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This phase 3 trial evaluated the safety and efficacy of inclisiran, a small interfering RNA that inhibits hepatic PCSK9 synthesis, in 482 adults with heterozygous familial hypercholesterolemia, who received subcutaneous injections of inclisiran or placebo on days 1, 90, 270, and 450. Changes in cholesterol were assessed up to day 540.

The effects on lipid profiles of pharmacologic inhibition of ATP citrate lyase, an enzyme in the cholesterol–biosynthesis pathway upstream of HMGCR (the target of statins), are similar to those of statins. This inhibition may lower the risk of cardiovascular disease.

Background Alirocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin–kexin type 9 (PCSK9), has been shown to reduce low-density lipoprotein (LDL) cholesterol levels in patients who are receiving statin therapy. Larger and longer-term studies are needed to establish safety and efficacy. Methods We conducted a randomized trial involving 2341 patients at high risk for cardiovascular events who had LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or more and were receiving treatment with statins at the maximum tolerated dose (the highest dose associated with an acceptable side-effect profile), with or without other lipid-lowering therapy. Patients were randomly assigned in a 2:1 ratio to receive alirocumab (150 mg) or placebo as a 1-ml subcutaneous injection every 2 weeks for 78 weeks. The primary efficacy end point was the percentage change in calculated LDL cholesterol level from baseline to week 24. Results At week 24, the difference between the alirocumab and placebo groups in the mean percentage change from baseline in calculated LDL cholesterol level was −62 percentage points (P<0.001); the treatment effect remained consistent over a period of 78 weeks. The alirocumab group, as compared with the placebo group, had higher rates of injection-site reactions (5.9% vs. 4.2%), myalgia (5.4% vs. 2.9%), neurocognitive events (1.2% vs. 0.5%), and ophthalmologic events (2.9% vs. 1.9%). In a post hoc analysis, the rate of major adverse cardiovascular events (death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization) was lower with alirocumab than with placebo (1.7% vs. 3.3%; hazard ratio, 0.52; 95% confidence interval, 0.31 to 0.90; nominal P=0.02). Conclusions Over a period of 78 weeks, alirocumab, when added to statin therapy at the maximum tolerated dose, significantly reduced LDL cholesterol levels. In a post hoc analysis, there was evidence of a reduction in the rate of cardiovascular events with alirocumab. (Funded by Sanofi and Regeneron Pharmaceuticals;

Torcetrapib, a cholesteryl ester transfer protein inhibitor, markedly raises levels of high-density lipoprotein cholesterol. Unexpectedly, in the ILLUMINATE trial, torcetrapib therapy in combination with atorvastatin, as compared with atorvastatin alone, increased the risk of death from both cardiovascular and noncardiovascular causes. The drug also raised blood pressure. Torcetrapib therapy in combination with atorvastatin, as compared with atorvastatin alone, increased the risk of death from both cardiovascular and noncardiovascular causes. Evidence supporting the proposition that high-density lipoprotein (HDL) cholesterol should be considered as a therapeutic target includes experimental models of atherosclerosis, 1 an inverse relationship to the risk of cardiovascular disease in humans, 2 clinical trials of drugs for which raising HDL cholesterol levels is a primary pharmacologic effect, 3 and the residual risk of cardiovascular disease associated with a low HDL cholesterol level after effective statin therapy. 4 Cholesteryl ester transfer protein (CETP) promotes the transfer of cholesteryl esters from HDL to other lipoproteins; the inhibition of this protein raises HDL cholesterol levels and decreases low-density lipoprotein (LDL) cholesterol levels. There is evidence . . .

In this secondary analysis of data from JUPITER, rosuvastatin, as compared with placebo, resulted in a reduced risk of symptomatic venous thromboembolism (including deep-vein thrombosis and pulmonary embolism). In this secondary analysis of data from JUPITER, rosuvastatin, as compared with placebo, resulted in a reduced risk of symptomatic venous thromboembolism (including deep-vein thrombosis and pulmonary embolism). Venous and arterial thrombosis are common, serious, and strongly age-related events that often occur together 1 , 2 and share some risk factors. 3 – 7 Controversies persist regarding the nature and extent of their shared pathways and whether treatments of demonstrated efficacy for one condition, including anticoagulant agents, antiplatelet therapy, thrombolytic agents, and statins, have consistent benefits for the primary or secondary prevention of the other. 8 – 10 The benefits of statins might accrue not only through their effects on lipid levels but also through their influence on thrombosis and inflammation. 11 – 13 Two prospective, observational studies showed that substantial and significant reductions in the . . .

In a family with high HDL, a genetic mutation was identified. In addition to higher HDL levels, carriers had reduced cholesterol efflux from macrophages, impaired platelet function, and attenuated adrenal steroidogenesis. No significant difference was seen in the carotid artery intima–media thickness. A low plasma level of high-density lipoprotein (HDL) cholesterol is a strong risk factor for cardiovascular disease. 1 This explains the interest in the development of HDL cholesterol–increasing drugs to reduce atherosclerosis. To develop such drugs, in-depth knowledge of human HDL metabolism is necessary. Our understanding of several potential targets for drug development has greatly benefited from the identification of families with specific HDL gene mutations. 2 – 5 A prominent example is the interest in inhibiting the cholesterol ester transfer protein (CETP) in response to the discovery that mutations in the CETP gene cause high HDL cholesterol levels. 6 Scavenger receptor class B . . .

