SummaryBackgroundUncertainties persist about the magnitude of associations of diabetes mellitus and fasting glucose concentration with risk of coronary heart disease and major stroke subtypes. We aimed to quantify these associations for a wide range of circumstances.MethodsWe undertook a meta-analysis of individual records of diabetes, fasting blood glucose concentration, and other risk factors in people without initial vascular disease from studies in the Emerging Risk Factors Collaboration. We combined within-study regressions that were adjusted for age, sex, smoking, systolic blood pressure, and body-mass index to calculate hazard ratios (HRs) for vascular disease.FindingsAnalyses included data for 698 782 people (52 765 non-fatal or fatal vascular outcomes; 8·49 million person-years at risk) from 102 prospective studies. Adjusted HRs with diabetes were: 2·00 (95% CI 1·83–2·19) for coronary heart disease; 2·27 (1·95–2·65) for ischaemic stroke; 1·56 (1·19–2·05) for haemorrhagic stroke; 1·84 (1·59–2·13) for unclassified stroke; and 1·73 (1·51–1·98) for the aggregate of other vascular deaths. HRs did not change appreciably after further adjustment for lipid, inflammatory, or renal markers. HRs for coronary heart disease were higher in women than in men, at 40–59 years than at 70 years and older, and with fatal than with non-fatal disease. At an adult population-wide prevalence of 10%, diabetes was estimated to account for 11% (10–12%) of vascular deaths. Fasting blood glucose concentration was non-linearly related to vascular risk, with no significant associations between 3·90 mmol/L and 5·59 mmol/L. Compared with fasting blood glucose concentrations of 3·90–5·59 mmol/L, HRs for coronary heart disease were: 1·07 (0·97–1·18) for lower than 3·90 mmol/L; 1·11 (1·04–1·18) for 5·60–6·09 mmol/L; and 1·17 (1·08–1·26) for 6·10–6·99 mmol/L. In people without a history of diabetes, information about fasting blood glucose concentration or impaired fasting glucose status did not significantly improve metrics of vascular disease prediction when added to information about several conventional risk factors.InterpretationDiabetes confers about a two-fold excess risk for a wide range of vascular diseases, independently from other conventional risk factors. In people without diabetes, fasting blood glucose concentration is modestly and non-linearly associated with risk of vascular disease.FundingBritish Heart Foundation, UK Medical Research Council, and Pfizer.

BACKGROUND The extent to which diabetes mellitus or hyperglycemia is related to risk of death from cancer or other nonvascular conditions is uncertain. METHODS We calculated hazard ratios for cause-specific death, according to baseline diabetes status or fasting glucose level, from individual-participant data on 123,205 deaths among 820,900 people in 97 prospective studies. RESULTS After adjustment for age, sex, smoking status, and body-mass index, hazard ratios among persons with diabetes as compared with persons without diabetes were as follows: 1.80 (95% confidence interval [CI], 1.71 to 1.90) for death from any cause, 1.25 (95% CI, 1.19 to 1.31) for death from cancer, 2.32 (95% CI, 2.11 to 2.56) for death from vascular causes, and 1.73 (95% CI, 1.62 to 1.85) for death from other causes. Diabetes (vs. no diabetes) was moderately associated with death from cancers of the liver, pancreas, ovary, colorectum, lung, bladder, and breast. Aside from cancer and vascular disease, diabetes (vs. no diabetes) was also associated with death from renal disease, liver disease, pneumonia and other infectious diseases, mental disorders, nonhepatic digestive diseases, external causes, intentional self-harm, nervous-system disorders, and chronic obstructive pulmonary disease. Hazard ratios were appreciably reduced after further adjustment for glycemia measures, but not after adjustment for systolic blood pressure, lipid levels, inflammation or renal markers. Fasting glucose levels exceeding 100 mg per deciliter (5.6 mmol per liter), but not levels of 70 to 100 mg per deciliter (3.9 to 5.6 mmol per liter), were associated with death. A 50-year-old with diabetes died, on average, 6 years earlier than a counterpart without diabetes, with about 40% of the difference in survival attributable to excess nonvascular deaths. CONCLUSIONS In addition to vascular disease, diabetes is associated with substantial premature death from several cancers, infectious diseases, external causes, intentional self-harm, and degenerative disorders, independent of several major risk factors. (Funded by the British Heart Foundation and others.)

