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As the population ages, the demographic of adults aged 75 years and older in the U.S. is projected to grow to 45 million by 2050. Hypercholesterolemia is directly linked to atherosclerotic cardiovascular disease (ASCVD), which remains the leading cause of death in older adults. However, primary prevention of ASCVD through lipid-lowering agents remains unclear among older adults owing to limited involvement of older adults in current trials, lack of dedicated trials, and evidence primarily derived from secondary and retrospective analyses. Therefore, this article aims to (1) review key updates from the latest guidelines on treatment of hypercholesterolemia in older adults, (2) highlight limitations of the current ASCVD risk scores in the geriatric population, (3) present outcomes from key studies on the use of lipid-lowering agents and associated side effects, including a brief review of novel agents such as bempedoic acid, although very few adults over age 75 were included in these trial, and (4) finally, highlight upcoming dedicated trials of statins in older adults for the primary prevention of important geriatric outcomes as well as ASCVD. [ABSTRACT FROM AUTHOR]

Key content: Lipid and triglyceride levels increase in pregnancy and do not pose problems for most women. However, pregnancy‐specific factors and genetic aberrations, especially mutations, may result in supraphysiological hypercholesterolaemia (HC) and severe hypertriglyceridaemia (sHTG).HC and sHTG are associated with complications in pregnancy, including acute pancreatitis, hyperviscosity syndrome and pre‐eclampsia.Abnormally high levels of lipids and triglycerides also affect fetal growth and the onset of gestational diabetes.The clinical presentation and diagnosis of HC and sHTG are varied.Management options include lifestyle and dietary restriction/modification, omega‐3, bile‐acid sequestrants, fenofibrate, statins and plasmapheresis. Learning objectives: To understand the physiological changes that occur in lipids in pregnancy and how these are modulated.To appreciate the importance of severe HC and HTG in pregnancy, including their effects on maternal morbidity and mortality.To understand the various approaches to management and the importance of multidisciplinary management. Ethical issues: Should every woman be screened for HTG and HC during pregnancy?How safe are statins and other treatments for lipid disorders in pregnancy?Should women with very severe HTG be discouraged from getting pregnant? [ABSTRACT FROM AUTHOR]

The escalating global burden of cardiovascular diseases (CVDs) is worrisome. The editorial emphasizes the critical role of individualized cardiovascular risk management, addressing controversies in cholesterol management and recognizing ethnicity-specific risk factors particularly considering genetic variations in Asian populations. It also delves into, creating awareness of hypertension and prevalent CVD including Ischaemic heart disease (IHD) and Heart failure (HF), their prevalence, and shifts in current management to tackle them. World Heart Day 2023, themed "Use Heart, Know Heart", emphasizes the significance of knowing our heart and heart health for a healthy life. [ABSTRACT FROM AUTHOR]

Background/Aim: Lipid-lowering drugs have been suggested to affect neurocognitive function. This review aimed to give the latest evidence on the way these agents affect neurocognitive function based on clinical trials. Materials and Methods: A systematic search concerning original studies from 2015 to 2020 was performed through the databases PubMed, EMBASE and Cochrane, according to the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. The trials enrolled numerous patients and were conducted in different areas of the world. The terms used are cholesterol, lipid-lowering drugs, statins and cognitive function. Results: Eleven randomized trials met the inclusion criteria. The trials included patients suffering from cardiovascular conditions. In particular, patients with coronary heart disease, coronary heart disease risk equivalents and hypercholesterolemia were tested. The trials included evolocumab, alirocumab, statin, ezetimibe or placebo. Conclusion: Lipid-lowering drugs seem to have no significant effect on neurocognitive function, but further research specifically focused on this matter is needed. [ABSTRACT FROM AUTHOR]

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Background: The 2013 American College of Cardiology/American Heart Association guidelines for the treatment of blood cholesterol found little evidence to support the use of nonstatin lipid-modifying medications to reduce atherosclerotic cardiovascular disease (ASCVD) events. Since publication of these guidelines, multiple randomized controlled trials evaluating nonstatin lipid-modifying medications have been published.Methods: We performed a systematic review to assess the magnitude of benefit and/or harm from additional lipid-modifying therapies compared with statins alone in individuals with known ASCVD or at high risk of ASCVD. We included data from randomized controlled trials with a sample size of >1,000 patients and designed for follow-up >1 year. We performed a comprehensive literature search and identified 10 randomized controlled trials for intensive review, including trials evaluating ezetimibe, niacin, cholesterol-ester transfer protein inhibitors, and PCSK9 inhibitors. The prespecified primary outcome for this review was a composite of fatal cardiovascular events, nonfatal myocardial infarction, and nonfatal stroke.Results: The cardiovascular benefit of nonstatin lipid-modifying therapies varied significantly according to the class of medication. There was evidence for reduced ASCVD morbidity with ezetimibe and 2 PSCK9 inhibitors. Reduced ASCVD mortality rate was reported for 1 PCSK9 inhibitor. The use of ezetimibe/simvastatin versus simvastatin in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) reduced the primary outcome by 1.8% over 7 years (hazard ratio: 0.90; 95% CI: 0.84-0.96], 7-year number needed to treat: 56). The PSCK9 inhibitor evolocumab in the FOURIER study (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) decreased the primary outcome by 1.5% over 2.2 years (hazard ratio: 0.80; 95% CI: 0.73-0.88; 2.2=year number needed to treat: 67). In ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab), alirocumab reduced the primary outcome by 1.6% over 2.8 years (hazard ratio: 0.86; 95% CI: 0.79-0.93; 2.8-year number needed to treat: 63). For ezetimibe and the PSCK9 inhibitors, rates of musculoskeletal, neurocognitive, gastrointestinal, or other adverse event risks did not differ between the treatment and control groups. For patients at high risk of ASCVD already on background statin therapy, there was minimal evidence for improved ASCVD risk or adverse events with cholesterol-ester transfer protein inhibitors. There was no evidence of benefit for the addition of niacin to statin therapy. Direct comparisons of the results of the 10 randomized controlled trials were limited by significant differences in sample size, duration of follow-up, and reported primary outcomes.Conclusions: In a systematic review of the evidence for adding nonstatin lipid-modifying therapies to statins to reduce ASCVD risk, we found evidence of benefit for ezetimibe and PCSK9 inhibitors but not for niacin or cholesterol-ester transfer protein inhibitors. [ABSTRACT FROM AUTHOR]

Background: Considerable interest exists among health care payers and pharmaceutical manufacturers in designing outcomes-based agreements (OBAs) for medications for which evidence on real-world effectiveness is limited at product launch.Objectives: To build hypothetical OBA models in which both payer and manufacturer can benefit.Methods: Models were developed for a hypothetical hypercholesterolemia OBA, in which the OBA was assumed to increase market access for a newly marketed medication. Fixed inputs were drug and outcome event costs from the literature over a 1-year OBA period. Model estimates were developed using a range of inputs for medication effectiveness, medical cost offsets, and the treated population size. Positive or negative feedback to the manufacturer was incorporated on the basis of expectations of drug performance through changes in the reimbursement level. Model simulations demonstrated that parameters had the greatest impact on payer cost and manufacturer reimbursement.Results: Models suggested that changes in the size of the population treated and drug effectiveness had the largest influence on reimbursement and costs. Despite sharing risk for potential product underperformance, manufacturer reimbursement increased relative to having no OBA, if the OBA improved market access for the new product. Although reduction in medical costs did not fully offset the cost of the medication, the payer could still save on net costs per patient relative to having no OBA by tying reimbursement to drug effectiveness.Conclusions: Pharmaceutical manufacturers and health care payers have demonstrated interest in OBAs, and under a certain set of assumptions both may benefit. [ABSTRACT FROM AUTHOR]

