These data suggest that both general adiposity and abdominal adiposity are associated with the risk of death and support the use of waist circumference or waist-to-hip ratio in addition to BMI in assessing the risk of death.

SummaryBackgroundLow-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease.MethodsWe did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose–response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th–95th percentile 1·04–13·5]) from 71 011 participants from 37 studies.FindingsIn the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10–1·17), coronary disease excluding myocardial infarction (1·06, 1·00–1·11), heart failure (1·09, 1·03–1·15), fatal hypertensive disease (1·24, 1·15–1·33); and fatal aortic aneurysm (1·15, 1·03–1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91–0·97). In comparison to those who reported drinking >0–≤100 g per week, those who reported drinking >100–≤200 g per week, >200–≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1–2 years, or 4–5 years, respectively.InterpretationIn current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being ...

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Importance Low-density lipoprotein (LDL) cholesterol-lowering alleles in or near NPC1L1 or HMGCR, encoding the respective molecular targets of ezetimibe and statins, have previously been used as proxies to study the efficacy of these lipid-lowering drugs. Alleles near HMGCR are associated with a higher risk of type 2 diabetes, mimicking the increased incidence of new-onset diabetes associated with statin treatment in randomized clinical trials. It is unknown whether alleles near NPC1L1 are also associated with the risk of type 2 diabetes. Objective To investigate whether LDL-lowering alleles in or near NPC1L1 and other genes encoding current or prospective molecular targets of lipid-lowering therapy (i.e. HMGCR, PCSK9, ABCG5/G8, LDLR) are associated with the risk of type 2 diabetes. Design, Setting and Participants The associations with type 2 diabetes and coronary artery disease of LDL-lowering genetic variants were investigated in meta-analyses of genetic association studies. Meta-analyses included 50,775 individuals with type 2 diabetes and 270,269 controls including three studies and 60,801 individuals with coronary artery disease and 123,504 controls from a published meta-analysis. Data collection took place in Europe and the United States between 1991 and 2016. Exposure LDL-lowering alleles in or near NPC1L1, HMGCR, PCSK9, ABCG5/G8, LDLR. Main Outcomes and Measures Odds ratio of type 2 diabetes and coronary artery disease. Results LDL-lowering genetic variants at NPC1L1 were inversely associated with coronary artery disease (odds ratio for a genetically-predicted reduction of 1 mmol/L in LDL cholesterol, 0.61; 95% confidence interval, 0.42-0.88; p=0.008) and directly associated with type 2 diabetes (2.42, 1.70-3.43; p<0.001). The odds ratio of type 2 diabetes for PCSK9 genetic variants was 1.19 (95% confidence interval, 1.02-1.38, p=0.03). For a given reduction in LDL cholesterol, genetic variants were associated with a similar reduction in coronary artery disease risk (I-squared for heterogeneity in genetic associations=0.0%; p=0.93). However, associations with type 2 diabetes were heterogeneous (I-squared=77.2%; p=0.002), indicating gene-specific associations with metabolic risk for LDL-lowering alleles. Conclusions and Relevance In this meta-analysis, exposure to LDL-cholesterol lowering genetic variants in or near NPC1L1 and other genes was associated with a higher risk of type 2 diabetes. These data provide insights into potential adverse effects of LDL cholesterol-lowering therapy.