Context Associations of major lipids and apolipoproteins with the risk of vascular disease have not been reliably quantified. Objective To assess major lipids and apolipoproteins in vascular risk. Design, Setting, and Participants Individual records were supplied on 302 430 people without initial vascular disease from 68 long-term prospective studies, mostly in Europe and North America. During 2.79 million person-years of follow-up, there were 8857 nonfatal myocardial infarctions, 3928 coronary heart disease [CHD] deaths, 2534 ischemic strokes, 513 hemorrhagic strokes, and 2536 unclassified strokes. Main Outcome Measures Hazard ratios (HRs), adjusted for several conventional factors, were calculated for 1-SD higher values: 0.52 loge triglyceride, 15 mg/dL high-density lipoprotein cholesterol (HDL-C), 43 mg/dL non-HDL-C, 29 mg/dL apolipoprotein AI, 29 mg/dL apolipoprotein B, and 33 mg/dL directly measured low-density lipoprotein cholesterol (LDL-C). Within-study regression analyses were adjusted for within-person variation and combined using meta-analysis. Results The rates of CHD per 1000 person-years in the bottom and top thirds of baseline lipid distributions, respectively, were 2.6 and 6.2 with triglyceride, 6.4 and 2.4 with HDL-C, and 2.3 and 6.7 with non-HDL-C. Adjusted HRs for CHD were 0.99 (95% CI, 0.94-1.05) with triglyceride, 0.78 (95% CI, 0.74-0.82) with HDL-C, and 1.50 (95% CI, 1.39-1.61) with non-HDL-C. Hazard ratios were at least as strong in participants who did not fast as in those who did. The HR for CHD was 0.35 (95% CI, 0.30-0.42) with a combination of 80 mg/dL lower non-HDL-C and 15 mg/dL higher HDL-C. For the subset with apolipoproteins or directly measured LDL-C, HRs were 1.50 (95% CI, 1.38-1.62) with the ratio non-HDL-C/HDL-C, 1.49 (95% CI, 1.39-1.60) with the ratio apo B/apo AI, 1.42 (95% CI, 1.06-1.91) with non-HDL-C, and 1.38 (95% CI, 1.09-1.73) with directly measured LDL-C. Hazard ratios for ischemic stroke were 1.02 (95% CI, 0.94-1.11) with triglyceride, 0.93 (95% CI, 0.84-1.02) with HDL-C, and 1.12 (95% CI, 1.04-1.20) with non-HDL-C. Conclusion Lipid assessment in vascular disease can be simplified by measurement of either total and HDL cholesterol levels or apolipoproteins without the need to fast and without regard to triglyceride.

BackgroundThe relevance to coronary heart disease (CHD) of cytokines that govern inflammatory cascades, such as interleukin-6 (IL-6), may be underestimated because such mediators are short acting and prone to fluctuations. We evaluated associations of long-term circulating IL-6 levels with CHD risk (defined as nonfatal myocardial infarction [MI] or fatal CHD) in two population-based cohorts, involving serial measurements to enable correction for within-person variability. We updated a systematic review to put the new findings in context.Methods and FindingsMeasurements were made in samples obtained at baseline from 2,138 patients who had a first-ever nonfatal MI or died of CHD during follow-up, and from 4,267 controls in two cohorts comprising 24,230 participants. Correction for within-person variability was made using data from repeat measurements taken several years apart in several hundred participants. The year-to-year variability of IL-6 values within individuals was relatively high (regression dilution ratios of 0.41, 95% confidence interval [CI] 0.28–0.53, over 4 y, and 0.35, 95% CI 0.23–0.48, over 12 y). Ignoring this variability, we found an odds ratio for CHD, adjusted for several established risk factors, of 1.46 (95% CI 1.29–1.65) per 2 standard deviation (SD) increase of baseline IL-6 values, similar to that for baseline C-reactive protein. After correction for within-person variability, the odds ratio for CHD was 2.14 (95% CI 1.45–3.15) with long-term average (“usual”) IL-6, similar to those for some established risk factors. Increasing IL-6 levels were associated with progressively increasing CHD risk. An updated systematic review of electronic databases and other sources identified 15 relevant previous population-based prospective studies of IL-6 and clinical coronary outcomes (i.e., MI or coronary death). Including the two current studies, the 17 available prospective studies gave a combined odds ratio of 1.61 (95% CI 1.42–1.83) per 2 SD increase in baseline IL-6 (corresponding to an odds ratio of 3.34 [95% CI 2.45–4.56] per 2 SD increase in usual [long-term average] IL-6 levels).ConclusionsLong-term IL-6 levels are associated with CHD risk about as strongly as are some major established risk factors, but causality remains uncertain. These findings highlight the potential relevance of IL-6–mediated pathways to CHD.

Background-Many epidemiological studies have reported on associations between serum triglyceride concentrations and the risk of coronary heart disease, but this association has not been reliably quantified. In the present study, we report 2 separate nested case-control comparisons in 2 different prospective, population-based cohorts, plus an updated meta-analysis of 27 additional prospective studies in general Western populations.