Introduction: Significant advancements in the treatment of hypercholesterolemia have recently been achieved. However, a considerable level of residual cardiovascular risk still affects patients' outcomes. Atherogenic dyslipidemia is one of the major constituents of residual risk. Fibrates, PPAR alpha agonists, which modify lipid profile and have numerous pleiotropic effects, seem to be drugs of choice in patients with atherogenic dyslipidemia. These drugs are effective both in monotherapy and combined therapy with statins. Areas covered: A review of clinical trials and experimental studies on fibrates and their use in the treatment of lipid disorders has been performed. Expert commentary: Fibrates are an effective and safe group of drugs to treat patients with atherogenic dyslipidemia. In this particular population of patients, they improve cardiovascular outcomes. Benefits of fibrate treatment extend beyond the impact of lipid profile. Significant improvements in carbohydrate metabolism, adipokines levels, thrombosis and inflammation were also noted. [ABSTRACT FROM AUTHOR]

Primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD) has become recently more complex than ever, leaving the clinicians perplexed with outdated guidelines and emerging evidence about new LDL-C lowering therapies. 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines have focused on high intensity statin therapy for specific groups of patients, while abandoning long established LDL-C goals, a strategy which no longer seems valid. PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors have emerged as the add-on therapy on top of statins and/or ezetimibe for the treatment of hypercholesterolemia and ASCVD prevention. In several clinical trials, PCSK9 inhibitors have demonstrated their safety and robust LDL-C-lowering power. One completed cardiovascular (CV) outcomes trial (FOURIER; Further Cardiovascular Outcomes Research with PCSK9 Inhibitions in Subjects with Elevated Risk) has demonstrated that PCSK9 inhibition reduces rates of CV death as well as non-fatal stroke and MI, while another major CV outcome trial is under way (ODYSSEY-OUTCOMES). Several trials studying CV benefits of novel LDL-C-lowering therapies are also being conducted. Prompt revision of ACC/AHA guidelines is necessary. In the meantime, physicians need to use clinical judgment integrating the most recent evidence into their practice. [ABSTRACT FROM PUBLISHER]

The 2018 Multidisciplinary Guideline on the Management of Blood Cholesterol calls for initiation and intensification of lipid-lowering therapy (LLT) if low density lipoprotein cholesterol (LDL-C) exceeds thresholds in high and very high (H/VH) risk patients. Despite LDL-C being a major modifiable cardiovascular risk factor, most patients fail to meet guideline thresholds. To assess the consequences of failure to achieve LDL-C guideline thresholds using the Family Heart Database of >324 million individuals. This retrospective analysis assessed annual cardiovascular event (CE) rates in H/VH risk patients as defined by the guidelines. It included individuals who had > 48 months of diagnosis, procedure, medication, and lab result data with > 3 cholesterol results. Patient histories were divided into contiguous episodes characterized by LLT use (including no therapy, mono and combination therapy), prescriptions filled, and LDL-C level. An 18-month baseline period was utilized to determine the covariates for the propensity score matching (PSM). Individuals with a cardiovascular event (CE) during the baseline were excluded. Cohorts included individuals either "Above Threshold" or "Below Threshold" for at least 70% of the study period (including baseline). Following the baseline period, individuals were observed for at least 30 months to determine the date of the first CE and annual incidence rates (AIR) were calculated. 39,117 and 17,232 individuals met the criteria for the Above Threshold and Below Threshold cohorts respectively. A 1:1 PSM resulted in 14,755 in each cohort. The AIRs were 2.2% and 1.5% for the Above Threshold and Below Threshold groups respectively, a 44.2% (p < 0.0002) higher rate in the Above Threshold group. Total CEs (first and subsequent) were also significantly higher 49% (p< 0.0002) in the Above Threshold than the Below Threshold group (3,510 vs 2,356). In this real-world evaluation of H/VH risk individuals achieving lipid guideline thresholds reduces cardiovascular events. Greater emphasis on achieving LDL-C control could improve cardiac health at a population level. Yes The Family Heart Foundation is a 501c3 public charity research and advocacy organization that receives contributions and sponsorships from individuals, foundations, and pharmaceutical companies. This research was partially funded by Amgen, although it played no role in study design, conduct, interpretation or plans for publication. [ABSTRACT FROM AUTHOR]

Heterozygous familial hypercholesterolemia (FH) is a genetic disorder characterized by high low-density lipoprotein cholesterol levels from birth, which exposes the arteries to high levels of atherogenic lipoproteins lifelong and results in a significantly increased risk of premature cardiovascular events. The diagnosis of FH, followed by an appropriate and early treatment is critical to reduce the cardiovascular burden in this population. Phase I-III clinical trials showed the benefit of proprotein convertase subtilisin kexin 9 inhibitors, both alirocumab and evolocumab, in these patients with an average low-density lipoprotein cholesterol reduction ranging from -40% to -60%. The aim of this review is to address the unmet needs in cholesterol management, elucidate the biology and the clinical benefit of proprotein convertase subtilisin kexin 9 inhibition and finally discuss the open gaps and future directions in the treatment of patients with heterozygous FH. [ABSTRACT FROM AUTHOR]

Background: Hypercholesterolemia is one of the main risk factors for cardiovascular disease. The first line treatment for hypercholesterolemia is statin therapy. When the expected low-density lipoprotein cholesterol (LDL-C) concentration is not achieved, the pharmacotherapy may be extended by combining the statin with the cholesterol absorption inhibitor ezetimibe.Methods/design: The study is designed as a randomized, open-label, single-center, crossover study evaluating the effectiveness of combined therapy with rosuvastatin and ezetimibe for hypercholesterolemia. The study is planned to include 200 patients with hypercholesterolemia ineffectively treated with statins for at least 6 weeks. After enrollment participants are randomized into one of two arms receiving rosuvastatin and ezetimibe. In the first arm the study drug is administered in the morning (8:00 am) for 6 weeks and then in the evening for the next 6 weeks; in the second arm the study drug is administered at first in the evening (8:00 pm) for the first 6 weeks and then in the morning for the following 6 weeks. In order to minimize non-adherence to the treatment, all patients will receive the study drug free of charge. The primary outcome of the study is change in LDL-C at 6 and 12 weeks of the treatment, depending on the time of day of study drug administration. The secondary endpoints include change in total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, apolipoproteins ApoB and Apo AI, non-HDL cholesterol, small, dense (sd)-LDL cholesterol, lipoprotein(a), glucose, glycated hemoglobin, high-sensitivity C-reactive protein, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, and creatine kinase at 6 and 12 weeks of the study drug treatment, as well as assessment of plasma fluorescence using stationary and time-resolved fluorescence spectroscopy at baseline and at 6 and 12 weeks of the therapy.Discussion: The RosEze trial is expected to demonstrate whether there is a significant difference in the effectiveness of the lipid-lowering therapy in reducing the concentration of cholesterol when the medications are taken in the morning compared with the evening time of day.Trial Registration: ClinicalTrials.gov, NCT02772640 . Registered on 28 March 2016. [ABSTRACT FROM AUTHOR]

As part of its single technology appraisal (STA) process, the UK National Institute for Health and Care Excellence (NICE) invited the manufacturer of evolocumab (Amgen) to submit evidence on the clinical and cost effectiveness of evolocumab. The appraisal assessed evolocumab as monotherapy or in combination with a statin with or without ezetimibe, or in combination with ezetimibe (without statin therapy), in adult patients with primary hypercholesterolaemia (which includes mixed dyslipidaemia), for whom statins do not provide optimal control of their low-density lipoprotein cholesterol (LDL-C) levels and/or for whom statins are contraindicated or not tolerated. The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology based on the company's submission to NICE. The evidence was derived mainly from four randomised controlled trials comparing evolocumab with either ezetimibe or placebo in adults with primary familial or non-familial hypercholesterolaemia, who were either able to take statins or who were statin intolerant. The clinical-effectiveness review found that evolocumab is efficacious at lowering LDL-C but that there was uncertainty regarding its impact on cardiovascular disease (CVD) outcomes. In response to the ERG's critique of the submitted health economic model, the company submitted an amended model, which also included a patient access scheme (PAS). Based on this, the deterministic incremental cost-effectiveness ratios (ICERs) for evolocumab against ezetimibe were above £74,000 and £45,000 per quality-adjusted life-year (QALY) gained within the non-familial primary and secondary prevention populations, respectively, whilst the ICER within the heterozygous familial hypercholesterolaemia (HeFH) population was approximately £23,000 per QALY gained. The final determination was that evolocumab would be a clinically and cost-effective use of UK NHS resource in certain patient subgroups. [ABSTRACT FROM AUTHOR]

