Search

Aims: Guidelines recommend targeting non-high-density lipoprotein cholesterol to reduce cardiovascular risk. We assessed the impact of baseline triglycerides on non-high-density lipoprotein cholesterol goal attainment in 10 phase 3 trials with alirocumab versus control ( n  = 4983)., Methods: Trials were grouped into four pools based on alirocumab dose (75-150 mg every 2 weeks), control (placebo/ezetimibe) and statin use. Baseline triglyceride quintiles were built within each pool. Non-high-density lipoprotein cholesterol goal attainment (very high risk: <100 mg/dl; moderate/high risk: <130 mg/dl), low-density lipoprotein cholesterol goal attainment (very high risk: <70 mg/dl; moderate/high risk: <100 mg/dl) and changes from baseline in lipid parameters were assessed at Week 24 among baseline triglyceride quintiles., Results: Higher baseline triglycerides were associated with a worse cardiovascular risk profile. Low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol increased with higher triglycerides, but the magnitude in non-high-density lipoprotein cholesterol was three- to four-fold higher compared with the increase in low-density lipoprotein cholesterol. Non-high-density lipoprotein cholesterol and low-density lipoprotein cholesterol percentage reductions from baseline with alirocumab were similar regardless of baseline triglycerides. A greater proportion of alirocumab-treated patients attained non-high-density lipoprotein cholesterol and low-density lipoprotein cholesterol goals compared with placebo or ezetimibe. Unlike low-density lipoprotein cholesterol goal attainment, non-high-density lipoprotein cholesterol goal attainment significantly declined with increasing baseline triglycerides ( p  < 0.05 for trend tests). A single standard deviation increase in baseline log(triglycerides) was significantly associated with lower odds ratios of attaining non-high-density lipoprotein cholesterol goals in the different pools and treatment (alirocumab/placebo/ezetimibe) groups, unlike low-density lipoprotein cholesterol goal attainment., Conclusion: Individuals with increased triglycerides have higher non-high-density lipoprotein cholesterol levels and lower rates of non-high-density lipoprotein cholesterol goal attainment (unlike low-density lipoprotein cholesterol goal attainment). Alirocumab improves non-high-density lipoprotein cholesterol goal attainment in this population. These results highlight the impact of triglycerides on non-high-density lipoprotein cholesterol and the need for novel therapies targeting triglyceride-related pathways.

Background: Statins inhibit proliferative signalling in oesophageal adenocarcinoma (OAC) and their use is associated with better survival in observational studies. The present study was undertaken to examine the feasibility of assessing adjuvant statin therapy in patients with operable OAC in a phase III RCT., Methods: For this multicentre, double-blind, parallel-group, randomized, placebo-controlled feasibility trial, adults with OAC (including Siewert I-II lesions) who had undergone oesophagectomy were centrally allocated (1 : 1) to simvastatin 40 mg or matching placebo by block randomization, stratified by centre. Participants, clinicians and investigators were blinded to treatment allocation. Patients received treatment for up to 1 year. Feasibility outcomes were recruitment, retention, drug absorption, adherence, safety, quality of life, generalizability and survival., Results: A total of 120 patients were assessed for eligibility at four centres, of whom 32 (26·7 per cent) were randomized, 16 in each group. Seven patients withdrew. Participants allocated to simvastatin had lower low-density lipoprotein cholesterol levels by 3 months (adjusted mean difference -0·83 (95 per cent c.i. -1·4 to -0·22) mmol/l; P = 0·009). Median adherence to medication was greater than 90 per cent between 3 and 12 months' follow-up. Adverse events were similar between the groups. Quality-of-life data were complete for 98·3 per cent of questionnaire items. Cardiovascular disease, diabetes and aspirin use were more prevalent in the non-randomized group, whereas tumour site, stage and grade were similar between groups. Survival estimates were imprecise., Conclusion: This RCT supports the conduct and informs the design considerations for a future phase III trial of adjuvant statin therapy in patients with OAC. Registration number: ISRCTN98060456 (www.isrctn/com)., (© 2019 The Authors. BJS Open published by John Wiley & Sons Ltd on behalf of BJS Society Ltd.)

Low-density lipoprotein cholesterol (LDL-C) has been identified as a causative factor for atherosclerosis and related coronary heart disease, and as the main target for cholesterol- and lipid-lowering therapy. Statin drugs inhibit cholesterol synthesis in the liver and are typically the first line of therapy to lower elevated levels of LDL-C. On the other hand, a different drug, Ezetimibe, inhibits the absorption of cholesterol by the small intestine and provides a different mechanism of action. Many clinical trials have been carried out on safety and efficacy evaluation of cholesterol lowering drugs. To synthesize the results from different clinical trials, we examine treatment level (aggregate) network meta-data from 29 double-blind, randomized, active, or placebo-controlled statins +/$-$ Ezetimibe clinical trials on adult treatment-naïve patients with primary hypercholesterolemia. In this article, we propose a new approach to carry out Bayesian inference for arm-based network meta-regression. Specifically, we develop a new strategy of grouping the variances of random effects, in which we first formulate possible sets of the groups of the treatments based on their clinical mechanisms of action and then use Bayesian model comparison criteria to select the best set of groups. The proposed approach is especially useful when some treatment arms are involved in only a single trial. In addition, a Markov chain Monte Carlo sampling algorithm is developed to carry out the posterior computations. In particular, the correlation matrix is generated from its full conditional distribution via partial correlations. The proposed methodology is further applied to analyze the network meta-data from 29 trials with 11 treatment arms., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a major development in the prevention of cardiovascular disease (CVD) and is one of the most significant discoveries since the development of statin therapy. Administration of two human monoclonal antibodies to PCSK9 (alirocumab and evolocumab) can significantly reduce low-density lipoprotein cholesterol (LDL-c) concentrations, thus improving lipid management. Accordingly, guidelines on the specific indications for alirocumab and evolocumab usage have been released. This multicentre study aimed to estimate the proportion of patients treated for an acute myocardial infarction (MI) who could be considered for PCSK9 inhibitors under the current National Institute for Health and Care Excellence (NICE) lipid targets criteria., Methods: The records of 596 patients in two large hospitals in Liverpool, UK were analysed. Information was collected on lipid profiles during and after admission, lipid-lowering therapy and previous CVD., Results: At least 2.2% of patients were eligible for PCSK9 inhibitors post-MI under the current NICE guidance. Additionally, 29% of patients failed to achieve LDL-c concentrations <2.0 mmol/L despite maximum statin therapy and failed to meet eligibility for PCSK9 inhibitors as per the NICE criteria. This cohort represents a group of patients 'in limbo', in which statin therapy alone is not sufficient to reduce LDL-c., Conclusions: PCSK9 inhibitors are expensive and so their use must be highly selective. At present, in a real-world setting with ezetimibe underprescribing, ~2% of patients are eligible and a further 30% are deprived of benefit and improved outcomes by lack of optimisation and/or potential use of PCSK9 inhibitors., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: Despite the success of statins, there remains unmet clinical need in cardiovascular disease (CVD) prevention. New proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors reduce low-density lipoprotein cholesterol (LDL-C) by 55-65%. Two PCSK9 inhibitors, evolocumab, and alirocumab, were approved for use in Norway but not yet for reimbursement through public national insurance. We aim to explore the cost-effectiveness of these compared with available treatments in a Norwegian setting., Methods and Results: A state transition Markov model was developed to model the cost-effectiveness of PCSK9 inhibitors for prevention of coronary heart disease, ischaemic strokes, and death among high-risk patient subpopulations in Norway, in both primary and secondary settings. Evolocumab and alirocumab are compared against ezetimibe and standard treatment. Risk of CVD is based on population incidence rates and adjusted according to baseline risk factors. Preventative effect of treatment was modelled according to absolute reduction in LDL-C. PCSK9 inhibitors were never found to be cost-effective in primary prevention. In secondary prevention they were cost-effective only for older, high-risk patients. The lowest cost-effectiveness ratios were for heterozygous familial hypercholesterolaemia patients and high-risk diabetics, with €63 200 and €68 400 per quality-adjusted life-year, respectively., Conclusion: High lifetime costs of PCSK9 inhibitors may not be offset by estimated health gains for most eligible patients. PCSK9 inhibitors are found in the model only to be cost-effective in secondary prevention for older patients with high absolute risk of CVD. This picture is likely to change as price decreases. Future research is needed to determine the long-term preventative effects of PCSK9 inhibitors., (© The Author 2017. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Context: The premenopausal circulating lipid profile may be linked to the hormonal profile and ovarian lipid metabolism., Objective: Assess how estradiol, progesterone, and ovarian lipid metabolism contributes to the premenopausal lipid profile; and evaluate the acute effects of a common hormonal oral contraceptive (OC) on circulating lipids., Design: Experimental crossover with repeated measures., Setting: Academic hospitals., Patients: Eight healthy, regularly menstruating women., Interventions: Participants underwent periodic serum sampling during a normal menstrual cycle; a standard 21-day, monophasic combined hormonal OC cycle (30 µg of ethinyl estradiol and 150 µg of levonorgestrel per day); menopause simulated by leuprolide acetate (22.5-mg depot); and an artificial menstrual cycle achieved via transdermal estradiol (50 to 300 µg/d) and vaginal micronized progesterone (100 to 300 mg/d)., Main Outcome Measures: Primary outcomes included evaluation of total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein cholesterol, triglycerides, and the total cholesterol to HDL cholesterol ratio. To estimate the effect of estradiol, progesterone, and ovarian lipid metabolism, all specimens except those from the OC cycle were analyzed. Subgroup analysis was conducted on the follicular and luteal phases. In a separate analysis, the effect of the OC was evaluated relative to the normal menstrual cycle., Results: Estradiol was significantly associated with increased levels of HDL cholesterol throughout the menstrual cycle and in the follicular phase. Ovarian effects were associated with reduced lipid levels, especially during the luteal phase. The OC was associated with an increased total cholesterol to HDL cholesterol ratio and triglycerides., Conclusion: Previously unappreciated factors including ovarian lipid metabolism may contribute to the premenopausal lipid profile., (Copyright © 2017 by the Endocrine Society)

