimed to assess the relation between plasma ascorbic acid and subsequent mortality due to all causes, cardiovascular disease, ischaemic heart disease, and cancer. METHODS We prospectively examined for 4 years the relation between plasma ascorbic acid concentrations and mortality due to all causes, and to cardiovascular disease, ischaemic heart disease, and cancer in 19 496 men and women aged 45-79 years. We recruited individuals by post using age-sex registers of general practices. Participants completed a health and lifestyle questionnaire and were examined at a clinic visit. They were followed-up for causes of death for about 4 years. Individuals were divided into sex-specific quintiles of plasma ascorbic acid. We used the Cox proportional hazard model to determine the effect of ascorbic acid and other risk factors on mortality. FINDINGS Plasma ascorbic acid concentration was inversely related to mortality from all-causes, and from cardiovascular disease, and ischaemic heart disease in men and women. Risk of mortality in the top ascorbic acid quintile was about half the risk in the lowest quintile (p<0.0001). The relation with mortality was continuous through the whole distribution of ascorbic acid concentrations. 20 micromol/L rise in plasma ascorbic acid concentration, equivalent to about 50 g per day increase in fruit and vegetable intake, was associated with about a 20% reduction in risk of all-cause mortality (p<0.0001), independent of age, systolic blood pressure, blood cholesterol, cigarette smoking habit, diabetes, and supplement use. Ascorbic acid was inversely related to cancer mortality in men but not women. INTERPRETATION Small increases in fruit and vegetable intake of about one serving daily has encouraging prospects for possible prevention of disease.

Are imprecise methods obscuring a relation between fat and breast cancer

Pooled analyses of cohort studies show no relation between fat intake and breast-cancer risk. However, food-frequency questionnaire (FFQ) methods used in these studies are prone to measurement error. We assessed diet with an FFQ and a detailed 7-day food diary in 13070 women between 1993 and 1997. We compared 168 breast-cancer cases incident by 2000 with four matched controls. Risk of breast cancer was associated with saturated-fat intake measured with the food diary (hazard ratio 1.22 [95% CI 1.06-1.40], p=0.005, per quintile increase in energy-adjusted fat intake), but not with saturated fat measured with the FFQ (1.10 [0.94-1.29], p=0.23). Dietary measurement error might explain the absence of a significant association between dietary fat and breast-cancer risk in cohort studies.

Body Fat Distribution and Risk of Coronary Heart Disease in Men and Women in the European Prospective Investigation Into Cancer and Nutrition in Norfolk Cohort A Population-Based Prospective Study

Background— Body fat distribution has been cross-sectionally associated with atherosclerotic disease risk factors, but the prospective relation with coronary heart disease remains uncertain. Methods and Results— We examined the prospective relation between fat distribution indices and coronary heart disease among 24 508 men and women 45 to 79 years of age using proportional hazards regression. During a mean 9.1 years of follow-up, 1708 men and 892 women developed coronary heart disease. The risk for developing subsequent coronary heart disease increased continuously across the range of waist-hip ratio. Hazard ratios (95% CI) of the top versus bottom fifth of waist-hip ratio were 1.55 (1.28 to 1.73) in men and 1.91 (1.44 to 2.54) in women after adjustment for body mass index and other coronary heart disease risk factors. Hazard ratios increased with waist circumference, but risk estimates for waist circumference without hip circumference adjustment were lower by 10% to 18%. After adjustment for waist circumference, body mass index, and coronary heart disease risk factors, hazard ratios for 1-SD increase in hip circumference were 0.80 (95% CI, 0.74 to 0.87) in men and 0.80 (95% CI, 0.69 to 0.93) in women. Hazard ratios for body mass index were greatly attenuated when we adjusted for waist-hip ratio or waist circumference and other covariates. Conclusions— Indices of abdominal obesity were more consistently and strongly predictive of coronary heart disease than body mass index. These simple and inexpensive measurements could be used to assess obesity-related coronary heart disease risk in relatively healthy men and women.