Background Ezetimibe added to statin therapy further reduces LDL-C and clinical atherosclerotic cardiovascular disease compared to statin alone. However, the number of effective and safe oral agents for patients not at LDL-C goal is limited. In prior clinical trials, gemcabene reduced LDL-C and was generally well-tolerated in nearly 900 patients treated for up to 12 weeks. Objective To evaluate the LDL-C lowering and safety of gemcabene as add-on to stable statin therapy in hypercholesterolemic patients. Methods This was an 8-week, double-blind, placebo-controlled, randomized, phase 2 study in men and postmenopausal women ≥18 and ≤65 years of age with LDL-C ≥130 mg/dL (3.4 mmol/L) while on low-intensity to high-intensity stable statin (the majority on moderate intensity) therapy. Sixty-six patients were randomized 1:1:1 to gemcabene 300 mg, 900 mg, or placebo QD. Results Gemcabene 300 mg and 900 mg produced a mean percent change in LDL-C of −23.4 ± 4.7% ( P = .005) and −27.7 ± 4.3% ( P < .001), respectively, vs −6.2 ± 4.3% for placebo. The median percent change in CRP was −26.1% ( P = .196) and −53.9% ( P < .001) for gemcabene 300 mg and 900 mg, respectively, vs −11.1% for placebo. Gemcabene 300 mg and 900 mg were well-tolerated with no significant difference in AEs compared to placebo. Conclusions Gemcabene as add-on to stable statin therapy demonstrated additional dose-dependent and statistically significant reductions in LDL-C of >20% and CRP >40% compared to placebo. The results support gemcabene-continued development for patients requiring LDL-C lowering beyond that provided by background statin therapy. [ABSTRACT FROM AUTHOR]

Simvastatin (SIM) and lovastatin (LOV) are two important active pharmaceutical ingredients from statin class, prescribed in the treatment of hypercholesterolemia. Our study presents the results obtained by our research group regarding the decomposition of SIM and LOV in oxidative atmosphere, by employing three isoconversional methods, namely Friedman, Kissinger-Akahira-Sunose and Flynn-Wall-Ozawa. The results obtained by Friedman method suggested a multistep degradation, while the ones obtained by Kissinger-Akahira-Sunose and Flynn-Wall-Ozawa suggested a single-step degradation. In order to validate the results, we used the NPK method, which allowed a concrete separation and nature of processes that contributed to the degradation of both statins. NPK method showed that both SIM and LOV are degraded by contribution of two distinctive chemical processes, and the mean values of activation energies are also reported. [ABSTRACT FROM AUTHOR]

Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases low-density lipoprotein cholesterol (LDL-C) concentrations through interference with normal physiologic hepatic LDL receptor (LDLR) recycling. Inhibiting PCSK9 results in improved LDLR recycling, increased LDLR availability on hepatocyte cell surfaces, and reduced blood LDL-C levels, making PCSK9 inhibition a novel therapeutic strategy for managing hypercholesterolemia. Monoclonal antibodies directed against PCSK9 have been developed for this purpose. A large number of clinical trials have demonstrated that monoclonal antibodies against PCSK9 yield substantial reductions in LDL-C when administered as monotherapy or in combination with statins to patients with nonfamilial and familial forms of hypercholesterolemia. Data from long-term trials demonstrate that the LDL-C-lowering effect of PCSK9 inhibitors is durable. These agents are generally well tolerated, and few patients discontinue treatment due to adverse events. Moreover, PCSK9 inhibitors do not appear to elicit the hepatic and muscle-related side effects associated with statin use. The ultimate value of PCSK9 inhibitors will be measured by their effect on clinical outcomes. Early evidence of a reduction in cardiovascular events after 1 year of treatment was shown in a prospective exploratory analysis of two ongoing long-term open-label extension evolocumab trials. Similarly, cardiovascular events were reduced in another exploratory analysis after >1 year of therapy with alirocumab. For the primary care physician, PCSK9 inhibitors represent a welcome additional option for lowering LDL-C in patients with familial forms of hypercholesterolemia and those with clinical atherosclerotic cardiovascular disease who are on maximally tolerated statin therapy. [ABSTRACT FROM AUTHOR]

Background: Familial hypercholesterolemia (FH) is the most common genetic disorder associated with premature atherosclerotic cardiovascular disease (ASCVD). There are sparse data on attainment of treatment targets; large registries that reflect real-life clinical practice can uniquely provide this information.Objectives: We sought to evaluate the achievement of low-density lipoprotein cholesterol (LDL-C) treatment goals in FH patients enrolled in a large national registry.Methods: The SAFEHEART study (Spanish Familial Hypercholesterolemia Cohort Study) is a large, ongoing registry of molecularly defined patients with heterozygous FH treated in Spain. The attainment of guideline-recommended plasma LDL-C goals at entry and follow-up was investigated in relation to use of lipid-lowering therapy (LLT).Results: The study recruited 4,132 individuals (3,745 of whom were ≥18 years of age); 2,752 of those enrolled were molecularly diagnosed FH cases. Mean follow-up was 5.1 ± 3.1 years; 71.8% of FH cases were on maximal LLT, and an LDL-C treatment target <100 mg/dl was reached by only 11.2% of patients. At follow-up, there was a significant increase in the use of ezetimibe, drug combinations with statins, and maximal LLT. The presence of type 2 diabetes mellitus, a defective allele mutation, ezetimibe use, and the absence of previous ASCVD were predictors of the attainment of LDL-C goals.Conclusions: Despite the use of intensified LLT, many FH patients continue to experience high plasma LDL-C levels and, consequently, do not achieve recommended treatment targets. Type of LDL-receptor mutation, use of ezetimibe, coexistent diabetes, and ASCVD status can bear significantly on the likelihood of attaining LDL-C treatment goals. [ABSTRACT FROM AUTHOR]

A high blood level of low-density lipoprotein cholesterol (LDL-C) remains a major risk factor for atherosclerotic cardiovascular disease (ASCVD), although data from 2005 through 2012 has shown a decline in high cholesterol (total and LDL cholesterol) along with an increase in the use of cholesterol-lowering medications. The most recent national guidelines (published in 2013) from the American College of Cardiology and the American Heart Association (ACC/AHA) expand previous recommendations for reducing cholesterol to include lifestyle modifications and medication use as part of complete cholesterol management and to lower risk for ASCVD. Because changes in cholesterol treatment guidelines might magnify existing disparities in care and medication use, it is important to describe persons currently eligible for treatment and medication use, particularly as more providers implement the 2013 ACC/AHA guidelines. To understand baseline estimates of U.S. adults on or eligible for cholesterol treatment, as well as to identify sex and racial/ethnic disparities, CDC analyzed data from the 2005-2012 National Health and Nutrition Examination Surveys (NHANES). Because the 2013 ACC/AHA guidelines focus on initiation or continuation of cholesterol treatment, adults meeting the guidelines' eligibility criteria as well as adults who were currently taking cholesterol-lowering medication were assessed as a group. Overall, 36.7% of U.S. adults or 78.1 million persons aged ≥21 years were on or eligible for cholesterol treatment. Within this group, 55.5% were currently taking cholesterol-lowering medication, and 46.6% reported making lifestyle modifications, such as exercising, dietary changes, or controlling their weight, to lower cholesterol; 37.1% reported making lifestyle modifications and taking medication, and 35.5% reported doing neither. Among adults on or eligible for cholesterol-lowering medication, the proportion taking cholesterol-lowering medication was higher for women than men and for non-Hispanic whites (whites) than Mexican-Americans and non-Hispanic blacks (blacks). Further efforts by clinicians and public health practitioners are needed to implement complementary and targeted patient education and disease management programs to reduce sex and racial/ethnic disparities among adults eligible for treatment of cholesterol. [ABSTRACT FROM AUTHOR]