Aims: To elucidate the effects of intensive LDL-C lowering treatment with a standard dose of statin and ezetimibe in patients with dyslipidaemia and high risk of coronary events, targeting LDL-C less than 70 mg/dL (1.8 mmol/L), compared with standard LDL-C lowering lipid monotherapy targeting less than 100 mg/dL (2.6 mmol/L)., Methods and Results: The HIJ-PROPER study is a prospective, randomized, open-label trial to assess whether intensive LDL-C lowering with standard-dose pitavastatin plus ezetimibe reduces cardiovascular events more than standard LDL-C lowering with pitavastatin monotherapy in patients with acute coronary syndrome (ACS) and dyslipidaemia. Patients were randomized to intensive lowering (target LDL-C < 70 mg/dL [1.8 mmol/L]; pitavastatin plus ezetimibe) or standard lowering (target LDL-C 90 mg/dL to 100 mg/dL [2.3-2.6 mmol/L]; pitavastatin monotherapy). The primary endpoint was a composite of all-cause death, non-fatal myocardial infarction, non-fatal stroke, unstable angina, and ischaemia-driven revascularization. Between January 2010 and April 2013, 1734 patients were enroled at 19 hospitals in Japan. Patients were followed for at least 36 months. Median follow-up was 3.86 years. Mean follow-up LDL-C was 65.1 mg/dL (1.68 mmol/L) for pitavastatin plus ezetimibe and 84.6 mg/dL (2.19 mmol/L) for pitavastatin monotherapy. LDL-C lowering with statin plus ezetimibe did not reduce primary endpoint occurrence in comparison with standard statin monotherapy (283/864, 32.8% vs. 316/857, 36.9%; HR 0.89, 95% CI 0.76-1.04, P = 0.152). In, ACS patients with higher cholesterol absorption, represented by elevated pre-treatment sitosterol, was associated with significantly lower incidence of the primary endpoint in the statin plus ezetimibe group (HR 0.71, 95% CI 0.56-0.91)., Conclusion: Although intensive lowering with standard pitavastatin plus ezetimibe showed no more cardiovascular benefit than standard pitavastatin monotherapy in ACS patients with dyslipidaemia, statin plus ezetimibe may be more effective than statin monotherapy in patients with higher cholesterol absorption; further confirmation is needed., Trial No: UMIN000002742, registered as an International Standard Randomized Controlled Trial., (© The Author 2017. Published by Oxford University Press on behalf of the European Society of Cardiology)

In the mid-1990s, the days of lipoprotein(a) [Lp(a)] were numbered and many people would not have placed a bet on this lipid particle making it to the next century. However, genetic studies brought Lp(a) back to the front-stage after a Mendelian randomization approach used for the first time provided strong support for a causal role of high Lp(a) concentrations in cardiovascular disease and later also for aortic valve stenosis. This encouraged the use of therapeutic interventions to lower Lp(a) as well numerous drug developments, although these approaches mainly targeted LDL cholesterol, while the Lp(a)-lowering effect was only a 'side-effect'. Several drug developments did show a potent Lp(a)-lowering effect but did not make it to endpoint studies, mainly for safety reasons. Currently, three therapeutic approaches are either already in place or look highly promising: (i) lipid apheresis (specific or unspecific for Lp(a)) markedly decreases Lp(a) concentrations as well as cardiovascular endpoints; (ii) PCSK9 inhibitors which, besides lowering LDL cholesterol also decrease Lp(a) by roughly 30%; and (iii) antisense therapy targeting apolipoprotein(a) which has shown to specifically lower Lp(a) concentrations by up to 90% in phase 1 and 2 trials without influencing other lipids. Until the results of phase 3 outcome studies are available for antisense therapy, we will have to exercise patience, but with optimism since never before have we had the tools we have now to prove Koch's extrapolated postulate that lowering high Lp(a) concentrations might be protective against cardiovascular disease., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)

