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Patients with homozygous familial hypercholesterolaemia respond inadequately to existing drugs. We aimed to assess the efficacy and safety of the microsomal triglyceride transfer protein inhibitor lomitapide in adults with this disease. We did a single-arm, open-label, phase 3 study of lomitapide for treatment of patients with homozygous familial hypercholesterolemia. Current lipid lowering therapy was maintained from 6 weeks before baseline through to at least week 26. Lomitapide dose was escalated on the basis of safety and tolerability from 5 mg to a maximum of 60 mg a day. The primary endpoint was mean percent change in levels of LDL cholesterol from baseline to week 26, after which patients remained on lomitapide through to week 78 for safety assessment. Percent change from baseline to week 26 was assessed with a mixed linear model. 29 men and women with homozygous familial hypercholesterolaemia, aged 18 years or older, were recruited from 11 centres in four countries (USA, Canada, South Africa, and Italy). 23 of 29 enrolled patients completed both the efficacy phase (26 weeks) and the full study (78 weeks). The median dose of lomitapide was 40 mg a day. LDL cholesterol was reduced by 50% (95% CI −62 to −39) from baseline (mean 8·7 mmol/L [SD 2·9]) to week 26 (4·3 mmol/L [2·5]; p<0·0001). Levels of LDL cholesterol were lower than 2·6 mmol/L in eight patients at 26 weeks. Concentrations of LDL cholesterol remained reduced by 44% (95% CI −57 to −31; p<0·0001) at week 56 and 38% (–52 to −24; p<0·0001) at week 78. Gastrointestinal symptoms were the most common adverse event. Four patients had aminotransaminase levels of more than five times the upper limit of normal, which resolved after dose reduction or temporary interruption of lomitapide. No patient permanently discontinued treatment because of liver abnormalities. Our study suggests that treatment with lomitapide could be a valuable drug in the management of homozygous familial hypercholesterolaemia. FDA Office of the Orphan Product Development, Aegerion Pharmaceuticals.

Familial hypercholesterolaemia is a common autosomal-dominant disorder caused by mutations in three known genes. DNA-based cascade testing is recommended by UK guidelines to identify affected relatives; however, about 60% of patients are mutation-negative. We assessed the hypothesis that familial hypercholesterolaemia can also be caused by an accumulation of common small-effect LDL-C-raising alleles. In November, 2011, we assembled a sample of patients with familial hypercholesterolaemia from three UK-based sources and compared them with a healthy control sample from the UK Whitehall II (WHII) study. We also studied patients from a Belgian lipid clinic (Hôpital de Jolimont, Haine St-Paul, Belgium) for validation analyses. We genotyped participants for 12 common LDL-C-raising alleles identified by the Global Lipid Genetics Consortium and constructed a weighted LDL-C-raising gene score. We compared the gene score distribution among patients with familial hypercholesterolaemia with no confirmed mutation, those with an identified mutation, and controls from WHII. We recruited 321 mutation-negative UK patients (451 Belgian), 319 mutation-positive UK patients (273 Belgian), and 3020 controls from WHII. The mean weighted LDL-C gene score of the WHII participants (0·90 [SD 0·23]) was strongly associated with LDL-C concentration (p=1·4 × 10−77; R2=0·11). Mutation-negative UK patients had a significantly higher mean weighted LDL-C score (1·0 [SD 0·21]) than did WHII controls (p=4·5 × 10−16), as did the mutation-negative Belgian patients (0·99 [0·19]; p=5·2 × 10−20). The score was also higher in UK (0·95 [0·20]; p=1·6 × 10−5) and Belgian (0·92 [0·20]; p=0·04) mutation-positive patients than in WHII controls. 167 (52%) of 321 mutation-negative UK patients had a score within the top three deciles of the WHII weighted LDL-C gene score distribution, and only 35 (11%) fell within the lowest three deciles. In a substantial proportion of patients with familial hypercholesterolaemia without a known mutation, their raised LDL-C concentrations might have a polygenic cause, which could compromise the efficiency of cascade testing. In patients with a detected mutation, a substantial polygenic contribution might add to the variable penetrance of the disease. British Heart Foundation, Pfizer, AstraZeneca, Schering-Plough, National Institute for Health Research, Medical Research Council, Health and Safety Executive, Department of Health, National Heart Lung and Blood Institute, National Institute on Aging, Agency for Health Care Policy Research, John D and Catherine T MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health, Unilever, and Departments of Health and Trade and Industry.