Pecan shell decoction has been used to treat diabetes and obesity-related diseases. In this study, the effects of a pecan shell aqueous extract (PSAE) were evaluated in diabetic and hypercholesterolemic Wistar rats, analyzing clinical signs and biochemical as well as genotoxic and mutagenic parameters, to assess its safe use and efficacy. Diabetes mellitus and hypercholesterolemia were induced with streptozotocin (STZ) and tyloxapol, respectively. Animals were orally administered PSAE (100 mg/kg body weight, b.w.) for 28 days. Biochemical analyses and genotoxicity were evaluated in blood samples and mutagenicity was evaluated in bone marrow. PSAE treatment decreased the blood glucose level and stabilized clinical signs of diabetes in diabetic rats. PSAE diminished the increase in total cholesterol and triglyceride levels in hypercholesterolemic rats. The urea levels were higher in diabetic rats than in treated ones; however, creatinine values were the same in all groups. Elevated transaminase levels were suggestive of liver injuries in diabetic rats, and were not altered by PSAE treatment. PSAE did not show genotoxic or mutagenic activities in diabetic and hypercholesterolemic rats, indicating its safe use at 100 mg/kg b.w. not only in healthy rats but also in rats with induced metabolic alterations. The findings on PSAE's efficacy may indicate that its successful and popular use is in accordance with our results. Thus, PSAE might be a potential candidate for medical purposes as a complementary treatment of diabetes and hypercholesterolemia. [ABSTRACT FROM AUTHOR]

Background and aims There is a paucity of data concerning the influence of lipid-lowering therapy on cardiovascular (CV) outcomes in patients with homozygous familial hypercholesterolaemia (FH). To redress this a retrospective analysis was undertaken of the demographic features, lipid levels, low density lipoprotein receptor and Autosomal Recessive Hypercholesterolaemia gene mutations, CV outcomes and vital status of 44 FH homozygotes referred to a single centre in the UK between 1964 and 2014. Methods Data were obtained from past publications, case records and death certificates. Differences in categorical and continuous variables between living and dead patients were analysed using Fisher's exact test and an independent t-test respectively. Results During the 50 years covered by this survey 13 patients have died, 30 are still alive and 1 was lost to follow up. The mean age of Alive patients was 32.6 ± 11.5 versus 28.3 ± 14.9 years in Dead ones (P = 0.31) and they were born 18 years later (P = 0.0001). Pre-treatment serum total cholesterol (TC) was similar in Alive and Dead (20.2 ± 5.1 v 21.3 ± 4.4 mmol/l, P = 0.52) but on-treatment TC was lower in Alive than Dead (8.1 ± 2.8 v 14.5 ± 6.0 mmol/l, P = 0.0001) and CV adverse events were far less frequent (eg aortic stenosis, 33% v 77%, P = 0.02). Conclusions The lower on-treatment TC and fewer CV adverse events in FH homozygotes still living reflect advances in apheresis and drug therapy since the 1990s. Further improvements in prognosis can be expected with the impending introduction of novel lipid-lowering agents. [ABSTRACT FROM AUTHOR]

Familial hypercholesterolaemia (FH) is an autosomal inherited disorder characterized by markedly elevated LDL-cholesterol (LDL-C) levels and an increased risk of premature atherosclerotic cardiovascular disease. Although FH is one of the most common genetic disorders, this disorder remains mostly undetected and its management is often suboptimal. High-intensity statins are standard treatment for patients with FH, but LDL-C levels in most patients treated with statin monotherapy remain above those recommended by guidelines. Combination therapy to lower LDL-C levels further-such as treatment with statins plus ezetimibe-has been successful, and combination of apheresis with high-intensity statin treatment is used in patients with homozygous FH and in those with heterozygous FH who are statin-refractory. Mipomersen, an inhibitor of apolipoprotein B-100 synthesis, and lomitapide, a microsomal triglyceride transfer protein inhibitor, reduce LDL-C levels further when added to high-intensity statin treatment in homozygous FH, but both have important adverse effects, such as increasing liver fat content. At present, PCSK9 inhibition (with alirocumab or evolocumab) is well tolerated and reduces LDL-C levels considerably in patients receiving the maximally tolerated statin treatment, and seems the most promising emerging treatment option. Nevertheless, data from outcome trials with hard end points for PCSK9 inhibitors, mipomersen, and lomitapide are still needed before these therapies become standard for patients with FH. [ABSTRACT FROM AUTHOR]

The genetic causes of cholesterol metabolism disorders usually lead to premature atherosclerosis. The most well recognized genetically caused hypercholesterolemia is familial hypercholesterolemia. Although the disease is well known, as the discovery of low-density lipoprotein receptor, the classical treatment with lipid-lowering drugs (statins, fibrates, ezetimibe, colesevelam) is still not adequate and new options are seeking. This review is an attempt to analyze the microsomal transfer protein ( MTP) inhibitors as a new approach for treatment of familial hypercholesterolemia, to reviews the literature according to MTP inhibitors and finally to provide original findings. [ABSTRACT FROM AUTHOR]

The article presents the authors views on the American College of Cardiology 2013 cholesterol guideline which recommended that those people with marked hypercholesterolemia be treated with low-density lipoprotein cholesterol (LDL-C)-lowering therapy proven to provide "net benefit" in randomized controlled trials. Topics include stating therapy for severe hypercholesterolemia, adding of a nonstarter therapy by the guideline, and use of LDL-C-lowering therapy to reduce Cardiovascular Disease.

Atorvastatin and ezetimibe are lipid-lowering drugs prescribed for the treatment of hypercholesterolemia. An LC–MS–MS method has been developed and validated for the simultaneous estimation of atorvastatin and ezetimibe in human plasma using pitavastatin as an internal standard. Liquid–liquid extraction was used for the purification and preconcentration of analytes from human plasma matrix. The chromatographic separation was achieved within 3.0 min by an isocratic mobile phase consisting of 0.2% formic acid in water–acetonitrile (30:70, v/v), flowing through Agilent Eclipse-plus C18, 100 × 4.6 mm, 3.5 µm analytical column, at a flow rate of 0.6 mL min–1. Multiple reaction monitoring transitions were measured in the positive ion mode for atorvastatin and internal standard, while ezetimibe was measured in negative ion mode. A detailed validation of the method was performed as per US-FDA guidelines and the standard curves were found to be linear in the range of 0.2–30.0 ng mL−1 with a mean correlation coefficient >0.999 for both drugs. In human plasma, atorvastatin and ezetimibe were stable for at least 36 days at –70 ± 5°C and 6 h at ambient temperature. After extraction from plasma, the reconstituted samples of atorvastatin and ezetimibe were stable in an autosampler at ambient temperature for 6 h. Also, the cited drugs were stable in plasma samples upon subjecting to three freeze thaw cycles. The method is simple, specific, sensitive, precise, accurate and suitable for bioequivalence and pharmacokinetic studies of this combination. [ABSTRACT FROM PUBLISHER]

The microsomal triglyceride transfer protein (MTP) inhibitor lomitapide is a licenced adjunct to a low-fat diet and other lipid-lowering medication, with or without low-density lipoprotein apheresis, for the treatment of adults with homozygous familial hypercholesterolaemia (HoFH). In a recently published phase 3 study, patients with HoFH received lomitapide in addition to maximally tolerated lipid-lowering therapy. Treatment with lomitapide resulted in a mean approximate 50% reduction in LDL-C levels after 26 weeks compared with baseline levels (p < 0.0001). This decrease in LDL-C was maintained at Weeks 56 and 78 (44% [p < 0.0001] and 38% [p = 0.0001], respectively). This paper offers clinical perspectives based on selected case histories of patients participating in the phase 3 lomitapide study. These cases provide illustrative examples of the efficacy of lomitapide, with or without apheresis, and show that the effective management of adverse effects can enable patients to remain on effective treatment. [ABSTRACT FROM AUTHOR]