Purpose of the Study: Statins and ezetimibe reduce low-density lipoprotein cholesterol (LDL-c) and cardiovascular disease (CVD) risk. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors lower LDL-c by 50%-70% and might be useful in refractory patients. The National Institute for Health and Care Excellence (NICE) technology appraisal guidance (TAG) recommends use of these drugs in secondary prevention and familial hypercholesterolaemia (FH) at differing LDL-c thresholds. We have estimated the proportion of patients in whom this third-line drug might be useful., Study Design: We used data from a lipid-lowering audit programme to study 72 with FH and/or CVD of 271 patients referred over 12 months who failed to achieve target total cholesterol (TC) and LDL-c levels. All 72 patients were treated with ezetimibe, and 69 cases also received statins. We used LDL-c thresholds 1.5-5.5 mmol/L to estimate how many of these refractory patients could benefit from PCSK9 inhibitors., Results: In 72 patients, TC and LDL-c targets were not met by 64 and 53 patients, respectively. We judged using the NICE TAG that only one patient (1.4% ezetimibe requiring and 0.4% total referrals) required a PCSK9 inhibitor., Conclusions: We determined that the proportion of patients eligible for a PCSK9 inhibitor at various TC and LDL-c levels is modest. This may reflect the use of all available statins in UK lipid clinics often at non-daily frequency. We suggest that cost-effective use of PCSK9 inhibitors requires prescribing being restricted to clinicians working in specialised lipid clinics., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Aims: Current diabetes guidelines recommend an individualized approach to glycaemic control. There are limited data on the contemporary and comprehensive management of patients with diabetes in relation to coronary artery disease (CAD)., Methods and Results: The Diabetes Mellitus Status in Canada (DM-SCAN) survey included 5123 patients with type 2 diabetes seen in primary care in November 2012. Primary care physicians (PCPs) collected clinical data and specified the A1C target for each patient on standardized forms. We compared management strategies and achievement of treatment targets in patients with and without CAD. Among the 4994 patients with data on CAD history, 22.5% had CAD. Primary care physicians were more likely to select a higher A1C target for patients with CAD (≤7.5 or ≤8.0%) versus without (≤7.0%). There was no difference in median A1C or in the proportion of patients with A1C ≤7.0% between the two groups. Compared with the group without known CAD, patients with CAD had a higher reported prevalence of hypoglycaemia in the preceding 6 months; more frequently received aspirin, statins, ACE inhibitors, or angiotensin receptor blockers, and were more likely to achieve blood pressure and low-density lipoprotein-cholesterol targets. Only 15.4 and 12.0% of patients with and without CAD (P = 0.002), respectively, achieved all three guideline-recommended targets., Conclusion: Compared with patients with diabetes without CAD, those with CAD more frequently had a less stringent A1C target selected by their PCPs but achieved similar glycaemic control. Overall, risk factor management remained suboptimal in both groups. There remains an important opportunity to improve the care and outcome of patients with diabetes.

Aims: We performed a network meta-analysis of randomized controlled trials (RCTs) in patients with primary hypercholesterolaemia to compare the impact of proprotein convertase subtilisin-kexin type 9 serine protease (PCSK9) inhibitors with placebo and ezetimibe on lipid levels and outcomes., Methods and Results: MEDLINE/PubMed, Cochrane CENTRAL, and ClinicalTrials.gov were searched for RCTs assessing PCSK9 inhibitors vs. other therapies in patients with primary hypercholesterolaemia. Network meta-analysis with both a frequentist approach and a Bayesian framework was performed to directly and indirectly compare PCSK9 inhibition on lipid levels with ezetimibe and placebo. Odds ratios with 95% confidence intervals (OR [95% CIs]) were generated with random-effects models to compare outcomes. Our meta-analysis included 17 RCTs with 13 083 patients that were randomized to PCSK9 inhibitors (n = 8250), placebo (n = 3957), ezetimibe (n = 846), or PCSK9 inhibitors and ezetimibe (n = 30). The mean age was 59 ± 10, 52% were male, 34% had coronary artery disease, 51% had hypertension, 19% had diabetes mellitus, baseline LDL of 122 ± 36 mg/dL, total cholesterol of 199 ± 39 mg/dL, and HDL of 51 ± 14 mg/dL. inhibitors significantly reduced LDL cholesterol by 57% relative to placebo (P < 0.001) and 36.1% relative to ezetimibe (P < 0.001). Proprotein convertase subtilisin-kexin type 9 serine protease inhibitors reduced the incidence of all-cause mortality [OR 0.43 (95% CI 0.22-0.82), P = 0.01] but was associated with an increased incidence of neurocognitive adverse events [OR 2.34 (95% CI 1.11-4.93), I(2) = 4%, P = 0.02] when compared with placebo., Conclusion: Proprotein convertase subtilisin-kexin type 9 serine protease inhibition significantly improved lipid profiles and reduced the incidence of all-cause mortality compared with placebo but had a higher rate of neurocognitive adverse events. Thus, PCSK9 inhibitor therapy may serve as an alternative for patients with statin intolerance and for those who do not respond to other lipid reduction therapy., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Competing Interests: M.J.C. has received research funding from CSL, Kowa, MSD, Pfizer and Randox Laboratories, and honoraria for participation in Speakers Bureaux and Advisory Boards of Amgen, AstraZeneca, Kowa, Merck, Pfizer, Sanofi-Regeneron, and Unilever. U.L. has received lecture/advisory board honoraria or research funding from Roche, Sanofi, Amgen, MSD, Pfizer, Servier, Menarini, Astra, St Jude, Orbus&Neich, and Terumo. S.B. reports no disclosures. S.B. has received research funding from Abbott, Abbott Diagnostics, Bayer, Boehringer Ingelheim, SIEMENS and Thermo Fisher. He received honoraria for lectures from Abbott, Abbott Diagnostics, Astra Zeneca, Bayer, Boehringer Ingelheim, Medtronic, Pfizer, Roche, SIEMENS Diagnostics, SIEMENS, Thermo Fisher and as member of Advisory Boards and for consulting for Boehringer Ingelheim, Bayer, Novartis, Roche and Thermo Fisher.