Homozygous familial hypercholesterolaemia is a rare genetic disorder in which both LDL-receptor alleles are defective, resulting in very high concentrations of LDL cholesterol in plasma and premature coronary artery disease. This study investigated whether an antisense inhibitor of apolipoprotein B synthesis, mipomersen, is effective and safe as an adjunctive agent to lower LDL cholesterol concentrations in patients with this disease. This randomised, double-blind, placebo-controlled, phase 3 study was undertaken in nine lipid clinics in seven countries. Patients aged 12 years and older with clinical diagnosis or genetic confirmation of homozygous familial hypercholesterolaemia, who were already receiving the maximum tolerated dose of a lipid-lowering drug, were randomly assigned to mipomersen 200 mg subcutaneously every week or placebo for 26 weeks. Randomisation was computer generated and stratified by weight (<50 kg vs ≥50 kg) in a centralised blocked randomisation, implemented with a computerised interactive voice response system. All clinical, medical, and pharmacy personnel, and patients were masked to treatment allocation. The primary endpoint was percentage change in LDL cholesterol concentration from baseline. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00607373. 34 patients were assigned to mipomersen and 17 to placebo; data for all patients were analysed. 45 patients completed the 26-week treatment period (28 mipomersen, 17 placebo). Mean concentrations of LDL cholesterol at baseline were 11·4 mmol/L (SD 3·6) in the mipomersen group and 10·4 mmol/L (3·7) in the placebo group. The mean percentage change in LDL cholesterol concentration was significantly greater with mipomersen (−24·7%, 95% CI −31·6 to −17·7) than with placebo (−3·3%, −12·1 to 5·5; p=0·0003). The most common adverse events were injection-site reactions (26 [76%] patients in mipomersen group vs four [24%] in placebo group). Four (12%) patients in the mipomersen group but none in the placebo group had increases in concentrations of alanine aminotransferase of three times or more the upper limit of normal. Inhibition of apolipoprotein B synthesis by mipomersen represents a novel, effective therapy to reduce LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia who are already receiving lipid-lowering drugs, including high-dose statins. ISIS Pharmaceuticals and Genzyme Corporation.

High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal. We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20 913 myocardial infarction cases, 95 407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12 482 cases of myocardial infarction and 41 331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol. Carriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher, p=8×10−13) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with non-carriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84–0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88–1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58–0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68–1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45–1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69–2·69, p=2×10−10). Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction. US National Institutes of Health, The Wellcome Trust, European Union, British Heart Foundation, and the German Federal Ministry of Education and Research.

Inhibition of proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) resulted in large reductions of low-density lipoprotein cholesterol (LDL-C) in phase 1 trials. We assessed the efficacy and safety of various doses and dosing intervals of REGN727, a monoclonal antibody to PCSK9, added to statins, to further lower LDL-C in patients with heterozygous familial hypercholesterolaemia. This multicentre, randomised, placebo-controlled phase 2 trial was done at 16 lipid clinics in the USA and Canada. Between Jan 18, 2011, and Nov 7, 2011, we enrolled adults with heterozygous familial hypercholesterolaemia and LDL-C concentrations of 2·6 mmol/L or higher on stable diet and statin dose, with or without ezetimibe. Patients were randomly assigned to receive REGN727 150 mg, 200 mg, or 300 mg every 4 weeks, or 150 mg every 2 weeks, or placebo every 2 weeks (ratio 1:1:1:1:1). Randomisation was stratified by concomitant use of ezetimibe at baseline. Investigators, study staff, and patients were masked to treatment group. Blinding was maintained by administration of placebo alternating with REGN727 for the groups of 4 week dosing. The primary endpoint was mean percent reduction in LDL-C from baseline at week 12 and was analysed in the modified intention-to-treat population with an analysis of covariance (ANCOVA) model with treatment group. This trial is registered in ClinicalTrials.gov, number NCT 01266876. 77 patients were randomly assigned to study groups (15–16 patients per group) and all were analysed. Least-squares (LS) mean LDL-C reduction from baseline to week 12 was 28·9% (SE 5·08) for 150 mg every 4 weeks (p=0·0113), 31·54% (4·91) for 200 mg every 4 weeks (p=0·0035), 42·53% (5·09) for 300 mg every 4 weeks (p<0·0001), and 67·90% (4·85) for 150 mg every 2 weeks (p<0·0001), compared with 10·65% (5·04) with placebo. One serious adverse event was reported with placebo and none with REGN727. No increases of more than three times the upper limit of normal were reported for hepatic transaminases or creatinine kinase. The most common adverse event was injection-site reaction with one patient in the group of 300 mg REGN727 terminating treatment. REGN727 was well tolerated and achieved substantial further LDL-C reduction in patients with heterozygous familial hypercholesterolaemia and elevated LDL-C treated with high-dose statins, with or without ezetimibe. REGN727 has the potential to provide optimum control of LDL-C in patients with this disorder. Sanofi US and Regeneron Pharmaceuticals Incorporated.