BACKGROUND There is debate about the value of assessing levels of C-reactive protein (CRP) and other biomarkers of inflammation for the prediction of first cardiovascular events. METHODS We analyzed data from 52 prospective studies that included 246,669 participants without a history of cardiovascular disease to investigate the value of adding CRP or fibrinogen levels to conventional risk factors for the prediction of cardiovascular risk. We calculated measures of discrimination and reclassification during follow-up and modeled the clinical implications of initiation of statin therapy after the assessment of CRP or fibrinogen. RESULTS The addition of information on high-density lipoprotein cholesterol to a prognostic model for cardiovascular disease that included age, sex, smoking status, blood pressure, history of diabetes, and total cholesterol level increased the C-index, a measure of risk discrimination, by 0.0050. The further addition to this model of information on CRP or fibrinogen increased the C-index by 0.0039 and 0.0027, respectively (P<0.001), and yielded a net reclassification improvement of 1.52% and 0.83%, respectively, for the predicted 10-year risk categories of “low” (<10%), “intermediate” (10% to <20%), and “high” (≥20%) (P<0.02 for both comparisons). We estimated that among 100,000 adults 40 years of age or older, 15,025 persons would initially be classified as being at intermediate risk for a cardiovascular event if conventional risk factors alone were used to calculate risk. Assuming that statin therapy would be initiated in accordance with Adult Treatment Panel III guidelines (i.e., for persons with a predicted risk of ≥20% and for those with certain other risk factors, such as diabetes, irrespective of their 10-year predicted risk), additional targeted assessment of CRP or fibrinogen levels in the 13,199 remaining participants at intermediate risk could help prevent approximately 30 additional cardiovascular events over the course of 10 years. CONCLUSIONS In a study of people without known cardiovascular disease, we estimated that under current treatment guidelines, assessment of the CRP or fibrinogen level in people at intermediate risk for a cardiovascular event could help prevent one additional event over a period of 10 years for every 400 to 500 people screened. (Funded by the British Heart Foundation and others.)

Objectives To determine whether maternal obesity during pregnancy is associated with increased mortality from cardiovascular events in adult offspring.Design Record linkage cohort analysis.Setting Birth records from the Aberdeen Maternity and Neonatal databank linked to the General Register of Deaths, Scotland, and the Scottish Morbidity Record systems.Population 37 709 people with birth records from 1950 to present day.Main outcome measures Death and hospital admissions for cardiovascular events up to 1 January 2012 in offspring aged 34-61. Maternal body mass index (BMI) was calculated from height and weight measured at the first antenatal visit. The effect of maternal obesity on outcomes in offspring was tested with time to event analysis with Cox proportional hazard regression to compare outcomes in offspring of mothers in underweight, overweight, or obese categories of BMI compared with offspring of women with normal BMI. Results All cause mortality was increased in offspring of obese mothers (BMI >30) compared with mothers with normal BMI after adjustment for maternal age at delivery, socioeconomic status, sex of offspring, current age, birth weight, gestation at delivery, and gestation at measurement of BMI (hazard ratio 1.35, 95% confidence interval 1.17 to 1.55). In adjusted models, offspring of obese mothers also had an increased risk of hospital admission for a cardiovascular event (1.29, 1.06 to 1.57) compared with offspring of mothers with normal BMI. The offspring of overweight mothers also had a higher risk of adverse outcomes. Conclusions Maternal obesity is associated with an increased risk of premature death in adult offspring. As one in five women in the United Kingdom is obese at antenatal booking, strategies to optimise weight before pregnancy are urgently required.

SummaryBackgroundGuidelines differ about the value of assessment of adiposity measures for cardiovascular disease risk prediction when information is available for other risk factors. We studied the separate and combined associations of body-mass index (BMI), waist circumference, and waist-to-hip ratio with risk of first-onset cardiovascular disease.MethodsWe used individual records from 58 cohorts to calculate hazard ratios (HRs) per 1 SD higher baseline values (4·56 kg/m2 higher BMI, 12·6 cm higher waist circumference, and 0·083 higher waist-to-hip ratio) and measures of risk discrimination and reclassification. Serial adiposity assessments were used to calculate regression dilution ratios.ResultsIndividual records were available for 221 934 people in 17 countries (14 297 incident cardiovascular disease outcomes; 1·87 million person-years at risk). Serial adiposity assessments were made in up to 63 821 people (mean interval 5·7 years [SD 3·9]). In people with BMI of 20 kg/m2 or higher, HRs for cardiovascular disease were 1·23 (95% CI 1·17–1·29) with BMI, 1·27 (1·20–1·33) with waist circumference, and 1·25 (1·19–1·31) with waist-to-hip ratio, after adjustment for age, sex, and smoking status. After further adjustment for baseline systolic blood pressure, history of diabetes, and total and HDL cholesterol, corresponding HRs were 1·07 (1·03–1·11) with BMI, 1·10 (1·05–1·14) with waist circumference, and 1·12 (1·08–1·15) with waist-to-hip ratio. Addition of information on BMI, waist circumference, or waist-to-hip ratio to a cardiovascular disease risk prediction model containing conventional risk factors did not importantly improve risk discrimination (C-index changes of −0·0001, −0·0001, and 0·0008, respectively), nor classification of participants to categories of predicted 10-year risk (net reclassification improvement −0·19%, −0·05%, and −0·05%, respectively). Findings were similar when adiposity measures were considered in combination. Reproducibility was greater for BMI (regression dilution ratio 0·95, 95% CI 0·93–0·97) than for waist circumference (0·86, 0·83–0·89) or waist-to-hip ratio (0·63, 0·57–0·70).InterpretationBMI, waist circumference, and waist-to-hip ratio, whether assessed singly or in combination, do not importantly improve cardiovascular disease risk prediction in people in developed countries when additional information is available for systolic blood pressure, history of diabetes, and lipids.FundingBritish Heart Foundation and UK Medical Research Council.