Aims: Proprotein convertase subtilisin kexin 9 (PCSK9) is an emerging target for the treatment of hypercholesterolaemia, but the clinical utility of PCSK9 levels to guide treatment is unknown. We aimed to prospectively assess the prognostic value of plasma PCSK9 levels in patients with acute coronary syndromes (ACS)., Methods and Results: Plasma PCSK9 levels were measured in 2030 ACS patients undergoing coronary angiography in a Swiss prospective cohort. At 1 year, the association between PCSK9 tertiles and all-cause death was assessed adjusting for the Global Registry of Acute Coronary Events (GRACE) variables, as well as the achievement of LDL cholesterol targets of <1.8 mmol/L. Patients with higher PCSK9 levels at angiography were more likely to have clinical familial hypercholesterolaemia (rate ratio, RR 1.21, 95% confidence interval, CI 1.09-1.53), be treated with lipid-lowering therapy (RR 1.46, 95% CI 1.30-1.63), present with longer time interval of chest pain (RR 1.29, 95% CI 1.09-1.53) and higher C-reactive protein levels (RR 1.22, 95% CI 1.16-1.30). PCSK9 increased 12-24 h after ACS (374 ± 149 vs. 323 ± 134 ng/mL, P < 0.001). At 1 year follow-up, HRs for upper vs. lower PCSK9-level tertiles were 1.13 (95% CI 0.69-1.85) for all-cause death and remained similar after adjustment for the GRACE score. Patients with higher PCSK9 levels were less likely to reach the recommended LDL cholesterol targets (RR 0.81, 95% CI 0.66-0.99)., Conclusion: In ACS patients, high initial PCSK9 plasma levels were associated with inflammation in the acute phase and hypercholesterolaemia, but did not predict mortality at 1 year., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Aims: We aimed to assess the prevalence and management of clinical familial hypercholesterolaemia (FH) among patients with acute coronary syndrome (ACS)., Methods and Results: We studied 4778 patients with ACS from a multi-centre cohort study in Switzerland. Based on personal and familial history of premature cardiovascular disease and LDL-cholesterol levels, two validated algorithms for diagnosis of clinical FH were used: the Dutch Lipid Clinic Network algorithm to assess possible (score 3-5 points) or probable/definite FH (>5 points), and the Simon Broome Register algorithm to assess possible FH. At the time of hospitalization for ACS, 1.6% had probable/definite FH [95% confidence interval (CI) 1.3-2.0%, n = 78] and 17.8% possible FH (95% CI 16.8-18.9%, n = 852), respectively, according to the Dutch Lipid Clinic algorithm. The Simon Broome algorithm identified 5.4% (95% CI 4.8-6.1%, n = 259) patients with possible FH. Among 1451 young patients with premature ACS, the Dutch Lipid Clinic algorithm identified 70 (4.8%, 95% CI 3.8-6.1%) patients with probable/definite FH, and 684 (47.1%, 95% CI 44.6-49.7%) patients had possible FH. Excluding patients with secondary causes of dyslipidaemia such as alcohol consumption, acute renal failure, or hyperglycaemia did not change prevalence. One year after ACS, among 69 survivors with probable/definite FH and available follow-up information, 64.7% were using high-dose statins, 69.0% had decreased LDL-cholesterol from at least 50, and 4.6% had LDL-cholesterol ≤1.8 mmol/L., Conclusion: A phenotypic diagnosis of possible FH is common in patients hospitalized with ACS, particularly among those with premature ACS. Optimizing long-term lipid treatment of patients with FH after ACS is required., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Reduction in low-density lipoprotein cholesterol (LDL-C), mainly with statins, has decreased the risk of cardiovascular events over the last few decades. However, there are several patient populations that warrant further decrease in LDL-C by additional cholesterol-lowering therapy other than statins. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a new class of drugs that have been shown to further decrease LDL-C by 50-70% when administered as a monotherapy or on a background therapy with statins. Proprotein convertase subtilisin/kexin type 9 inhibitors are also an excellent example of drug development in which discovery of gene mutations and its clinical effects have rapidly progressed into successful preclinical and clinical studies with multiple Phases 1-3 clinical trials completed or ongoing to date. This review summarizes the rapid evolution of the drug from genetic discovery to identification of targets for the drugs, to animal and human testing, and to large clinical outcomes trials, followed by discussion on foreseeable challenges of PCSK9 inhibitors., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Aim: Patients with resistant hypertension are at high risk for adverse cardiovascular events. Efforts have been focused on lowering the surrogate endpoint of blood pressure (BP) with scant focus on reduction of hard cardiovascular endpoints. However, whether or not intensive lipid lowering is beneficial for reducing the risk of cardiovascular events in this high-risk cohort is not known., Methods and Results: We evaluated 10 001 patients with coronary artery disease and a low-density lipoprotein cholesterol level <130 mg/dL, randomized to atorvastatin 80 vs. 10 mg, enrolled in the Treating to New Targets trial. Treatment-resistant hypertension (TRH) was defined as BP ≥140 mmHg despite being on three antihypertensive agents or <140 mmHg on four or more agents. Subjects were followed up for a median duration of 4.9 years. The primary outcome was major cardiovascular events (composite of non-fatal myocardial infarction (MI), fatal coronary heart disease (CHD), resuscitated cardiac arrest, and stroke). Among the 10 001 patients in the trial, 1112 (11.1%) patients had TRH. Atorvastatin 80 mg, in patients with TRH, was associated with a significant reduction in the risk of the primary outcome (HR = 0.70; 95% CI 0.52-0.93; P = 0.01), driven largely by a significant reduction in CHD deaths (HR = 0.55; 95% CI 0.32-0.97; P = 0.04). In addition, atorvastatin 80 mg was associated with a reduction in major coronary events (HR = 0.67; 95% CI 0.49-0.93; P = 0.02), and any cardiovascular or coronary event and with a trend (P = 0.05) towards reduction in all-cause mortality (HR = 0.68; 95% CI 0.46-1.01) when compared with atorvastatin 10 mg. The results were similar when analysed for the two separate components of the TRH cohort., Conclusion: In subjects with TRH, intensive lipid lowering with atorvastatin 80 mg is associated with a significant reduction in cardiovascular events., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2013. For permissions please email: journals.permissions@oup.com.)

Aims: Statins can inhibit the progression of coronary atherosclerosis. We aimed to characterize clinical factors that associate with differing measures of coronary atheroma volume following potent statin therapy., Methods and Results: SATURN employed serial intravascular ultrasound (IVUS) to monitor changes in measures of coronary atheroma burden [total atheroma volume (TAV) and per cent atheroma volume (PAV)] in 1039 patients with coronary artery disease, treated with rosuvastatin (40 mg) or atorvastatin (80 mg) daily for 24 months. Rosuvastatin-treated patients demonstrated greater reductions in low-density lipoprotein cholesterol (LDL-C, 47 vs. 40%, P < 0.001) and greater increases in high-density lipoprotein cholesterol (HDL-C, 13 vs. 10%, P = 0.02). These alterations in the lipid profile associated with greater TAV (-6.4 vs. -4.4 mm(3), P = 0.01), but not PAV (-1.22 vs. -0.99%, P = 0.17) regression. Greater TAV reductions with rosuvastatin vs. atorvastatin occurred in patients with diabetes (P = 0.01, treatment by diabetic status interaction P-value 0.05). Greater PAV reductions with rosuvastatin were evident in females (P = 0.01, treatment by sex interaction P-value 0.03) and in those with greater than or equal to median baseline LDL-C (P = 0.02, treatment by LDL-C group interaction P-value 0.03) or HDL-C levels (P = 0.02, treatment by HDL-C group interaction P-value 0.04). On multivariable analysis assessing change in TAV and PAV, both higher baseline TAV and PAV independently associated with TAV and PAV regression, respectively (standardized estimates: TAV -0.25, P < 0.001; PAV -0.23, P < 0.001)., Conclusion: Higher-risk patients, particularly those with greater baseline coronary atheroma volume, are more likely to experience less disease progression with potent statin therapy.

Dyslipidaemias play a key role in determining cardiovascular risk; the discovery of statins has contributed a very effective approach. However, many patients do not achieve, at the maximal tolerated dose, the recommended goals for low-density lipoprotein-cholesterol (LDL-C), non-high-density lipoprotein-cholesterol, and apolipoprotein B (apoB). Available agents combined with statins can provide additional LDL-C reduction, and agents in development will increase therapeutic options impacting also other atherogenic lipoprotein classes. In fact, genetic insights into mechanisms underlying regulation of LDL-C levels has expanded potential targets of drug therapy and led to the development of novel agents. Among them are modulators of apoB containing lipoproteins production and proprotein convertase subtilisin/kexin type-9 inhibitors. Alternative targets such as lipoprotein(a) also require attention; however, until we have a better understanding of these issues, further LDL-C lowering in high and very high-risk patients will represent the most sound clinical approach.

Aims: Statins reduce LDL cholesterol (LDL-C) and the risk of vascular events, but it remains uncertain whether there is clinically relevant genetic variation in their efficacy. This study of 18 705 individuals aims to identify genetic variants related to the lipid response to simvastatin and assess their impact on vascular risk response., Methods and Results: A genome-wide study of the LDL-C and apolipoprotein B (ApoB) response to 40 mg simvastatin daily was performed in 3895 participants in the Heart Protection Study, and the nine strongest associations were tested in 14 810 additional participants. Selected candidate genes were also tested in up to 18 705 individuals. There was 90% power to detect differences of 2.5% in LDL-C response (e.g. 42.5 vs. 40% reduction) in the genome-wide study and of 1% in the candidate gene study. None of the associations from the genome-wide study was replicated, and nor were significant associations found for 26 of 36 candidates tested. Novel lipid response associations with variants in LPA, CELSR2/PSRC1/SORT1, and ABCC2 were found, as well as confirmatory evidence for published associations in LPA, APOE, and SLCO1B1. The largest and most significant effects were with LPA and APOE, but were only 2-3% per allele. Reductions in the risk of major vascular events during 5 years of statin therapy among 18 705 high-risk patients did not differ significantly across genotypes associated with the lipid response., Conclusions: Common genetic variants do not appear to alter the lipid response to statin therapy by more than a few per cent, and there were similar large reductions in vascular risk with simvastatin irrespective of genotypes associated with the lipid response to simvastatin. Consequently, their value for informing clinical decisions related to maximizing statin efficacy appears to be limited.