Since torcetrapib, an inhibitor of cholesteryl ester transfer protein, markedly increases levels of high-density lipoprotein cholesterol and lowers levels of low-density lipoprotein cholesterol, in principle it might have a beneficial effect on atherosclerosis. However, in this clinical trial, torcetrapib had no beneficial effect on carotid atherosclerosis, as assessed by ultrasonographic measurement of carotid intima–media thickness. The reasons for this finding are unclear, but the drug did increase blood pressure slightly. In this clinical trial, torcetrapib had no beneficial effect on carotid atherosclerosis, as assessed by ultrasonographic measurement of carotid intima–media thickness.Published Online March 26, 2007 (DOI:10.1056/NEJMoa071359) Guidelines for the prevention and management of cardiovascular disease focus on reducing levels of low-density lipoprotein (LDL) cholesterol by means of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (collectively referred to as statins). 1 , 2 However, recent meta-analyses have shown that even with the most aggressive treatment, 3 , 4 these drugs reduce the risk of a major coronary event by only 30%. 5 This finding, combined with an estimation that mortality from cardiovascular causes will increase worldwide by 90% by the year 2020, as compared with that in 1990, 6 illustrates the need for new efficacious treatments. A review of four large, prospective epidemiologic studies . . .

Inclisiran, a small interfering RNA therapeutic, reduces hepatic synthesis of PCSK9. In two separate randomized trials, subcutaneous injections of inclisiran on day 1, day 90, and then every 6 months reduced LDL cholesterol levels by approximately 50% at month 17, with a modest excess of injection-site adverse events.

Comprehensive Whole-Genome and Candidate Gene Analysis for Response to Statin Therapy in the Treating to New Targets (TNT) Cohort John F. Thompson, PhD ; Craig L. Hyde, PhD ; Linda S. Wood, MS ; Sara A. Paciga, MA ; David A. Hinds, PhD ; David R. Cox, MD, PhD ; G. Kees Hovingh, MD, PhD and John J.P. Kastelein, MD, PhD From the Helicos BioSciences (J.F.T.), Cambridge, Mass; Molecular Medicine (J.F.T., L.S.W., S.A.P.) and Statistical Applications (C.L.H.), Pfizer Global Research and Development, Groton, Conn; Perlegen Sciences (D.A.H., D.R.C.), Mountain View, Calif; and Department of Vascular Medicine (G.K.H., J.J.P.K.), Academic Medical Center, Amsterdam, The Netherlands. Correspondence to John J.P. Kastelein, MD, PhD, Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, Room F4-159.2, 1105 AZ Amsterdam, The Netherlands. E-mail j.j.kastelein{at}amc.uva.nl or j.s.jansen@amc.uva.nl Received September 9, 2008; accepted January 26, 2009. Background— Statins are effective at lowering low-density lipoprotein cholesterol and reducing risk of cardiovascular disease, but variability in response is not well understood. To address this, 5745 individuals from the Treating to New Targets (TNT) trial were genotyped in a combination of a whole-genome and candidate gene approach to identify associations with response to atorvastatin treatment. Methods and Results— A total of 291 988 single-nucleotide polymorphisms (SNPs) from 1984 individuals were analyzed for association with statin response, followed by genotyping top hits in 3761 additional individuals. None was significant at the whole-genome level in either the initial or follow-up test sets for association with low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or triglyceride response. In addition to the whole-genome platform, 23 candidate genes previously associated with statin response were analyzed in these 5745 individuals. Three SNPs in apoE were most highly associated with low-density lipoprotein cholesterol response, followed by 1 in PCSK9 with a similar effect size. At the candidate gene level, SNPs in HMGCR were also significant though the effect was less than with those in apoE and PCSK9 . rs7412/ apoE had the most significant association ( P =6 x 10 –30 ), and its high significance in the whole-genome study ( P =4 x 10 –9 ) confirmed the suitability of this population for detecting effects. Age and gender were found to influence low-density lipoprotein cholesterol response to a similar extent as the most pronounced genetic effects. Conclusions— Among SNPs tested with an allele frequency of at least 5%, only SNPs in apoE are found to influence statin response significantly. Less frequent variants in PCSK9 and smaller effect sizes in SNPs in HMGCR were also revealed. Key Words: genetics • hypercholesterolemia • hydroxymethylglutaryl coenzyme A reductase inhibitors • myocardial infarction   CLINICAL PERSPECTIVE The online-only Data Supplement is available at http://circgenetics.ahajournals.org/cgi/content/full/CIRCGENETICS.108.818062/DC1. Related Article Comprehensive Whole-Genome and Candidate Gene Analysis for Response to Statin Therapy in the Treating to New Targets (TNT) Cohort John F. Thompson, Craig L. Hyde, Linda S. Wood, Sara A. Paciga, David A. Hinds, David R. Cox, G. Kees Hovingh, and John J.P. Kastelein Circ Cardiovasc Genet 2009 2: 173-181. [Abstract] [Full Text] [PDF] Home | Subscriptions | Archives | Feedback | Authors | Help | Circulation Journals Home | AHA Journals Home | Search Copyright © 2009 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited. var _rsCI=\"us-lippincott\"; var _rsCG=\"0\"; var _rsDN=\"//secure-us.imrworldwide.com/\"; var _rsSE=1; var _rsSM=1.0;

Familial hypercholesterolemia is marked by very elevated low-density lipoprotein cholesterol levels and premature cardiovascular disease. This 20-year follow-up study showed that statin initiation during childhood in affected persons slowed the progression of carotid intima–media thickness and reduced the risk of cardiovascular disease in adulthood.