Background and Objective: Inter-individual variability exists in the statin (HMG-CoA reductase inhibitor) lipid-lowering response, which is partially attributed to genetic factors. The polymorphic enzyme P450 oxidoreductase (POR) transfers electrons from nicotinamide adenine dinucleotide phosphate (NADPH) to cytochrome P450 (CYP) 3A enzymes, which metabolize atorvastatin and simvastatin. The POR*28 allele is associated with increased activity of CYP3A enzymes. We analyzed the association of the POR*28 allele with response to atorvastatin and simvastatin. Methods: A total of 207 atorvastatin-treated adults were included in the study. An independent population of 210 simvastatin-treated adults served as a replication cohort. Total cholesterol (TChol) and low-density lipoprotein cholesterol (LDL-C) were measured at baseline and after 6 months of treatment. The POR*28 allele was analyzed with a TaqMan assay. Results: The POR*28 allele was associated with a non-significant trend towards lower percentage mean reduction of TChol (−35.5 % in *1/*1, −33.7 % in *1/*28, and −29.5 % in *28/*28 individuals) and LDL-C (−42.6 % in *1/*1, −41.7 % in *1/*28, and −37.8 % in *28/*28 individuals) in response to atorvastatin. This trend was not observed in the replication cohort of simvastatin-treated patients. No sex-gene interaction was observed regarding the effect of the POR*28 allele on the statin lipid-lowering response in either statin-treated patient cohort. Conclusion: The POR*28 allele was not associated with the lipid-lowering effect of atorvastatin and the results were replicated in an independent simvastatin-treated population. The hypothesized effect of the POR*28 allele on the lipid-lowering response to CYP3A-metabolized statins can potentially be masked by relevant confounding or uncontrolled factors; therefore, further studies in different populations are required. [ABSTRACT FROM AUTHOR]

Objectives: Familial hypercholesterolemia (FH) is an autosomal dominant disease caused mainly by LDLR mutations. This study assessed the influence of the presence and type of LDLR mutation on lipid profile and the response to lipid-lowering therapy in Brazilian patients with heterozygous FH. Methods: For 14 ± 3 months, 156 patients with heterozygous FH receiving atorvastatin were followed. Coding sequences of the LDLR gene were bidirectionally sequenced, and the type of LDLR mutations were classified according to their probable functional class. Results: The frequencies of the types of LDLR mutations were: null-mutation (n = 40, 25.6%), defective-mutation (n = 59, 37.8%), and without an identified mutation (n = 57, 36.6%). Baseline total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were higher in patients carrying a null mutation (9.9 ± 1.9 mmol/L, 7.9 ± 1.7 mmol/L), compared to those with a defective (8.9 ± 2.2 mmol/L, 7.0 ± 2.0 mmol/L), or no mutation (7.9 ± 1.9 mmol/L, 5.8 ± 1.9 mmol/L) (p < 0.001). After treatment, the proportion of patients attaining an LDL-C<3.4 mmol/L was significantly different among groups: null (22.5%), defective (27.1%), and without mutations (47.4%) (p = 0.02). The presence of LDLR mutations was independently associated with higher odds of not achieving the LDL-C cut-off (OR 9.07, 95% CI 1.41–58.16, p = 0.02). Conclusions: Our findings indicate that the presence and type of LDLR mutations influence lipid profile and response to lipid-lowering therapy in Brazilian patients with heterozygous FH. Thus, more intensive care with pharmacological therapeutics should be performed in patients who have a molecular analysis indicating the presence of a LDLR mutation. [ABSTRACT FROM AUTHOR]

Abstract: Background: Previous studies have reported that the attainment of goals for low-density lipoprotein cholesterol (LDL-C) are globally suboptimal, but contemporary data are scarce. The CEntralized Pan-Asian survey on tHE Under-treatment of hypercholeSterolemia (CEPHEUS-PA) is the largest evaluation of pharmacological treatment for hypercholesterolemia in Asia. The study reported here analyzed the Taiwan cohort in CEPHEUS-PA to identify the determinants of successful treatment. Methods: The patients eligible for this study were adults (≥18 years old) with hypercholesterolemia and with at least two coronary heart disease (CHD) risk factors who had been receiving lipid-lowering drugs for at least 3 months before enrollment, without adjustment for at least 6 weeks before enrollment. Demographic and clinical information and lipid concentrations were recorded. Cardiovascular risk levels and LDL-C targets were determined using the updated Adult Treatment Panel III. Results: In this group of 999 Taiwanese patients, 50%, 25%, and 24% had LDL-C goals set at <70 mg/dL, <100 mg/dL, and <130 mg/dL, respectively. The overall attainment rate was 50%, with the lowest rate in patients set at the most stringent target (22%), followed by those whose therapeutic goals were <100 mg/dL (69%) and <130 mg/dL (87%). The success of LDL-C control was lower in patients with multiple risk factors other than CHD or its equivalents than in those without these multiple risk factors (37% vs. 53%, p < 0.001), and lower in patients with metabolic syndrome than in those without (43% vs. 66%, p < 0.001). Baseline LDL-C and cardiovascular risk were inversely associated with goal attainment, whereas treatment with statins was directly associated with the achievement of LDL-C goals. Patients with diabetes (odds ratio 0.49, 95% confidence interval 0.29–0.84, p = 0.010) and with metabolic syndrome (odds ratio 0.15, 95% confidence interval 0.05–0.40, p < 0.001) were less likely to be treated with statins. Conclusion: This study showed that there is a discrepancy between the updated Adult Treatment Panel III recommendations for LDL-C control and the control attained by this group of Taiwanese patients. In particular, treatment with statins was largely underused in patients with diabetes and in those with metabolic syndrome. These findings highlight the need for more intensive treatment in high-risk patients and those with multiple risk factors, particularly patients with metabolic syndrome. [Copyright &y& Elsevier]

Background: Statins (HMG-CoA reductase inhibitors) represent a major class of compounds for the treatment of hypercholesterolemia due to their ability to inhibit de novo cholesterol synthesis. In addition to their hypolipidemic effects, chemoprotective properties have been attributed to statins as well. These effects involve multiple mechanisms, which, however, are not known in detail. The aim of our study was to assess in non-malignant as well as cancer cells the impact of simvastatin on the amount of cytosolic lipid droplets (LDs) implicated in many biological processes including proliferation, inflammation, carcinogenesis, apoptosis, necrosis or growth arrest. Methods: Human embryonic kidney cells HEK-293T and human pancreatic cancer cells MiaPaCa-2 were treated with simvastatin (6 and 12 μM) for 24 and 48 hours respectively. Neutral lipid probe Nile Red was used for detection of LDs by fluorescence microscopy. Cellular cholesterol content was determined by HPLC. Changes in expression of genes related to lipid metabolism in simvastatin-treated MiaPaCa-2 cells were examined by DNA microarray analysis. Validation of gene expression changes was performed using quantitative RT-PCR. Results: The treatment of the cells with simvastatin increased their intracellular content of LDs in both non-malignant as well as cancer cells, partially due to the uptake of cholesterol and triacylglyceroles from medium; but in particular, due to enhanced synthesis of triacylglyceroles as proved by significant overexpression of genes related to de novo synthesis of triacylglyceroles and phospholipids. In addition, simvastatin also markedly influenced expression of genes directly affecting cell proliferation and signaling. Conclusions: Simvastatin treatment led to accumulation of cytosolic LDs within the examined cells, a phenomenon which might contribute to the antiproliferative effects of statins. [ABSTRACT FROM AUTHOR]

Abstract: Hypercholesterolemia and dyslipidemia are independent risk factors for cardiovascular disease and death. Statins are the drugs of choice to decrease plasma cholesterol and have other beneficial actions beyond lipid-lowering leading to substantial improvements in cardiovascular morbidity and mortality. However, evaluation of the effects of statins to reduce overall morbidity and mortality must integrate metabolic consequences of statin therapy with its lipid-lowering effect. Indeed, reduction in LDL-cholesterol to target level achieved by statins does not completely eliminate risk of cardiovascular disease and may elevate metabolic risk factors that contribute to dysregulation of metabolic homeostasis. This may lead to increased incidence of diabetes and its cardiovascular complications that are explained, in part, by reciprocal relationships between insulin resistance and endothelial dysfunction. Genetic factors may determine 40–60% of total cholesterol levels and 70% of the efficacy of statin treatments. Metabolic and cardiovascular phenotypes that are either genetically determined or environmentally acquired are also important determinants of responses to specific statins. Moreover, differences between biological outcomes of specific statins or increasing dosages of statins result in differential metabolic actions due to off-target or unknown mechanism that have important implications for the use of statins to reduce overall morbidity and mortality. In this review, we discuss differential cardiovascular and metabolic pleiotropic actions of specific statins that interact in a context-dependent manner with patient phenotypes and genotypes. These important considerations may influence progression of atherosclerosis, risk of diabetes, and modulation of insulin resistance that help determine overall morbidity and mortality in patients undergoing statin therapy. [Copyright &y& Elsevier]