Familial hypercholesterolaemia (FH) is an autosomal dominant genetic disorder, associated with elevated levels of low-density lipoprotein-cholesterol (LDL-C), which can lead to premature cardiovascular disease. Early diagnosis of FH is important to prevent morbidity and mortality. Familial hypercholesterolaemia is usually diagnosed using clinical characteristics, such as family history, and cholesterol levels; however, genetic testing may provide a definite diagnosis of FH by detecting a pathological mutation. Current guidelines highlight the importance of reducing LDL-C levels in patients with FH. Statins are the current standard treatment for the majority of these patients, and have been shown to be effective in reducing the incidence of cardiovascular heart disease in patients with FH. Nevertheless, many FH patients do not achieve their target LDL-C levels; as such, new treatment options are required to decrease LDL-C levels beyond those currently achieved. There are currently several new classes of pharmacotherapy under investigation to control LDL-C levels. These include agents which modify LDL-C production, such as inhibitors of apolipoprotein B, or those which affect LDL-C catabolism, such as inhibition of pro-protein convertase subtilisin/kexin 9, a protein which is responsible for the degradation of the LDL receptor. Therapies which raise high-density lipoprotein cholesterol are also being evaluated. In this article, we consider the diagnosis of FH and the goals of therapy and review the current and potential future treatment options for patients with FH.

Aims: To assess the long-term efficacy, safety and tolerability of pitavastatin (2 and 4 mg) in elderly patients (≥ 65 years of age) with primary hypercholesterolaemia or combined (mixed) dyslipidaemia., Design: Patients (n = 545) who had completed a 12-week double-blind comparative study (core study) of pitavastatin and pravastatin entered a 60-week, open-label, multicentre extension study of pitavastatin. The initial daily dose was 2 mg, increasing to 4 mg after 8 weeks if necessary to achieve treatment targets. The proportion of patients attaining European Atherosclerosis Society (EAS) and National Cholesterol Education Program Adult Treatment Plan III (NCEP ATP III) targets for low-density lipoprotein cholesterol (LDL-C) was determined., Results: Of the patients enrolled, 539 received at least one dose of pitavastatin (safety population: men, 45.5%; Caucasian, 99.1%; mean age, 70.3 years; range, 65-89 years). Only 17% of patients required up-titration to pitavastatin 4 mg. After 60 weeks, NCEP ATP III and EAS targets were attained by 93.8% and 89.0% of patients, respectively. Plasma LDL-C declined by 43.4% and high-density lipoprotein cholesterol increased by 9.6% versus core-study baseline values. Pitavastatin was well tolerated: the most common treatment-emergent adverse events were nasopharyngitis, mild/moderate myalgia and hypertension. There were no cases of severe myalgia, myopathy, myositis or rhabdomyolysis, and no significant findings on urinalysis, vital signs or 12-lead ECG., Conclusion: Long-term pitavastatin treatment (2 and 4 mg) is effective in lowering LDL-C levels and has a good safety and tolerability profile in elderly patients.

Aim: To compare the safety and efficacy of once-daily pitavastatin (1, 2, and 4 mg) and pravastatin (10, 20, and 40 mg) in elderly patients (≥ 65 years of age) with primary hypercholesterolaemia or combined (mixed) dyslipidaemia., Design: After a 6-8-week washout/dietary period, patients were randomized to six treatment groups (1, 2, or 4 mg pitavastatin vs. 10, 20, or 40 mg pravastatin) in a 12-week multicentre double-blind study. Patients (n = 942; men, 44.3%; Caucasian, 99.3%; mean age, 70 years; age range, 65-89 years) in all groups were well matched for duration of disease and diagnosis., Results: Mean decreases in low-density lipoprotein cholesterol over 12 weeks were 31.4-44.3% with pitavastatin 1-4 mg and 22.4-34.0% with pravastatin 10-40 mg (p < 0.001 for all dose comparisons). Compared with pravastatin, pitavastatin provided greater decreases in total cholesterol and apolipoprotein B in all dose groups (p < 0.001) and triglycerides in the low-dose (p = 0.001) and higher-dose (p = 0.016) groups, and greater increases in high-density lipoprotein cholesterol in the intermediate-dose (p = 0.013) and higher-dose (p = 0.023) groups. The proportions of patients achieving the European Atherosclerosis Society target with pitavastatin and pravastatin, respectively, were: low doses, 59.9 and 37.9%; intermediate doses, 79.5 and 51.0%; higher doses, 88.1 and 65.7% (p < 0.001 for all comparisons). Both statins were well tolerated, with no reports of myopathy or rhabdomyolysis., Conclusion: Pitavastatin provides superior efficacy and comparable tolerability to pravastatin in elderly patients.

Aims: Ezetimibe reduces low-density lipoprotein cholesterol (LDL-C) but has complex actions on cholesterol transport and metabolism, and thus, LDL-C reduction may not solely define its overall effects. We explored the relationship between treatment effects and cumulative exposure to ezetimibe, with its effects on carotid intima-media thickness (CIMT) in ARBITER 6-HALTS., Methods and Results: This analysis includes the 159 patients randomized to ezetimibe within ARBITER 6-HALTS that completed the final imaging endpoint assessment. Eligibility criteria for ARBITER 6-HALTS included known coronary artery disease (CAD) or high risk for coronary heart disease, and treatment with a statin with LDL-C <100 mg/dL and high-density lipoprotein cholesterol <50 or 55 mg/dL for men and women, respectively. The mean CIMT was measured in the far wall of the distal common carotid artery. We analysed the univariate and multivariate relationships of the change in CIMT with baseline characteristics, on-treatment effects, and cumulative ezetimibe exposure (treatment duration × dose × adherence). Ezetimibe reduced LDL-C from 84 ± 23 to 66 ± 20 mg/dL. No net effect on CIMT was observed (baseline CIMT 0.898 ± 0.151 mm; net change -0.002 mm; P = 0.52). There was an inverse relationship between LDL-C and change in CIMT such that greater reductions in LDL-C were associated with greater CIMT progression (r = -0.266; P < 0.001). Change in CIMT also had univariate associations with baseline LDL-C, triglycerides (TG), high-sensitive C-reactive protein, and systolic blood pressure and was directly associated with the change in TG and inversely associated with the change in high-sensitive C-reactive protein. Multivariable models controlling for change in LDL-C, cumulative ezetimibe exposure, and baseline and on-treatment variables showed that both increased LDL-C reduction (P = 0.005) and cumulative drug exposure (P = 0.02) were associated with ezetimibe-associated CIMT progression., Conclusion: Among CAD and high-risk patients on statin therapy in the ARBITER-6 trial, ezetimibe leads to paradoxical progression of CIMT in association with both greater LDL-C reduction and cumulative drug exposure. These findings may suggest the presence of off-target actions of ezetimibe., Trial Registration: ClinicalTrials.gov number: NCT00397657.

Objectives: To determine statin usage pattern and evaluate whether new generation statins are actually needed by the patients receiving them., Methods: This retrospective cohort included patients receiving first-time statins at a tertiary care hospital in Thailand. Using electronic medical records from 2005, its indication was determined based on history of coronary heart disease (CHD) and CHD-risk equivalents. The lipid profiles tested within 30 days prior to the first date of statins prescription were analysed. Each patient was assessed as to whether statin was needed based on low-density lipoprotein cholesterol (LDL-C) reduction capacity and lipid goals., Results: A total of 2479 first-time statin users was included. Ninety percent of the users received simvastatin, while 8% and 2% received atorvastatin and pravastatin respectively. More than half (58.0%) used statins for primary prevention, although all usage of atorvastatin was considered not needed. Considering the use of statin for secondary prevention to achieve the LDL-C goal of <130mg/dl (3.37mmol/l), more than 80% of atorvastatin users could be switched to simvastatin. Only 8% of simvastatin usage would not be able to achieve this target. When the LDL-C goal was <70mg/dl (1.81mmol/l), 40.2% simvastatin users was considered appropriate, while 58.6% needed atorvastatin to be prescribed., Conclusion: A substantial proportion of patients did not need statins therapy, particularly for primary prevention. In addition, atorvastatin use is mostly not needed except in patients requiring statins for secondary prevention to achieve the LDL-C goal of <70mg/dl (1.81mmol/l). The findings should prompt hospital policy makers to develop measures to ensure the proper use of statins in their clinical settings., (© 2011 The Authors. IJPP © 2011 Royal Pharmaceutical Society.)

