Emanuele Di Angelantonio

Diabetes Mellitus, Fasting Glucose, and Risk of Cause-Specific Death

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.).

Association of Dietary, Circulating, and Supplement Fatty Acids With Coronary Risk: A Systematic Review and Meta-analysis

BACKGROUND Guidelines advocate changes in fatty acid consumption to promote cardiovascular health. PURPOSE To summarize evidence about associations between fatty acids and coronary disease. DATA SOURCES MEDLINE, Science Citation Index, and Cochrane Central Register of Controlled Trials through July 2013. STUDY SELECTION Prospective, observational studies and randomized, controlled trials. DATA EXTRACTION Investigators extracted data about study characteristics and assessed study biases. DATA SYNTHESIS There were 32 observational studies (530,525 participants) of fatty acids from dietary intake; 17 observational studies (25,721 participants) of fatty acid biomarkers; and 27 randomized, controlled trials (103,052 participants) of fatty acid supplementation. In observational studies, relative risks for coronary disease were 1.02 (95% CI, 0.97 to 1.07) for saturated, 0.99 (CI, 0.89 to 1.09) for monounsaturated, 0.93 (CI, 0.84 to 1.02) for long-chain ω-3 polyunsaturated, 1.01 (CI, 0.96 to 1.07) for ω-6 polyunsaturated, and 1.16 (CI, 1.06 to 1.27) for trans fatty acids when the top and bottom thirds of baseline dietary fatty acid intake were compared. Corresponding estimates for circulating fatty acids were 1.06 (CI, 0.86 to 1.30), 1.06 (CI, 0.97 to 1.17), 0.84 (CI, 0.63 to 1.11), 0.94 (CI, 0.84 to 1.06), and 1.05 (CI, 0.76 to 1.44), respectively. There was heterogeneity of the associations among individual circulating fatty acids and coronary disease. In randomized, controlled trials, relative risks for coronary disease were 0.97 (CI, 0.69 to 1.36) for α-linolenic, 0.94 (CI, 0.86 to 1.03) for long-chain ω-3 polyunsaturated, and 0.89 (CI, 0.71 to 1.12) for ω-6 polyunsaturated fatty acid supplementations. LIMITATION Potential biases from preferential publication and selective reporting. CONCLUSION Current evidence does not clearly support cardiovascular guidelines that encourage high consumption of polyunsaturated fatty acids and low consumption of total saturated fats. PRIMARY FUNDING SOURCE British Heart Foundation, Medical Research Council, Cambridge National Institute for Health Research Biomedical Research Centre, and Gates Cambridge.

Lipoprotein-associated phospholipase A2 and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies

Summary Background Lipoprotein-associated phospholipase A2 (Lp-PLA2), an inflammatory enzyme expressed in atherosclerotic plaques, is a therapeutic target being assessed in trials of vascular disease prevention. We investigated associations of circulating Lp-PLA2 mass and activity with risk of coronary heart disease, stroke, and mortality under different circumstances. Methods With use of individual records from 79 036 participants in 32 prospective studies (yielding 17 722 incident fatal or non-fatal outcomes during 474 976 person-years at risk), we did a meta-analysis of within-study regressions to calculate risk ratios (RRs) per 1 SD higher value of Lp-PLA2 or other risk factor. The primary outcome was coronary heart disease. Findings Lp-PLA2 activity and mass were associated with each other (r=0·51, 95% CI 0·47–0·56) and proatherogenic lipids. We noted roughly log-linear associations of Lp-PLA2 activity and mass with risk of coronary heart disease and vascular death. RRs, adjusted for conventional risk factors, were: 1·10 (95% CI 1·05–1·16) with Lp-PLA2 activity and 1·11 (1·07–1·16) with Lp-PLA2 mass for coronary heart disease; 1·08 (0·97–1·20) and 1·14 (1·02–1·27) for ischaemic stroke; 1·16 (1·09–1·24) and 1·13 (1·05–1·22) for vascular mortality; and 1·10 (1·04–1·17) and 1·10 (1·03–1·18) for non-vascular mortality, respectively. RRs with Lp-PLA2 did not differ significantly in people with and without initial stable vascular disease, apart from for vascular death with Lp-PLA2 mass. Adjusted RRs for coronary heart disease were 1·10 (1·02–1·18) with non-HDL cholesterol and 1·10 (1·00–1·21) with systolic blood pressure. Interpretation Lp-PLA2 activity and mass each show continuous associations with risk of coronary heart disease, similar in magnitude to that with non-HDL cholesterol or systolic blood pressure in this population. Associations of Lp-PLA2 mass and activity are not exclusive to vascular outcomes, and the vascular associations depend at least partly on lipids. Funding UK Medical Research Council, GlaxoSmithKline, and British Heart Foundation.