Several studies have reported limited or no reduction in serum cholesterol in response to probiotic formulations. Recently, probiotics have shown promise in treating metabolic disease due to improved strain selection and delivery technologies. The aim of the present study was to evaluate the cholesterol-lowering efficacy of a yoghurt formulation containing microencapsulated bile salt hydrolase (BSH)-active Lactobacillus reuteri NCIMB 30242, taken twice per d over 6 weeks, in hypercholesterolaemic adults. A total of 114 subjects completed this double-blind, placebo-controlled, randomised, parallel-arm, multi-centre study. This interventional study included a 2-week washout, 2-week run-in and 6-week treatment period. Subjects were randomised to consume either yoghurts containing microencapsulated L. reuteri NCIMB 30242 or placebo yoghurts. Over the intervention period, subjects consuming yoghurts containing microencapsulated L. reuteri NCIMB 30242 attained significant reductions in LDL-cholesterol (LDL-C) of 8·92 % (P = 0·016), total cholesterol (TC) of 4·81 % (P = 0·031) and non-HDL-cholesterol (HDL-C) of 6·01 % (P = 0·029) over placebo, and a significant absolute change in apoB-100 of − 0·19 mmol/l (P = 0·049). Serum concentrations of TAG and HDL-C were unchanged over the course of the study. Present results show that consumption of microencapsulated BSH-active L. reuteri NCIMB 30242 yoghurt is efficacious and safe for lowering LDL-C, TC, apoB-100 and non-HDL-C in hypercholesterolaemic subjects. The efficacy of microencapsulated BSH-active L. reuteri NCIMB 30242 yoghurts appears to be superior to traditional probiotic therapy and akin to that of other cholesterol-lowering ingredients. [ABSTRACT FROM PUBLISHER]

The assumption that statin therapy can decrease asymmetric dimethylarginine through lowering low-density lipoprotein cholesterol levels seems logical and yet arises some controversy. The aim of the present study is to compare the effects of moderate (40 mg) to high (80 mg) simvastatin doses on asymmetric dimethylarginine and total homocysteine levels in patients with newly detected severe hypercholesterolemia (after target LDL-C levels, ≤2.6 mmol/L, are reached). The study included 120 adult patients with newly detected severe hypercholesterolemia (total cholesterol ≥7.5 mmol/L and low-density lipoprotein cholesterol ≥4.9 mmol/L). Asymmetric dimethylarginine levels were determined by enzyme-linked immunosorbent assay, total homocysteine-by a high-performance liquid chromatographic method. There was a statistically significant decrease in total cholesterol, triglycerides, low-density lipoprotein cholesterol, and apolipoprotein-B levels as well as in the apolipoprotein-B/apolipoprotein-A1 index after a 1-month therapy with 40 mg simvastatin ( P <0.001). Asymmetric dimethylarginine and total homocysteine levels were also decreased but the difference did not reach statistical significance ( P= 0.571; P= 0.569). A dose-dependent effect was established, comparing the influence of moderate (40 mg) to high (80 mg) simvastatin doses on the tested atherogenic biomarkers (lipid profile, apolipoprotein-A1, and apolipoprotein-B). Asymmetric dimethylarginine and total homocysteine levels were lowered significantly with 80 mg simvastatin ( P <0.001; P= 0.038). In conclusion, optimizing the target values of low-density lipoprotein cholesterol, a moderate dose (40 mg) of simvastatin has no effect on asymmetric dimethylarginine and total homocysteine in contrast to a high dose (80 mg) after target LDL-C levels are reached (≤2.6 mmol/L) in patients with newly detected severe hypercholesterolemia. [ABSTRACT FROM AUTHOR]

Aims: The relationship between variants in SLCO1B1 and SLCO2B1 genes and lipid-lowering response to atorvastatin was investigated. Material and Methods: One-hundred-thirty-six unrelated individuals with hypercholesterolemia were selected and treated with atorvastatin (10 mg/day/4 weeks). They were genotyped with a panel of ancestry informative markers for individual African component of ancestry (ACA) estimation by SNaPshot® and SLCO1B1 (c.388A>G, c.463C>A and c.521T>C) and SLCO2B1 (-71T>C) gene polymorphisms were identified by TaqMan® Real-time PCR. Results: Subjects carrying SLCO1B1 c.388GG genotype exhibited significantly high low-density lipoprotein (LDL) cholesterol reduction relative to c.388AA+c.388AG carriers (41 vs. 37%, p = 0.034). Haplotype analysis revealed that homozygous of SLCO1B1*15 (c.521C and c.388G) variant had similar response to statin relative to heterozygous and non-carriers. A multivariate logistic regression analysis confirmed that c.388GG genotype was associated with higher LDL cholesterol reduction in the study population (OR: 3.2, CI95%:1.3-8.0, p < 0.05). Conclusion: SLCO1B1 c.388A>G polymorphism causes significant increase in atorvastatin response and may be an important marker for predicting efficacy of lipid-lowering therapy. [ABSTRACT FROM AUTHOR]

Long-term data on the effects of cholesterol-lowering regimens on low-density lipoprotein cholesterol levels and cardiovascular events in patients with familial hypercholesterolemia (FH) are lacking. The present study evaluated the effectiveness of long-term intensive lipid-lowering therapy on the natural history of FH. Of approximately 1,000 adult patients with heterozygous FH treated from 1974 to 2008, the charts of 327 were randomly selected for review. FH was defined according to the Simon Broome Registry Group criteria. The recorded data included age; gender; lipid levels with diet only, with each lipid-lowering regimen, and at the most recent visit during treatment; the length of follow-up; cardiovascular events; and revascularization procedures. The lipid assay calibrations and standardization were unchanged throughout the study period. Of the 327 patients, 60% were men, the mean age at diagnosis was 38 ± 14 years, and the mean follow-up was 15 ± 8 years. The baseline and most recent low-density lipoprotein cholesterol levels during treatment were 256 ± 60 mg/dl and 116 ± 46 mg/dl, respectively, for a mean reduction of 55% from baseline (p <0.0001). At their most recent visit, 24% of all subjects were treated with statin monotherapy, 55% with a statin plus another agent, and 21% with triple therapy; 44% received a statin-ezetimibe combination. The interval between recurrent cardiovascular events tended to increase from 5.3 ± 4.8 years before treatment to 7.4 ± 6.7 years after referral (p = 0.1303). In conclusion, advances in drug therapy during the past 3 decades has led to substantial reductions in low-density lipoprotein cholesterol levels and appears to diminish the cardiovascular risk in patients with FH. [ABSTRACT FROM AUTHOR]

Abstract: Simvastatin is a hypolipidemic drug which is used to control hypercholesterolemia and to prevent cardiovascular disease. In the current study, the effects of high and low doses of simvastatin treatment on tibia of healthy rats were investigated. Wistar rats were used for the control, 20mg and 50mg simvastatin-treated groups. Molecular investigations were performed using Fourier transform infrared spectroscopy. In the bones of the two groups of simvastatin-treated rats, the relative mineral/matrix ratio (p <0.001), relative carbonate content (p <0.001), carbonate/amide I ratio (p <0.001) and crystallinity (p <0.001) decreased significantly compared to the control group. Low dose of simvastatin treatment is more effective in reducing the relative carbonate content indicating the amount of carbonate substitution for phosphate in the mineral crystal. The olefinic band almost disappeared in the high dose of simvastatin-treated group which implies a decrease in unsaturation and an increase in lipid peroxidation. The higher frequency value and the bandwidth of CH2 asymmetric stretching band for the 50mg treated group imply more disordered (p <0.001) and fluid (p <0.001) membrane structure. Low dose of simvastatin is more effective in strengthening the bone than high dose simvastatin treatment. High dose simvastatin treatment induces lipid peroxidation and changes the lipid composition and concentration, which are known to affect membrane physical properties. [Copyright &y& Elsevier]