Purpose: Lipid and transaminase levels after conversion from immediate-release niacin to extended-release niacin were evaluated., Methods: All patients who had their medications converted from Niaspan to Slo-Niacin between March 2008 and January 2009 were considered for evaluation. Subjects who took =2000 mg of Niaspan were automatically converted to Slo-Niacin in a 1:1 dosing ratio conversion. Mean aspartate transaminase (AST) and alanine transaminase (ALT) levels and lipid values (low-density-lipoprotein [LDL] cholesterol, high-density-lipoprotein [HDL] cholesterol, and triglyceride levels) during Niaspan therapy were compared with the means of these values obtained after at least 90 days of Slo-Niacin therapy. Data were analyzed using the Wilcoxon rank-order test and frequency distributions., Results: Of the 1172 patients who were identified as having had their Niaspan switched to Slo-Niacin after formulary conversion, 142 met the inclusion criteria for this study. The majority of the patients had a decrease or no change in AST (72.5%) and ALT (69%) levels after at least 90 days of Slo-Niacin therapy. None of the patients had transaminase levels greater than three times the upper limit of normal during Slo-Niacin therapy. Differences in AST, ALT, triglyceride, and LDL cholesterol levels were not statistically significant between Niaspan and Slo-Niacin. On the other hand, patients' mean HDL cholesterol level was significantly greater with Slo-Niacin therapy than with Niaspan (42 mg/dL versus 40 mg/dL, respectively; p < 0.05)., Conclusion: Formulary conversion from Niaspan to Slo-Niacin resulted in a small but significant increase in HDL cholesterol concentration and no significant change in ALT or AST level.

Purpose: The efficacy and safety of phytosterols for the management of dyslipidemia are reviewed., Summary: Phytosterols have been evaluated in over 40 clinical trials. The incorporation of 2 g of phytosterols daily into margarine, mayonnaise, orange juice, olive oil, low-fat milk, yogurt, and tablets is associated with significant reductions in low-density-lipoprotein (LDL) cholesterol from baseline over 1-12 months in adults with normal or high cholesterol, in children, and in patients with type 2 diabetes mellitus. Phytosterol dosages of 1.6-3 g daily have been shown to reduce LDL cholesterol by 4.1-15% versus placebo within the first month of therapy. One meta-analysis found mean reductions of 10-11%, but results vary. Several placebo-controlled trials found that the addition of phytosterols to statin therapy was associated with reductions of 7-20% in LDL cholesterol for up to 1.5 years. Overall, phytosterols are useful for reducing LDL cholesterol in patients who cannot reach their treatment goal by diet alone or who are taking maximum tolerated doses of statins. These products offer an alternative to statins in patients who cannot take statins or whose statin dosage is restricted because of potential drug interactions or concomitant diseases. Commonly reported adverse effects are primarily gastrointestinal in nature., Conclusion: Phytosterol therapy produces an average 10-11% reduction in LDL cholesterol concentration, but it is unknown whether this effect persists beyond two years. Phytosterol products are well tolerated and have few drug interactions, but their long-term safety has not been established. Current evidence is sufficient to recommend phytosterols for lowering LDL cholesterol in adults.

Context: Oral contraceptives with estrogen plus progestin are likely to influence apolipoprotein B (apoB)-containing lipoprotein metabolism by changing the expression of different enzymes or receptors that play a major role in this metabolism. However, the precise changes in apoB kinetic parameters induced by oral contraceptives that are now currently used are unknown., Objectives: We studied the impact of Moneva, containing 30 microg ethinylestradiol and 75 microg gestodene, on the apoB production rate and fractional catabolic rate of very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL)., Design: Using a 16-h [(13)C]leucine infusion, we performed an apoB kinetic study in nine normolipidemic women before and 3 months after beginning Moneva., Results: On Moneva, serum triglycerides increased moderately (+12%, P = 0.04) in the fed state, whereas serum LDL remained unchanged. LDL particles were richer in triglycerides in women on Moneva (7.5 +/- 1.5 vs. 4.3 +/- 1.0% of total LDL mass, P < 0.01). The apoB production rate of VLDL, IDL, and LDL increased by 49 (P = 0.04), 55 (P = 0.05), and 51% (P = 0.01), respectively. The fractional catabolic rate of apoB in LDL increased by 36% (P = 0.04). Consequently, the serum LDL apoB pool size remained unchanged (26.49 +/- 6.98 vs. 23.96 +/- 5.37 mg/kg)., Conclusion: Oral contraception with ethinylestradiol plus gestodene induces an increase in the production rate of apoB-containing lipoproteins all along the VLDL-->IDL-->LDL cascade. The increased production rate of apoB in LDL is counterbalanced by a higher fractional catabolic rate of apoB in LDL, thus precluding an increase in the concentration of atherogenic LDL particles.

In the present study, the molecular mechanisms by which CM108, a flavone derivative, improves lipid profiles were investigated further. Hyperlipidaemia was induced by oral administration of high cholesterol and fat. After 4 weeks of treatment, the lipid levels in the serum, liver and faeces were measured and the liver genes involved in lipid metabolism were analysed to explore the molecular mechanisms of lowering lipids. CM108 modulated lipid profiles, including elevating the level of high-density lipoprotein cholesterol (HDL-C; 40%) and reducing serum levels of triglyceride (10%), total cholesterol (10%) and low-density lipoprotein cholesterol (26%). Levels of triglyceride and total cholesterol in the liver were reduced by 18% and 24%, respectively. Increased HDL-C level was attributed to the synergic effects of CM108 in increasing levels of ATP-binding cassette transporter (ABC)A1, apolipoprotein AI and apolipoprotein AII in the liver. Intriguingly, CM108 induced genes, including fatty acid transport protein, acyl-CoA synthetase and lipoprotein lipase that are important for more efficient fatty acid beta-oxidation, thereby reducing serum and liver triglyceride levels. In addition, induction of ABCG5, ABCG8 and cholesterol 7alpha-hydroxylase contributed to cholesterol metabolism, leading to decreases in serum and liver cholesterol levels. Thus, the genes involved in lipid metabolism were systemically modulated by CM108, which contributed to the improvement of lipid profiles in hyperlipidaemic rats.

Aims: Statins inhibit oxidative stress, but the interplay between cholesterol lowering and antioxidant vitamins is still unclear. Aims of the study were to assess if statins inhibit oxidative stress independently from cholesterol lowering, to assess the behaviour of vitamin E simultaneously with the changes of oxidative stress, to determine in vitro if atorvastatin was able to directly influence platelet-mediated LDL oxidation and vitamin E consumption., Methods and Results: In 30 hypercholesterolaemic patients (HC) and 20 healthy subjects (HS), urinary isoprostanes and plasma vitamin E were determined. The HC were randomized to diet or diet plus atorvastatin 10 mg/day. Compared with HS, HC had higher isoprostanes and lower vitamin E levels. The statin-allocated group showed a reduction of isoprostanes after only 3 days (-18.8%, P < 0.01); after 30 days, a stronger reduction of isoprostanes was noted (-37.1%, P < 0.01) whereas an increase of vitamin E (+42%, P < 0.01) and a reduction of cholesterol (-24.9%, P < 0.01) were observed. The diet-allocated group showed a weak decrease of cholesterol after 30 days. In vitro study showed that atorvastatin dose-dependently inhibited platelet-mediated LDL oxidation and isoprostane formation with a mechanism involving NADPH-oxidase., Conclusion: The study provides the first evidence that atorvastatin exerts an early antioxidant effect that could contribute to enhancing circulating vitamin E.