LDL-cholesterol concentrations: a genome-wide association study

Summary Background LDL cholesterol has a causal role in the development of cardiovascular disease. Improved understanding of the biological mechanisms that underlie the metabolism and regulation of LDL cholesterol might help to identify novel therapeutic targets. We therefore did a genome-wide association study of LDL-cholesterol concentrations. Methods We used genome-wide association data from up to 11 685 participants with measures of circulating LDL-cholesterol concentrations across five studies, including data for 293 461 autosomal single nucleotide polymorphisms (SNPs) with a minor allele frequency of 5% or more that passed our quality control criteria. We also used data from a second genome-wide array in up to 4337 participants from three of these five studies, with data for 290 140 SNPs. We did replication studies in two independent populations consisting of up to 4979 participants. Statistical approaches, including meta-analysis and linkage disequilibrium plots, were used to refine association signals; we analysed pooled data from all seven populations to determine the effect of each SNP on variations in circulating LDL-cholesterol concentrations. Findings In our initial scan, we found two SNPs (rs599839 [p=1·7×10−15] and rs4970834 [p=3·0×10−11]) that showed genome-wide statistical association with LDL cholesterol at chromosomal locus 1p13.3. The second genome screen found a third statistically associated SNP at the same locus (rs646776 [p=4·3×10−9]). Meta-analysis of data from all studies showed an association of SNPs rs599839 (combined p=1·2×10−33) and rs646776 (p=4·8×10−20) with LDL-cholesterol concentrations. SNPs rs599839 and rs646776 both explained around 1% of the variation in circulating LDL-cholesterol concentrations and were associated with about 15% of an SD change in LDL cholesterol per allele, assuming an SD of 1 mmol/L. Interpretation We found evidence for a novel locus for LDL cholesterol on chromosome 1p13.3. These results potentially provide insight into the biological mechanisms that underlie the regulation of LDL cholesterol and might help in the discovery of novel therapeutic targets for cardiovascular disease.

Television viewing and low participation in vigorous recreation are independently associated with obesity and markers of cardiovascular disease risk: EPIC-Norfolk population-based study

Objective: This study describes the associations between sedentary behaviour (television viewing) and participation in vigorous recreational activity with obesity and with biomarkers of cardiovascular disease (CVD) risk profile.Design: Cross-sectional analysis of the EPIC-Norfolk cohort study.Setting: The study is a population-based study of participants living in Norfolk, UK.Subjects: A total of 15 515 men and women aged between 45 and 74 y, recruited through General Practice lists, who completed the detailed physical activity questionnaire.Results: Following exclusion of those with self-reported myocardial infarction, stroke and diabetes, 14 189 participants remained for the analysis. Self-reported television viewing was positively and participation in vigorous activity negatively associated with markers of obesity, blood pressure and plasma lipids. In multiple regression analysis, adjusting for age, alcohol, smoking, treatment for hypertension, vigorous and total physical activity, these associations remained significant. For women who participated in more than 1 h/week of vigorous activity and who watched fewer than 2 h of television each day, the adjusted mean body mass index was 1.92 kg/m2 less than for women who reported participating in no vigorous activity and who watched more than 4 h of television each day (P<0.001). The equivalent figure for men was 1.44 kg/m2 (P<0.001). In a similar analysis, with blood pressure as the outcome, mean diastolic blood pressure difference between the extreme groups of vigorous activity and television viewing was 3.6 mmHg in men (P<0.001) and 2.7 mmHg (P=0.001) in women.Conclusions: These data suggest that time spent participating in vigorous recreational physical activity and television viewing, an indicator of a sedentary lifestyle, are associated with obesity and markers of CVD disease risk independent of total reported physical activity. Whether these observations represent the true underlying aetiological relations or are a manifestation of the different precision with which the subdimensions of activity are measured remains uncertain.

Early Age at Menarche Associated with Cardiovascular Disease and Mortality

CONTEXT The relationship between age at menarche and cardiovascular disease remains unclear. Two recent studies found an inverse association between age at menarche and all-cause mortality. OBJECTIVE The aim of this study was to examine the relationship between age at menarche and cardiovascular disease risk factors, events, and mortality. DESIGN, SETTING, AND PARTICIPANTS A population-based prospective study involving 15,807 women, aged 40-79 yr in 1993-1997 and followed up to March 2007 for cardiovascular disease events (median follow-up 10.6 yr) and February 2008 for mortality (median follow-up 12.0 yr) was used. MAIN OUTCOME MEASURES Odds ratios for cardiovascular disease risk factors and hazard ratios for incident cardiovascular disease and mortality were calculated. RESULTS There were 3888 incident cardiovascular disease events (1323 coronary heart disease, 602 stroke, and 1963 other) and 1903 deaths (640 cardiovascular disease, 782 cancer, and 481 other) during follow-up. Compared with other women, those who had early menarche (<12 yr) had higher risks of hypertension [1.13 (1.02-1.24)], incident cardiovascular disease [1.17 (1.07-1.27)], incident coronary heart disease [1.23 (1.06-1.43)], all-cause mortality [1.22 (1.07-1.39)], cardiovascular disease mortality [1.28 (1.02-1.62)], and cancer mortality [1.25 (1.03-1.51)], adjusted for age, physical activity, smoking, alcohol, educational level, occupational social class, oral contraceptive use, hormone replacement therapy, parity, body mass index, and waist circumference. CONCLUSIONS Early age at menarche (before age 12 yr) was associated with increased risk of cardiovascular disease events, cardiovascular disease mortality, and overall mortality in women, and this association appeared to be only partly mediated by increased adiposity.