Association of cholesteryl ester transfer protein genotypes with CETP mass and activity, lipid levels, and coronary risk

CONTEXT The importance of the cholesteryl ester transfer protein (CETP) pathway in coronary disease is uncertain. Study of CETP genotypes can help better understand the relevance of this pathway to lipid metabolism and disease risk. OBJECTIVE To assess associations of CETP genotypes with CETP phenotypes, lipid levels, and coronary risk. DATA SOURCES Studies published between January 1970 and January 2008 were identified through computer-based and manual searches using MEDLINE, EMBASE, BIOSIS, Science Citation Index, and the Chinese National Knowledge Infrastructure Database. Previously unreported studies were sought through correspondence with investigators. STUDY SELECTION Relevant studies related principally to 3 common (TaqIB [rs708272], I405V [rs5882], and -629C>A [rs1800775]) and 3 uncommon (D442G [rs2303790], -631C>A [rs1800776], and R451Q [rs1800777]) CETP polymorphisms. DATA EXTRACTION Information on CETP genotypes, CETP phenotypes, lipid levels, coronary disease, and study characteristics was abstracted from publications, supplied by investigators, or both. RESULTS Ninety-two studies had data on CETP phenotypes, lipid levels, or both in 113,833 healthy participants, and 46 studies had data on 27,196 coronary cases and 55,338 controls. For each A allele inherited, individuals with the TaqIB polymorphism had lower mean CETP mass (-9.7%; 95% confidence interval [CI], -11.7% to -7.8%), lower mean CETP activity (-8.6%; 95% CI, -13.0% to -4.1%), higher mean high-density lipoprotein cholesterol (HDL-C) concentrations (4.5%; 95% CI, 3.8%-5.2%), and higher mean apolipoprotein A-I concentrations (2.4%; 95% CI, 1.6%-3.2%). The pattern of findings was very similar with the I405V and -629C>A polymorphisms. The combined per-allele odds ratios (ORs) for coronary disease were 0.95 (95% CI, 0.92-0.99) for TaqIB, 0.94 (95% CI, 0.89-1.00) for I405V, and 0.95 (95% CI, 0.91-1.00) for -629C>A. CONCLUSIONS Three CETP genotypes that are associated with moderate inhibition of CETP activity (and, therefore, modestly higher HDL-C levels) show weakly inverse associations with coronary risk. The ORs for coronary disease were compatible with the expected reductions in risk for equivalent increases in HDL-C concentration in available prospective studies.

Separate and combined associations of body-mass index and abdominal adiposity with cardiovascular disease: collaborative analysis of 58 prospective studies

BACKGROUND Guidelines 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. METHODS We used individual records from 58 cohorts to calculate hazard ratios (HRs) per 1 SD higher baseline values (4.56 kg/m(2) 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. RESULTS Individual 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/m(2) 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). INTERPRETATION BMI, 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. FUNDING British Heart Foundation and UK Medical Research Council.Summary Background Guidelines 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. Methods We 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. Results Individual 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). Interpretation BMI, 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. Funding British Heart Foundation and UK Medical Research Council.

Genetic Associations with Valvular Calcification and Aortic Stenosis

BACKGROUND Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease. METHODS We determined genomewide associations with the presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis. RESULTS One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aortic-valve calcification (odds ratio per allele, 2.05; P=9.0×10(-10)), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aortic-valve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P=1.5×10(-8) and P=1.8×10(-8), respectively), but the findings were not replicated consistently. CONCLUSIONS Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aortic-valve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.).

Body-mass index and all-cause mortality: Individual-participant-data meta-analysis of 239 prospective studies in four continents.

Summary Background Overweight and obesity are increasing worldwide. To help assess their relevance to mortality in different populations we conducted individual-participant data meta-analyses of prospective studies of body-mass index (BMI), limiting confounding and reverse causality by restricting analyses to never-smokers and excluding pre-existing disease and the first 5 years of follow-up. Methods Of 10 625 411 participants in Asia, Australia and New Zealand, Europe, and North America from 239 prospective studies (median follow-up 13·7 years, IQR 11·4–14·7), 3 951 455 people in 189 studies were never-smokers without chronic diseases at recruitment who survived 5 years, of whom 385 879 died. The primary analyses are of these deaths, and study, age, and sex adjusted hazard ratios (HRs), relative to BMI 22·5–<25·0 kg/m2. Findings All-cause mortality was minimal at 20·0–25·0 kg/m2 (HR 1·00, 95% CI 0·98–1·02 for BMI 20·0–<22·5 kg/m2; 1·00, 0·99–1·01 for BMI 22·5–<25·0 kg/m2), and increased significantly both just below this range (1·13, 1·09–1·17 for BMI 18·5–<20·0 kg/m2; 1·51, 1·43–1·59 for BMI 15·0–<18·5) and throughout the overweight range (1·07, 1·07–1·08 for BMI 25·0–<27·5 kg/m2; 1·20, 1·18–1·22 for BMI 27·5–<30·0 kg/m2). The HR for obesity grade 1 (BMI 30·0–<35·0 kg/m2) was 1·45, 95% CI 1·41–1·48; the HR for obesity grade 2 (35·0–<40·0 kg/m2) was 1·94, 1·87–2·01; and the HR for obesity grade 3 (40·0–<60·0 kg/m2) was 2·76, 2·60–2·92. For BMI over 25·0 kg/m2, mortality increased approximately log-linearly with BMI; the HR per 5 kg/m2 units higher BMI was 1·39 (1·34–1·43) in Europe, 1·29 (1·26–1·32) in North America, 1·39 (1·34–1·44) in east Asia, and 1·31 (1·27–1·35) in Australia and New Zealand. This HR per 5 kg/m2 units higher BMI (for BMI over 25 kg/m2) was greater in younger than older people (1·52, 95% CI 1·47–1·56, for BMI measured at 35–49 years vs 1·21, 1·17–1·25, for BMI measured at 70–89 years; pheterogeneity<0·0001), greater in men than women (1·51, 1·46–1·56, vs 1·30, 1·26–1·33; pheterogeneity<0·0001), but similar in studies with self-reported and measured BMI. Interpretation The associations of both overweight and obesity with higher all-cause mortality were broadly consistent in four continents. This finding supports strategies to combat the entire spectrum of excess adiposity in many populations. Funding UK Medical Research Council, British Heart Foundation, National Institute for Health Research, US National Institutes of Health.

Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies.

Summary Background Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling. Methods In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125 222 participants. We also compared the frequency of Asp358Ala in 51 441 patients with coronary heart disease and in 136 226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6. Findings The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele ≥0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3% (95% CI 30·4–38·2) and of interleukin 6 by 14·6% (10·7–18·4), and mean concentration of C-reactive protein was reduced by 7·5% (5·9–9·1) and of fibrinogen by 1·0% (0·7–1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4% (1·8–5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes. Interpretation Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease. Funding British Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation.

B-Type Natriuretic Peptides and Cardiovascular Risk Systematic Review and Meta-Analysis of 40 Prospective Studies

Background— Measurement of B-type natriuretic peptide (BNP) concentration or its precursor (N-terminal fragment [NT-proBNP]) is recommended in patients with symptoms of left ventricular dysfunction and in other settings, but the relevance of these peptides to cardiovascular disease (CVD) in general populations or in patients with stable vascular disease is uncertain. Methods and Results— Data were collated from 40 long-term prospective studies involving a total of 87 474 participants and 10 625 incident CVD outcomes. In a comparison of individuals in the top third with those in the bottom third of baseline values of natriuretic peptides, the combined risk ratio (RR), adjusted for several conventional risk factors, was 2.82 (95% confidence interval [CI], 2.40 to 3.33) for CVD. Analysis of the 6 studies with at least 250 CVD outcomes (which should be less prone to selective reporting than are smaller studies) yielded an adjusted RR of 1.94 (95% CI, 1.57 to 2.39). RRs were broadly similar with BNP or NT-proBNP (RR, 2.89 [95% CI, 1.91 to 4.38] and 2.82 [95% CI, 2.35 to 3.38], respectively) and by different baseline vascular risk (RR, 2.68 [95% CI, 2.07 to 3.47] in approximately general populations; RR, 3.35 [95% CI, 2.38 to 4.72] in people with elevated vascular risk factors; RR, 2.60 [95% CI, 1.99 to 3.38] in patients with stable CVD). Assay of BNP or NT-proBNP in addition to measurement of conventional CVD risk factors yielded generally modest improvements in risk discrimination. Conclusions— Available prospective studies indicate strong associations between circulating concentration of natriuretic peptides and CVD risk under a range of different circumstances. Further investigation is warranted, particularly in large general population studies, to clarify any predictive utility of these markers and to better control for publication bias.

Lipoprotein(a) Levels and Risk of Future Coronary Heart Disease: Large-Scale Prospective Data.

BACKGROUND Large-scale prospective data are needed to determine whether associations between lipoprotein(a) (Lp[a]) and coronary heart disease (CHD) risk are independent of established risk factors, to characterize the shape of this relationship, and to quantify associations in relevant subgroups. METHODS Levels of Lp(a) were measured in samples obtained at baseline from 2047 patients who had first-ever nonfatal myocardial infarction or who died of CHD during the study and from 3921 control participants in the Reykjavik Study (n=18 569), as well as in paired samples obtained 12 years apart from 372 participants to quantify within-person fluctuations. RESULTS Baseline Lp(a) levels had little or no correlation with known cardiovascular risk factors, such as age, sex, total cholesterol level, and blood pressure. The Lp(a) values were highly consistent from decade to decade, with a regression dilution ratio (calculated on the log scale) of 0.92 (95% confidence interval, 0.85-0.99). The odds ratio for CHD, unaltered after adjustment for several established risk factors (age, sex, smoking status, blood pressure, total cholesterol, triglycerides level, diabetes mellitus, and body mass index), was 1.60 (95% confidence interval, 1.38-1.85) in a comparison of extreme thirds of baseline Lp(a) levels. Odds ratios were progressively higher with increasing Lp(a) levels and did not vary materially by several individual- or study-level characteristics. CONCLUSIONS There are independent, continuous associations between Lp(a) levels and risk of future CHD in a broad range of individuals. Levels of Lp(a) are highly stable within individuals across many years and are only weakly correlated with known risk factors. Further assessment of their possible role in CHD prevention is warranted.