The American cranberry (Vaccinium macrocarpon) is one of the three commercially important fruits native to North America. Cranberries are a particularly rich source of phenolic phytochemicals, including phenolic acids (benzoic, hydroxycinnamic, and ellagic acids) and flavonoids (anthocyanins, flavonols, and flavan-3-ols). A growing body of evidence suggests that polyphenols, including those found in cranberries, may contribute to reducing the risk of cardiovascular disease (CVD) by increasing the resistance of LDL to oxidation, inhibiting platelet aggregation, reducing blood pressure, and via other anti-thrombotic and anti-inflammatory mechanisms. Research regarding the bioactivity of cranberries and their constituents on risk factors for CVD is reviewed.

Many antiretroviral therapies, including efavirenz, are associated with increased serum concentrations of low-density lipoprotein cholesterol. In a small 52-week randomized study, we found that switching from efavirenz to nevirapine was associated with significantly decreased low-density lipoprotein cholesterol levels, compared with continuation of efavirenz therapy (P<.04). A switch to nevirapine was associated with no severe adverse events.

Purpose: The effectiveness of rosuvastatin versus atorvastatin in reducing lipid levels and achieving low-density-lipoprotein (LDL) cholesterol goals in patients treated in a usual care setting was studied., Methods: Electronic medical and pharmacy administrative claims from a western U.S. health plan with approximately 8 million covered members were extracted and used in this retrospective, longitudinal cohort study. Patients age 18 years or older who were newly initiated on rosuvastatin or atorvastatin between August 1, 2003, and June 30, 2004, were included. Propensity-score matching on baseline characteristics was used to minimize selection bias between groups. Administrative claims and medical records were used to assign patients a cardiovascular risk status and corresponding LDL cholesterol goal using guidelines from the National Cholesterol Education Program (NCEP). Changes in lipid levels and attainment rates of goal LDL cholesterol levels were estimated after accounting for baseline covariates using regression techniques., Results: A total of 453 patients met the study criteria. The mean dose of rosuvastatin was 11 mg compared with 15 mg for atorvastatin. After adjusting for baseline differences between groups, patients receiving rosuvastatin had significantly greater mean percent reductions in LDL cholesterol, total cholesterol, and non-high-density-lipoprotein (non-HDL) cholesterol than did patients receiving atorvastatin (p < 0.001 for all comparisons). No significant differences were found in HDL cholesterol and triglyceride levels between groups. Attainment rates for NCEP LDL cholesterol goals were significantly higher in patients receiving rosuvastatin., Conclusion: Patients treated in a usual care setting with rosuvastatin had significantly greater reductions in LDL cholesterol, non-HDL cholesterol, and total cholesterol levels compared with those receiving atorvastatin. Patients receiving rosuvastatin were more likely to attain NCEP LDL cholesterol goals compared with patients treated with atorvastatin.

Several studies have shown that increased levels of low-density lipoprotein (LDL) cholesterol predict cardiovascular events. The Adult Treatment Panel II (ATP II) introduced the principle of therapeutic lifestyle changes, including plant sterols/stanols for the management of LDL cholesterol. Plant sterols and stanols in fat matrices effectively lower LDL cholesterol levels in hypercholesterolemic, diabetic, and healthy human volunteers. Recent studies also show that sterols (2 g/d) lower LDL cholesterol even when incorporated in nonfat matrices. In addition, they may reduce biomarkers of oxidative stress and inflammation. Plant sterols and stanols exert their hypocholesterolemic effects possibly by interfering with the uptake of both dietary and biliary cholesterol from the intestinal tract. Present evidence is accumulating to promote their use for lowering LDL cholesterol levels, as a first line of therapy (as well as adjunctive therapy) in patients on statin therapy.

Background: During haemodialysis (HD), polymorphonuclear cells (PMNs) and platelets are activated and release various granule products, including myeloperoxidase (MPO) and platelet factor 4 (PF4). MPO triggers the generation of reactive oxygen species, leading to irreversible protein, carbohydrate and lipid modification. PF4 probably also contributes to oxidative stress. As previously shown, HD-induced PMN degranulation is almost completely abolished during citrate anticoagulation, most probably due to its calcium chelation ability., Methods: In the present study, apart from HD-induced PMN and platelet degranulation, oxidative stress was analysed during three modes of anticoagulation. Heparin, dalteparin and citrate (HDhep, HDdal and HDcit) were compared in a randomized, crossover fashion in eight chronic HD patients. Multiple blood samples were taken during the third HD session of each modality, from both the afferent and efferent line. Besides the degranulation markers MPO and PF4, various markers of oxidative stress were measured, including oxidized low-density lipoprotein (ox-LDL), malondialdehyde (MDA) and carboxymethyllysine (CML)., Results: During HDhep and HDdal, marked degranulation was observed shortly after the start of HD. In contrast, during HDcit, PF4 and MPO levels remained unaltered, suggesting no release at all. After 1 week of HDcit, ox-LDL levels were markedly reduced [median 26% (3-65%), P=0.01], if compared with HDhep and HDdal. As regards MDA and CML, no differences were found., Conclusions: This study shows first, that HD-induced PMN and platelet degranulation are early, most probably calcium-dependent processes and, secondly, that the formation of ox-LDL is clearly dependent on the type of anticoagulant applied.

The feasibility of using solid dosage forms containing stanol lecithin to lower human LDL-cholesterol was investigated. The particle size distribution of a coarse aqueous dispersion of a stanol lecithin mixture was determined at various weight ratios of the components. At a stanol-to-lecithin weight ratio of 1.00-1.50, dispersions could be spray dried and the solid reconstituted with water to produce a particle size distribution that was similar to that of the aqueous dispersion from which it was derived. Two solid dosage forms containing this spray-dried stanol lecithin preparation had different disintegration times--tablets less than 10 min and capsules greater than 45 min. Each delivery system was then tested for LDL-cholesterol reduction activity in a placebo-controlled, double-blind clinical trial containing a total of 52 subjects. After a six-week treatment period, the group that received rapidly disintegrating stanol lecithin tablets (1.26 g stanols daily) experienced a decrease in both LDL-cholesterol and the ratio of LDL-cholesterol to HDL-cholesterol by 10.4% (P = 0.01) and 11.5% (P = 0.03), respectively, relative to placebo. On the other hand, with slowly disintegrating capsules (1.01 g daily) there was no statistically significant difference in any lipid parameter between the active group and placebo group. Taken together, these studies demonstrate that for maximum LDL-cholesterol reduction activity the stanol lecithin formulation must be delivered in a rapidly dispersible form to reach the site of cholesterol absorption.

