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.

BACKGROUNDIn a previous study, a single injection of inclisiran, a chemically synthesized small interfering RNA designed to target PCSK9 messenger RNA, was found to produce sustained reductions in low-density lipoprotein (LDL) cholesterol levels over the course of 84 days in healthy volunteers. METHODSWe conducted a phase 2, multicenter, double-blind, placebo-controlled, multipleascending-dose trial of inclisiran administered as a subcutaneous injection in patients at high risk for cardiovascular disease who had elevated LDL cholesterol levels. Patients were randomly assigned to receive a single dose of placebo or 200, 300, or 500 mg of inclisiran or two doses (at days 1 and 90) of placebo or 100, 200, or 300 mg of inclisiran. The primary end point was the change from baseline in LDL cholesterol level at 180 days. Safety data were available through day 210, and data on LDL cholesterol and proprotein convertase subtilisin-kexin type 9 (PCSK9) levels were available through day 240. RESULTSA total of 501 patients underwent randomization. Patients who received inclisiran had dose-dependent reductions in PCSK9 and LDL cholesterol levels. At day 180, the least-squares mean reductions in LDL cholesterol levels were 27.9 to 41.9% after a single dose of inclisiran and 35.5 to 52.6% after two doses (P<0.001 for all comparisons vs. placebo). The two-dose 300-mg inclisiran regimen produced the greatest reduction in LDL cholesterol levels: 48% of the patients who received the regimen had an LDL cholesterol level below 50 mg per deciliter (1.3 mmol per liter) at day 180. At day 240, PCSK9 and LDL cholesterol levels remained significantly lower than at baseline in association with all inclisiran regimens. Serious adverse events occurred in 11% of the patients who received inclisiran and in 8% of the patients who received placebo. Injection-site reactions occurred in 5% of the patients who received injections of inclisiran. CONCLUSIONSIn our trial, inclisiran was found to lower PCSK9 and LDL cholesterol levels among patients at high cardiovascular risk who had elevated LDL cholesterol levels. Original ArticleThe New England Journal of Medicine Downloaded from nejm.org at IMPERIAL COLLEGE LONDON on May 3, 2017. For personal use only. No other uses without permission.Copyright © 2017 Massachusetts Medical Society. All rights reserved.n engl j med 376;15 nejm.org April 13, 2017 1431Inclisir an in Patients with Elevated LDL Cholesterol L ow-density lipoprotein (LDL) cholesterol is a causal factor in atherosclerotic cardiovascular disease. Statins have been shown to reduce LDL cholesterol levels and cardiovascular events in large outcome trials, findings that have made them the therapeutic cornerstone of clinical practice.1 Despite the proven efficacy of statins, there is considerable variability in individual responses to these drugs.2 Furthermore, some observational data suggest that as many as half of persons who begin statin therapy discontinue it within a year.3 Moreover, among patients receiving statin therapy who are at high...

Background: Contemporary studies suggest that familial hypercholesterolemia (FH) is more frequent than previously reported and increasingly recognized as affecting individuals of all ethnicities and across many regions of the world. Precise estimation of its global prevalence and prevalence across World Health Organization regions is needed to inform policies aiming at early detection and atherosclerotic cardiovascular disease (ASCVD) prevention. The present study aims to provide a comprehensive assessment and more reliable estimation of the prevalence of FH than hitherto possible in the general population (GP) and among patients with ASCVD. Methods: We performed a systematic review and meta-analysis including studies reporting on the prevalence of heterozygous FH in the GP or among those with ASCVD. Studies reporting gene founder effects and focused on homozygous FH were excluded. The search was conducted through Medline, Embase, Cochrane, and Global Health, without time or language restrictions. A random-effects model was applied to estimate the overall pooled prevalence of FH in the general and ASCVD populations separately and by World Health Organization regions. Results: From 3225 articles, 42 studies from the GP and 20 from populations with ASCVD were eligible, reporting on 7 297 363 individuals/24 636 cases of FH and 48 158 patients/2827 cases of FH, respectively. More than 60% of the studies were from Europe. Use of the Dutch Lipid Clinic Network criteria was the commonest diagnostic method. Within the GP, the overall pooled prevalence of FH was 1:311 (95% CI, 1:250–1:397; similar between children [1:364] and adults [1:303], P =0.60; across World Health Organization regions where data were available, P =0.29; and between population-based and electronic health records–based studies, P =0.82). Studies with ≤10 000 participants reported a higher prevalence (1:200–289) compared with larger cohorts (1:365–407; P <0.001). The pooled prevalence among those with ASCVD was 18-fold higher than in the GP (1:17 [95% CI, 1:12–1:24]), driven mainly by coronary artery disease (1:16; [95% CI, 1:12–1:23]). Between-study heterogeneity was large ( I 2 >95%). Tests assessing bias were nonsignificant ( P >0.3). Conclusions: With an overall prevalence of 1:311, FH is among the commonest genetic disorders in the GP, similarly present across different regions of the world, and is more frequent among those with ASCVD. The present results support the advocacy for the institution of public health policies, including screening programs, to identify FH early and to prevent its global burden.