Background: Reducing low-density lipoprotein cholesterol (LDL-C) is the primary goal of therapy in patients with hypercholesterolemia and coronary heart disease (CHD). Methods: This double blind placebo-controlled study enrolled patients 18 to 75 years of age with primary hypercholesterolemia and established CHD who were taking a stable daily dose of simvastatin 20 mg. Patients were randomized to ezetimibe/simvastatin 10/20 mg (eze/simva; n = 56) or simvastatin 40 mg (simva; n = 56) for 6 weeks. Percent change from baseline in LDL-C, total cholesterol, high-density lipoprotein cholesterol (HDL-C), and triglycerides were assessed by use of the Student t test. The percent of patients achieving LDL-C less than 100 mg/dL (<2.6 mmol/L) or less than 80 mg/dL (<2.0 mmol/L) was analyzed via logistic regression with terms for treatment, baseline LDL-C, age, and gender. Results: Baseline characteristics were similar between groups. Treatment with eze/simva combination resulted in significantly greater reductions in LDL-C, total cholesterol, and triglycerides versus doubling the dose of simva to 40 mg (all P < .01). Significantly more patients achieved LDL-C less than 100 mg/dL (<2.6 mmol/L) and less than 80 mg/dL (<2.0 mmol/L) with ezetimibe/simvastatin versus doubling the dose of simva to 40 mg (73.2% vs 25.0%; P < .001) for simvastatin. Changes in HDL-C were similar between treatments. Both treatments were generally well tolerated. Conclusion: In high-risk CHD patients with hypercholesterolemia, treatment with eze/simva combination resulted in significantly greater reductions in LDL-C, total cholesterol and triglycerides, as well as greater achievement of recommended LDL-C targets, compared with doubling the simvastatin dose to 40 mg over the 6-week period. (Clinical trial registration number: NCT00423579) [ABSTRACT FROM AUTHOR]

Abstract: Background: Heterozygous familial hypercholesterolemia (heFH) is a common autosomal dominant hereditary disorder caused by mutations in the LDL-receptor gene that lead to elevated plasma levels of low-density lipoprotein-cholesterol (LDL-c). Robust lowering of LDL-c levels is essential for risk reduction of premature cardiovascular diseases and early death. European and Dutch guidelines recommend to treat LDL-c to plasma levels <2.5mmol/l. In the present study we evaluated the treatment of heFH patients in The Netherlands. Methods: A cross-sectional study was conducted in outpatient lipid clinics of three Academic Centers and two regional hospitals. Patient records of known heFH patients were retrieved and data were reviewed on the use of lipid-lowering medication, plasma lipids and lipoproteins, safety laboratory results and reasons for not achieving treatment goals. Results: The data of 1249 patients with heFH were available. Nearly all patients (96%) were on statin treatment. The treatment goal for LDL-c <2.5mmol/l was achieved in 261 (21%) patients. Among those who did not reach LDL-c goals, 261 (27%) were on combination therapy of maximum statin dose and ezetimibe. Main reason (32%) why patients did not use maximum therapy despite an LDL-c ≥2.5mmol/l, was acceptance of a higher target LDL-c level by the treating physician. An alternative treatment goal of >50% LDL-c reduction, as recommended in the NICE guidelines, was achieved in 47% of patients with an LDL-c ≥2.5mmol/l and not using maximum therapy. Conclusion: Only a small proportion of patients with heFH reaches the LDL-c treatment target of <2.5mmol/l. These results emphasize the need for better monitoring, better utilization of available medication and for new treatment options in heFH to further decrease LDL-c levels. [Copyright &y& Elsevier]

Abstract: Low density lipoprotein (LDL) apheresis is now accepted as the treatment of choice for patients with homozygous familial hypercholesterolaemia and for heterozygotes with cardiovascular disease refractory to lipid-lowering drug therapy. However, a paucity of evidence has meant that detailed guidance on the extent of cholesterol reduction required to prevent the onset or progression of cardiovascular disease in these high risk patients is lacking. This review defines criteria for expressing the efficacy of apheresis, proposes target levels of total and LDL cholesterol for homozygotes and heterozygotes based on recent follow-up studies and suggests a scheme for monitoring cardiovascular disease in these patients. Establishing a uniform approach to data collection would facilitate the setting up of national or multi-national registers and might eventually provide the information needed to formulate evidence-based guidelines for LDL apheresis. [Copyright &y& Elsevier]

AbstractBackground:Surveys evaluating plasma lipid goal attainment in patients with coronary heart disease have shown that hypercholesterolaemia is inadequately treated. Limited data account for the reasons behind this. The aim of the CEntralized Pan-European survey on tHEUnder-treatment of hypercholeSterolaemia (CEPHEUS) survey was to evaluate the current use and efficacy of lipid-lowering drugs (LLD), and to identify possible patient/physician characteristics associated with failure to achieve low-density lipoprotein cholesterol (LDL-C) targets recommended by the 2003 European guidelines (Third Joint Task Force).Methods:CEPHEUS was a European, multi-centre, cross-sectional survey conducted in eight countries and involved patients on LLD for >3 months (stable medication >6 weeks). One visit was scheduled for data collection, including fasting lipids. In all but one country, physicians and patients filled in a questionnaire about aspects of hypercholesterolaemia and treatment.Clinical trial registration:NCT00542867 (ClinicalTrials.gov).Results:Of the 15 199 patients recruited, 14 478 were included in the final analyses. The mean age was 63.2 years, and 45 of patients were female. Overall, 55.3 of the patients achieved their LDL-C target. In multivariate analyses, the factors identified as positive predictors for achieving LDL-C goals included normal body mass index, not smoking, not having metabolic syndrome, being on statin therapy and good treatment adherence.Limitations:The population was a selected group of subjects treated with LLD, and the results cannot be extrapolated to the general population. Patient consent was obtained, which may have selected more motivated patients and induced a positive bias. The physician and patient questionnaires were not validated, but were only used for exploratory purposes.Conclusion:Only 55.3 of patients using LLD achieved the LDL-C target recommended in the 2003 European guidelines. [ABSTRACT FROM AUTHOR]

AbstractRecent guidelines recommend strict goals for low-density lipoprotein cholesterol (LDL-C) (1.8–2.6 mmol/L; 70–100 mg/dL). However, these goals are not always met and many primary and secondary prevention patients are not optimally controlled. Both the under-prescription of lipid-lowering medication and lack of adherence to prescribed medications could account for this situation. In this issue of the journal, two studies evaluated the under-treatment of hypercholesterolemia in European countries, as well as patient/physician characteristics that are related to poor control of LDL-C. This editorial considers the implications of these findings. While we have come far in recent years in terms of treating hypercholesterolemia, we still have considerable room for improvement and progress towards evidence-based clinical practice. [ABSTRACT FROM AUTHOR]

Although fundamental cause theory has been highly influential in shaping the research literature on health disparities, there have been few empirical demonstrations of the theory, particularly in dynamic perspective. In this study, we examine how income disparities in cholesterol levels have changed with the emergence of statins, an expensive and potent new drug technology. Using nationally representative data from 1976 to 2004, we find that income gradients for cholesterol were initially positive, but then reversed and became negative in the era of statin use. While the advantaged were previously more likely to have high levels of cholesterol, they are now less likely. We consider our case study against a broader theoretical framework outlining the relationship between technology innovation and health disparities. We find that the influence of technologies on socioeconomic disparities is subject to two important modifiers: (1) the nature of the technological change and (2) the extent of its diffusion and adoption. [ABSTRACT FROM AUTHOR]