In this clinical trial involving patients with established cardiovascular disease, the addition of niacin to intensive statin therapy provided no additional clinical benefit over a period of 3 years, despite favorable changes in lipid levels. More than 18 million North Americans have coronary heart disease, and despite profound advances in both pharmacologic and interventional management, both morbidity and mortality remain appreciable. 1 , 2 Elevated low-density lipoprotein (LDL) cholesterol levels are an established predictor of the risk of coronary heart disease. Multiple primary and secondary prevention trials have shown a significant reduction of 25 to 35% in the risk of cardiovascular events with statin therapy 3 ; however, residual risk persists despite the achievement of target LDL cholesterol levels. Epidemiologic studies have shown that, in addition to elevated LDL cholesterol levels, low levels of high-density lipoprotein (HDL) cholesterol . . .

Patients with hyperlipidemia were assigned to receive the PCSK9 antibody evolocumab or placebo on a background of lipid-lowering therapy. At 52 weeks, the least-squares mean reduction in LDL cholesterol from baseline for evolocumab versus placebo was 57%. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a serine protease that is produced predominantly in the liver, is secreted into the plasma and plays a major role in regulating levels of low-density lipoprotein (LDL) cholesterol by binding to hepatic LDL receptors and promoting their degradation. 1 , 2 In short-term (8-to-12-week), placebo-controlled, phase 2 trials, PCSK9 inhibitors have been shown to significantly reduce LDL cholesterol levels. 3 – 9 Four of these trials involved the use of evolocumab (AMG 145), a fully human monoclonal PCSK9 antibody, and assessed different doses and regimens in diverse patient populations with varying lipid phenotypes, cardiovascular disease risks, and baseline . . .

In a cohort of healthy volunteers, cholesterol efflux capacity was correlated with carotid intima–media thickness. In a cohort of patients with or without angiographically confirmed coronary disease, cholesterol efflux capacity predicted coronary disease status. A robust inverse association between the level of high-density lipoprotein (HDL) cholesterol and the risk of cardiovascular disease has fostered intensive research seeking to target HDL metabolism for therapeutic gain. 1 , 2 However, some findings have called into question the hypothesis that pharmacologic increases in HDL cholesterol levels are necessarily beneficial. Several therapies, including nicotinic acid and fibric acid derivatives, increase HDL cholesterol levels, but linking these increases to clinical risk reduction has proved challenging. 3 , 4 Most strikingly, an inhibitor of cholesteryl ester transfer protein (CETP) was associated with an increase in the number of cardiovascular events, despite a 72% increase . . .

In a phase 2 trial, patients with hypercholesterolemia received 80 mg atorvastatin and placebo, 10 mg atorvastatin and an antibody to PCSK9, or 80 mg atorvastatin and an antibody to PCSK9 for 8 weeks. Reductions from baseline in LDL cholesterol were 17.3%, 66.2%, and 73.2%, respectively. Reducing levels of low-density lipoprotein (LDL) cholesterol is a cornerstone of the prevention of cardiovascular disease. 1 , 2 European and U.S. guidelines recommend lowering LDL cholesterol to less than 100 mg per deciliter (2.6 mmol per liter) in persons with established cardiovascular disease and to less than 70 mg per deciliter (1.8 mmol per liter), or by 50% or more, in those at highest risk. 3 , 4 Statins are highly efficacious in lowering LDL cholesterol. However, many patients, especially those with very high initial LDL cholesterol levels and those who have unacceptable side effects with high-dose statins, do not reach recommended target . . .

In a 2-year clinical trial, the addition of ezetimibe to simvastatin had no effect on the progression of atherosclerosis, as measured by carotid-artery intima–media thickness, despite the additional lowering of levels of low-density lipoprotein cholesterol and C-reactive protein by ezetimibe when added to simvastatin. However, the study was not powered to assess clinical end points. The addition of ezetimibe to simvastatin had no effect on the progression of atherosclerosis, as measured by carotid-artery intima–media thickness, despite the additional lowering of levels of low-density lipoprotein cholesterol and C-reactive protein. A reduction in levels of low-density lipoprotein (LDL) cholesterol constitutes one of the cornerstones in the prevention of cardiovascular disease. In recent trials comparing various statins or the same statin at various doses, aggressive therapy to lower LDL cholesterol levels was associated with a reduction in rates of cardiovascular events. 1 – 4 However, administration of the highest approved statin dose offers only limited additional lowering of LDL cholesterol at the expense of an increased incidence of side effects. 5 Therefore, novel compounds that further reduce LDL cholesterol levels when added to statin therapy are of interest. A recently introduced compound, ezetimibe, selectively . . .