Conclusion:There is no benefit of statin therapy on all-cause mortality in a high-risk primary prevention setting.Summary: The Justification for the Use of Statins in Prevention Intervention Trial Evaluating Rosuvastatin (JUPITER) reported that patients with comparatively low levels of low-density lipoprotein (LDL) cholesterol (Ͻ130 mg/dL) and baseline levels of high-sensitivity C-reactive protein (HS-CRP; Ͼ2 mg/L) reduced all-cause mortality by 20% (Ridker PM, N Eng J Med 2008;359:2195-207). However, the JUPITER findings have been questioned as occurring by chance or as being an exaggerated observation (Yusuf S, Lancet 2009;373:1152-5). The authors undertook a new metaanalysis of published clinical trials (including information previously unpublished by such studies) to assess whether statins reduce all-cause mortality in the setting of high-risk primary prevention populations. The goal was to determine if statin therapy reduces all-cause mortality in intermediate-to high-risk individuals without a history of cardiovascular disease.The authors identified trials for the analysis through computerized literature searches of MEDLINE and Cochrane databases from January 1970 to May 2009. Trials had to be prospective, randomized, and controlled, evaluating statin therapy in individuals free from cardiovascular disease at baseline. Data were extracted for the number of patients randomized and for mean duration of follow-up. The number of incident deaths was obtained though the principle publication or by correspondence with investigators. For the analysis, 11 studies were identified and data combined from the studies, with the sample effects pooled using a random-effects model analysis with heterogeneity assessed with the I 2 statistic.Data were available on 65,229 participants followed-up for approximately 244,000 person-years, during which 2793 deaths occurred. Use of statins in this high-risk primary prevention setting was not associated with a statistically significant reduction (RR, 0.91; 95% CI, 0.83-1.01) in all-cause mortality. There was no statistical evidence of heterogeneity among studies (I 2 ϭ 23%; 95% CI, 0%-61%; P ϭ .23).Comment: Three-quarters of patients who take statins take them for primary prevention. Depending on perspective, their study has enormous implications for expenditures (from payers perspective) or revenue (from industry perspective). An editorial by Dr Lee A. Green in the same issue of Archives of Internal Medicine (2010;170:1007-8), points out this advocates for lipid-lowering therapy for primary prevention feel benefit would likely accrue over a longer time of observation. Skeptics postulate little incremental benefit will accrue later. Accompanying the Ray et al meta-analysis is another article in the same issue of Archives of Internal Medicine by de Lorgeril et al, "Cholesterol Lowering, Cardiovascular Diseases, and the Rosuvastatin-JUPITER Controversy, A Critical Reappraisal" (2010;170:1032-6), in which the authors point out that the JUPITER trial is the only trial that has shown b...

In recent years, there has been growing interest in the possible use of nutraceuticals to improve and optimize dyslipidemia control and therapy. Based on the data from available studies, nutraceuticals might help patients obtain theraputic lipid goals and reduce cardiovascular residual risk. Some nutraceuticals have essential lipid-lowering properties confirmed in studies; some might also have possible positive effects on nonlipid cardiovascular risk factors and have been shown to improve early markers of vascular health such as endothelial function and pulse wave velocity. However, the clinical evidence supporting the use of a single lipid-lowering nutraceutical or a combination of them is largely variable and, for many of the nutraceuticals, the evidence is very limited and, therefore, often debatable. The purpose of this position paper is to provide consensus-based recommendations for the optimal use of lipid-lowering nutraceuticals to manage dyslipidemia in patients who are still not on statin therapy, patients who are on statin or combination therapy but have not achieved lipid goals, and patients with statin intolerance. This statement is intended for physicians and other healthcare professionals engaged in the diagnosis and management of patients with lipid disorders, especially in the primary care setting.

Force on practical clinical guidance for proprotein convertase subtilisin/kexin type 9 inhibition in patients with atherosclerotic cardiovascular disease or in familial hypercholesterolaemia.

The EAS FHSC is an international initiative involving a network of investigators interested in FH from around 70 countries.• Information on FH prevalence is lacking in most countries; where available, data tend to align with contemporary estimates.• FH diagnosis and management varies widely across countries, with overall suboptimal identification and under-treatment.• In most countries diagnosis primarily relies on DLCN criteria, and less frequently on Simon Broom or MEDPED.• Therapy for FH is not universally reimbursed, and criteria vary across countries. Access to PCSK9i and apheresis is limited.

Among patients with vascular disease, there is very substantial variation in estimated 10-year risk of recurrent vascular events. If all modifiable risk factors were at guideline-recommended targets, half of the patients would have a 10-year risk <10%. These data suggest that even with optimal treatment, many patients with vascular disease will remain at >20% and even >30% 10-year risk, clearly delineating an area of substantial unmet medical need.