Objective: The aim of the study was to compare the efficacy/safety of doubling the dose of low-, medium- and high-potency statins on lipids/lipoproteins versus ezetimibe/simvastatin (EZE/SIMVA) 10/40 mg in patients with a recent coronary event. Methods: In this open-label study, patients were stratified by baseline statin therapy (low, medium and high potency) and randomized equally to statin dose doubling or EZE/SIMVA 10/40 mg for 12 weeks. Primary analysis concerned change in low-density lipoprotein cholesterol for the whole population. Treatment-by-stratum interaction evaluated the consistency of treatment effect across statin potency strata. Post hoc analysis of between-group efficacy within strata was performed using ANCOVA. Results: Within each stratum, EZE/SIMVA produced significantly greater reductions in low-density lipoprotein cholesterol, total cholesterol, apolipoprotein B and non-high-density lipoprotein cholesterol (HDL-C) compared to statin doubling. Numerical trends toward smaller between-group reductions were observed with higher-potency statins and reached statistical significance for apolipoprotein B and non-HDL-C. No significant between-group differences in HDL-C and C-reactive protein were observed within each stratum. EZE/SIMVA produced larger reductions in triglycerides versus low-potency statin, whereas it was similarly effective compared with intermediate-/high-potency statins. The safety/tolerability profiles of the treatments were similar across the strata. Conclusions: EZE/SIMVA 10/40 mg produced greater improvements in lipids with a similar safety profile compared to doubling the dose of low-, medium- and high-potency statins. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: The effect of a strong, lipophilic statin (pitavastatin) on the thoracic aorta has not yet been elucidated. The purpose of the present study was to evaluate the effects of pitavastatin (P) therapy on plaque components and morphology in the thoracic aorta by transesophageal echocardiography (TEE) and clarify the impact of the therapy on media and intima in patients with hypercholesterolemia. Sixty-four media and 64 intima of the thoracic aorta were investigated in 32 patients with hypercholesterolemia. The corrected integrated backscatter (c-IBS) values in the thoracic aortic wall and intima-media thickness (IMT) at the same site were measured before and after P therapy or diet (D) for 7 mo. Moreover, c-IBS values in media were measured in 168 patients without hypercholesterolemia to estimate age-dependent changes. C-IBS values in media were correlated with age (r = 0.84, p < 0.001). C-IBS and IMT of media in the P group significantly decreased from −17.8 ± 2.4 to −20.1 ± 3.7 dB and from 1.7 ± 0.3 to 1.5 ± 0.3 mm, respectively (p < 0.001), whereas those in the D group significantly increased from −18.3 ± 2.0 to −16.7 ± 2.1 dB and from 1.6 ± 0.3 to 1.7 ± 0.2 mm, respectively (p < 0.001). IMT in intima in the P group significantly decreased from 3.7 ± 0.4 to 3.3 ± 0.4 mm (p < 0.001). C-IBS in intima in the P group significantly increased from −10.2 ± 2.2 to −6.9 ± 1.7 dB, which indicated plaque stabilization. Pitavastatin improved the atherosis measured by IMT and sclerosis measured by c-IBS values in the media and induced stabilization and regression of plaques in the intima of the thoracic aorta. (E-mail: masanori@ya2.so-net.ne.jp) [Copyright &y& Elsevier]

Colesevelam hydrochloride (Cholestagel, WelChol) is an orally administered, non-absorbable, polymeric, bile-acid-binding agent with a higher affinity for glycocholic acid in vitro and greater capacity for binding bile acids in vivo than other bile-acid-binding agents.In randomized controlled trials in patients with primary hypercholesterolemia, colesevelam monotherapy reduced mean serum low-density lipoprotein-cholesterol (LDL-C) levels by 9–19%. In combination with an HMG-CoA reductase inhibitor (statin) or fenofibrate, colesevelam induced additive reductions in LDL-C 10–16% greater than those achieved by monotherapy with a statin (in patients with primary hypercholesterolemia) or fenofibrate (in patients with mixed hyperlipidemia). Colesevelam was generally well tolerated, with a relatively low incidence of gastrointestinal adverse events and a high compliance rate. Thus, colesevelam provides a useful addition to primary therapy with statins in the treatment of primary hypercholesterolemia, or fenofibrate in the treatment of mixed hyperlipidemia. [ABSTRACT FROM AUTHOR]

BACKGROUND: Signal detection is a crucial element in recognising new adverse drug reactions (ADRs) as soon as possible. HMG-CoA reductase inhibitors (‘statins’), the most potent cholesterol-lowering drugs, are generally well tolerated but can occasionally lead to liver toxicity. Pre- and postmarketing studies on statins revealed an incidence of 0.1–3% elevation in hepatic transaminase levels. However, these elevations are asymptomatic, reversible, dose related or probably due to other causes. Postmarketing studies clearly showed the lack of evidence of hepatotoxicity from statins, apart from some isolated case reports of serious hepatic damage described in the literature. It is still unclear whether serious hepatic reactions are dose related and more frequent than the expected rate in the general population. OBJECTIVE: In this study, the hypothesis that fluvastatin could cause serious liver injuries more than the other statins is investigated, in the light of a quantitative and qualitative signal analysis, drug consumption data and evidence from the literature. METHODS: The Italian Interregional Group of Pharmacovigilance (Gruppo Interregionale di Farmacovigilanza; GIF) is an example of signal detection within the Italian spontaneous ADR reporting system. The GIF database holds reports of suspected ADRs submitted by five Italian pharmacovigilance regional centres. In the GIF database, all reports of suspected ADRs are classified according to the WHO criteria for causality assessment. The reactions are coded according to the WHO Adverse Reaction Terminology and classified as serious or non-serious events on the basis of the WHO Critical Term List. Every 6 months the GIF database is analysed to extract potential signals through a qualitative case-by-case analysis and using a quantitative methodology called proportional reporting ratio (PRR). This methodology permitted us to identify the potential signal ‘fluvastatin and hepatic reactions’. RESULTS: At 31 December 2004, the GIF database contained 35 757 reports with an annual reporting rate of 170 reports per million inhabitants. We found a total of 1260 reports of ADRs related to statins, including 178 of hepatic reactions. Sixty-nine reports were attributed to fluvastatin, which showed the highest PRR in comparison with the other statins. Fluvastatin was associated with 33 serious reactions, mainly hepatitis and cholestatic hepatitis. The number of reports of severe hepatotoxicity associated with fluvastatin started to increase from 2002. About half of them did not report other suspected or concomitant drugs and in one third the hepatotoxicity occurred after <1 month of therapy. Twenty-seven out of 33 patients were female, and fluvastatin was administered at 80 mg/day in 81% of cases reporting complete data on drug dosage. CONCLUSION: In the literature, serious hepatic reactions are rarely described in patients taking statins; however, data gathered by GIF suggest that cases of hepatotoxicity are reported more often than expected. In addition, GIF data seem to reveal that fluvastatin is more likely to cause hepatic reactions than the other statins. However, this is a preliminary signal and future evaluations are certainly needed to confirm it and to quantify this possible risk. [ABSTRACT FROM AUTHOR]

Chunghyul-dan has inhibitory effects on HMG-CoA reductase and pancreatic lipase. We investigated whether Chunghyul-dan has therapeutic effects on humans with hypercholesterolemia. This study was a case-control, open-labeled clinical study. Subjects were treated with Chunghyul-dan (600 mg/day) or Atorvastatin (10 mg/day) for 8 weeks. Serum lipids were checked at baseline after 4 and 8 weeks of medication. While, Chunghyul-dan showed significant lipid-lowering effects, it was less effective than Atorvastatin. In comparison with the histological controls, Chunghyul-dan's effects were superior to placebo. On safety assessment, there was no adverse effect with the use of Chunghyul-dan in hepatic or renal toxicity. In conclusion, we suggest that Chunghyul-dan is a useful herbal medicine for hypercholesterolemia. [ABSTRACT FROM AUTHOR]

Clinical guidelines for cholesterol testing and management have been updated recently. With the evolving recognition of benefits and intensified recommendations for cholesterol management, many more patients will require cholesterol-lowering drugs. All the statins share similar adverse-effect profiles, with a low overall frequency of undesirable effects. Emerging data associate statins with a decreased risk of Alzheimer's disease; however, we report two women who experienced significant cognitive impairment temporally related to statin therapy. One woman took atorvastatin, and the other First took atorvastatin, then was rechallenged with simvastatin. Clinicians should be aware of cognitive impairment and dementia as potential adverse effects associated with statin therapy. [ABSTRACT FROM AUTHOR]