Background: Statins have been reported to have direct vascular effects independent of cholesterol reduction. To assess the antihypertensive effect of statins, a crossover study was designed to compare the depressor effect of pravastatin and probucol in hypertensive patients undergoing long-term treatment with antihypertensive drugs., Methods: The subjects enrolled in this study were 52 hypertensive patients (22 men and 30 women, mean age 62.8 +/- 9.3 years) who were treated with the same antihypertensive drugs for more than 1 year and had serum cholesterol levels of more than 5.69 mmol/L. In 26 subjects, pravastatin at a dose of 10 mg/d was given first for 6 months followed by treatment with probucol at a dose of 500 mg/d, and vice versa in the remaining 26 subjects. Serum lipids, apolipoproteins, glucose, and insulin were measured on the final day of the control period, and pravastatin and probucol treatments. The homeostatic model assessment insulin resistance index (HOMA-IR) was used to assess insulin resistance., Results: The blood pressure decreased after pravastatin treatment (141.2 +/- 4.7/81.3 +/- 4.9 to 136.5 +/- 5.3/80.6 +/- 5.1 mm Hg, P <.001/.499), but did not decrease after probucol treatment (141.2 +/- 4.7/81.3 +/- 4.9 to 141.4 +/- 4.9/80.8 +/- 4.9 mm Hg, P =.832/.634). Total cholesterol decreased significantly after pravastatin (6.69 +/- 0.69 to 5.23 +/- 0.77 mmol/L, P <.001) and probucol treatment (6.69 +/- 0.69 to 5.53 +/- 0.64 mmol/L, P <.001). The HOMA-IR was decreased by probucol (1.92 +/- 0.78 to 1.57 +/- 0.59, P =.029), whereas pravastatin had no effect on HOMA-IR., Conclusions: It can be concluded that the depressor effect of pravastatin may have an additional benefit in the treatment of hypertensive patients with hyperlipidemia without any adverse effect on insulin sensitivity.

Purpose: The frequency, onset, mechanisms, and causes of dyslipidemia after renal transplantation are reviewed in the context of the adverse impact of lipid alterations, recent guidelines, and the available treatment options., Summary: At least 60% of adult renal transplant recipients develop dyslipidemia, which occurs within one month of the initiation of immunosuppressive therapy and continues indefinitely unless treated. Cyclosporine, sirolimus, and prednisone are mainly implicated, and the lipid profile differs between individual agents. In recognition that lipid alterations in these patients are linked with development of ischemic heart disease, vascular mortality, and graft deterioration, the National Kidney Foundation has recently released guidelines suggesting a low-density-lipoprotein (LDL) cholesterol goal of < 100 mg/dL for these patients. Statins and diet therapy are recommended as first-line agents for achieving goal LDL cholesterol levels in this population. Recent evidence proved a reduction in adverse cardiovascular events when fluvastatin was utilized in one large-scale trial. Care should be taken with aggressive dosage adjustment because of the potential for a pharmacokinetic interaction with cyclosporine and a resultant increase in the risk of myopathy or rhabdomyolysis. Other options for improving the lipid profile include modifications in the immunosuppressive regimen, the addition of other lipid-modifying agents, and using alternative lipid-modifying agents., Conclusion: Statins and diet therapy should be used as first-line treatments in renal transplant recipients with dyslipidemia. Other strategies, including modification of the immunosuppressive regimen, and the addition of other lipid-modifying agents, have also yielded positive results.

Background: Serum paraoxonase 1 (PON1) is an oxidant-sensitive enzyme associated with high-density lipoprotein (HDL) that inhibits the atherogenic oxidation of low-density lipoprotein (LDL). In haemodialysis patients, production of reactive oxygen species, such as hypochlorous acid (HOCl) and hydrogen peroxide, is increased and serum PON1 arylesterase is abnormally low. We have examined the effect of HOCl and the uraemic milieu on serum PON1 arylesterase activity and the ability of HDL to inhibit LDL oxidation in vitro., Methods: Serum was incubated with HOCl, hydrogen peroxide and products of HOCl reaction with excess cysteine, lysine and taurine and then serum PON1 arylesterase and serum protein tryptophan fluorescence were measured. The ability of plasma HDL fractions isolated by a dextran-sulphate method, to protect LDL from mild oxidation in air, was determined by a fluorimetric method using oxidation of 2,7-dichlorofluorescein (DCFH)., Results: Incubation of healthy serum with HOCl in the range 6.5-32.9 mmol/l resulted in a linear decrease in serum PON1 arylesterase activity to 40% of that without HOCl and a parallel decrease in protein tryptophan fluorescence. The HOCl-induced decrease in serum PON1 activity was completely removed by reaction of HOCl with a 2.7-fold excess of alpha-amino acids but not taurine. In serum incubated for 1 week, the decrease in serum PON1 activity was significantly (P = 0.04) less while the increase in protein fluorescent advanced glycation end-products was significantly larger (P = 0.01) in haemodialysis patients compared with healthy subjects. The mean decrease in mild oxidation of LDL was not significantly different on addition of HDL-rich fractions from haemodialysis patients (100 +/- 6%, n = 7) and healthy subjects (95 +/- 6%, n = 7) or on addition of the HDL-rich fraction from plasma treated with 0.95 mmol/l HOCl (95%) and control HDL (96%). The fraction rich in HDL and other high molecular weight compounds from plasma that had been incubated with increasing HOCl concentrations up to 1.9 mmol/l significantly (P = 0.001) increased (471%) the oxidation of DCFH., Conclusions: These results suggest that high concentrations of HOCl that severely oxidize serum proteins and tryptophan residues in the active site of PON1 are required to decrease PON1 arylesterase activity in serum. In haemodialysis patients, overproduction of HOCl that leads to high concentrations of severely oxidized proteins and increased oxidants in plasma might also contribute to low serum PON1 arylesterase activity, but does not appear to impair the ability of an HDL molecule to protect LDL from mild oxidation.

Background: This study investigates the effect of amlodipine on arterial compliance (AC), and the effect of atorvastatin on AC when given in combination with amlodipine., Methods: Twenty-one consecutive hypertensive hyperlipidemic patients were included in this study. Patients were followed every month for 6 months (3 months of amlodipine therapy and 3 months of amlodipine and atorvastatin combination)., Results: During the 3 months of amlodipine monotherapy, large and small AC were improved by 26% and 38%, respectively, and the systemic vascular resistance was reduced by 10%. The addition of atorvastatin during the next 3 months improved small AC by an additional 42% and decreased the systemic vascular resistance by another 5%, but large AC and blood pressure did not change., Conclusions: Amlodipine improves large and small AC, and the beneficial effect of atorvastatin on small AC is additive to the effect achieved by amlodipine.

Background: This study aims to address the question, "Does equivalent blood pressure (BP) reduction by cilazapril alone or in combination with low dose of both cilazapril and hydrochlorothiazide have an equal effect on lowering oxidation of plasma LDL?", Methods: Fifteen patients with untreated arterial hypertension were enrolled. Patients received 5 mg/d cilazapril (C5) for 6 weeks and were treated with a combination of 2.5 mg/d cilazapril and 12.5 mg/d hydrochlorothiazide (C2.5,HCTz) for an additional 2 months to achieve the same BP reduction as in the initial period. Treatment with a combination of 5 mg/d cilazapril and 12.5 mg/d hydrochlorothiazide (C5,HCTz) was administered for an additional 6 weeks., Results: Treatment with C5 or in combination with C2.5,HCTz lowered systolic BP by the same magnitude (P <.05). Treatment with C5,HCTz decreased systolic BP an additional 7% and diastolic BP by 6% (P <.05). The LDL of 15 hypertensive patients demonstrated a 16.7% shorter lag time to initiation of peroxidation and 8.5% higher malonyldialdehyde levels at point of maximal peroxidation than LDL from 10 healthy controls (P <.05). Treatment with C5 decreased LDL tendency to peroxidation (lag time was prolonged by 43%, P <.05; malonyldialdehyde levels decreased by 8.3%). The combined treatment of C2.5,HCTz achieved the same BP reduction, but did not increase LDL resistance to peroxidation. Treatment with C5,HCTz achieved the same reduction in malonyldialdehyde levels in LDL than C5 therapy, but prolonged lag time by 17% (P <.05)., Conclusions: The decreased tendency of LDL to peroxidation in hypertensive patients treated by cilazapril is due to the inherent effect of cilazapril, and not to a reduction in BP.