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• We present a novel approach to the adaptation of implementation recommendations from clinical guidelines into implementation strategies, using care of familial hypercholesterolaemia as an example. • We provide guidance on how implementation strategies can be tailored to local-contexts by key partners. • We draw upon existing programs in the literature to highlight how the application of this process is feasible. The International Atherosclerosis Society (IAS) published an evidence-informed guidance for familial hypercholesterolemia (FH) that provides both clinical and implementation recommendations. We reference examples of strategies from the literature to explore how these implementation recommendations can be tailored into implementation strategies at the local-level for stakeholders guided by a framework proposed by Sarkies and Jones. Four authors of the IAS guidance selected two published exemplar implementation recommendations for detection, management, and general implementation. Each recommendation was described as an implementation strategy using Proctor's guidance for specifying and reporting implementation strategies. It recommends reporting the actor (who), action (what), action-target (who is impacted), temporality (how often), and dose (how much) for each implementation strategy. Detection: A centralized cascade testing model, mobilized nurses (actor) to relative's homes, after the diagnosis of the proband (temporality), once (dose) to consent, obtain a blood sample and health information (action) on relatives (action-target). Management: A primary care initiative to improve FH management included an educational session (action) with clinicians (action-target), computer-based reminder message and message to patients to have their cholesterol screened once (dose) at a visit or outreach (temporality) by researchers (actor). General: A partnership between a statewide public pathology provider, local public hospital network, primary health network, government health ministry, and an academic university (actors) was established to implement a primary-tertiary shared care model (action) to improve the detection of FH (action-target). We demonstrate that implementation recommendations can be specified and reported for different local contexts with examples on monitoring, evaluation, and sustainability in practice. [ABSTRACT FROM AUTHOR]

Accumulation of lipoprotein X (LpX) in blood can cause severe hypercholesterolemia and cutaneous xanthomas. Monocytes sensitively sense lipid changes in circulation and contribute to inflammation. However, how monocytes respond to LpX is undefined. We examined the phenotype of monocytes from a patient, who had LpX, severe hypercholesterolemia, and extensive cutaneous xanthomas, and effects of semiselective plasmapheresis therapy (SPPT). Fluorescence-activated cell sorting and adhesion assays were used to examine monocyte phenotype and ex vivo oxidized low-density lipoprotein uptake and adhesion in the patient before and after treatment with SPPT. Effects of plasma from the patient on the phenotype and adhesion of monocytes from a healthy participant were determined. SPPT improved hypercholesterolemia and cutaneous xanthomas. Before treatment, the patient had lower frequency of nonclassical monocytes but higher frequency of intermediate monocytes than the control participant. Before treatment, monocytes from the patient with LpX showed more intracellular lipid accumulation, alterations in several cell surface markers and intracellular cytokines, as well as enhanced oxidized low-density lipoprotein uptake and reduced adhesion compared with control. After SPPT, the phenotypes of monocytes from the patient with LpX were similar to control monocytes. Incubation with plasma from the patient before treatment as compared with plasma from the control participant or the patient after treatment increased CD11c expression and adhesion of monocytes from a healthy participant. LpX-induced hypercholesterolemia increased lipid accumulation and altered the phenotype of monocytes, which may contribute to cutaneous xanthoma development. Removal of LpX by SPPT reduced lipid accumulation and improved monocyte phenotype, likely contributing to xanthoma resolution. • Cutaneous xanthomas presented in a woman with lipoprotein X (LpX)-induced hypercholesterolemia. • LpX-induced hypercholesterolemia increased lipid accumulation in monocytes. • LpX-induced hypercholesterolemia altered phenotypes of circulating monocytes. • Removal of LpX by plasma exchange reduced size of the cutaneous xanthomas. • Removal of LpX by plasma exchange improved monocyte phenotypes. [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]

Objective To explore the hypoglycaemic and hypocholesterolemic potential of conventional and supercritical extracts of black cumin. Methods Purposely, rat modelling was carried out for 2 months by designing three studies i.e. study I (normal rats), study II (hyperglycaemic rats) and study III (hypercholesterolemic rats). Each study was further divided into three groups based on diet i.e. control, functional diet (contained extract of black cumin prepared by using conventional solvent) and nutraceutical diet (contained extract of black cumin prepared by supercritical fluid extraction system). Results During whole trial, an abating trend was observed in the level of serum cholesterol with maximum reduction (12.8%) in nutraceutical group of study III. Low density lipoprotein and triglyceride level was also lowered maximum in study III as 17.1% and 11.6%, respectively. Whereas, highest decline in glucose level was in nutraceutical group of study II as 11.2%. Conclusions Inclusion of black cumin extracts in diet significantly lowers the occurrence of hyperglycaemia and hypercholesterolaemia. Furthermore, hypoglycaemic and hypocholesterolemic potential of nutraceutical diet is more prominent as compared to functional diet. [ABSTRACT FROM AUTHOR]

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]

The treatment of hypercholesterolemia with bile acid (BA) sequestrants results in upregulation of BA synthesis through the classical pathway initiated by cholesterol 7a-hydroxylase (CYP7A1). To characterize the detailed dynamics of serum lipid and BA concentrations and the BA synthesis rate in response to treatment with BA sequestrants and to determine whether the -203A/C promoter polymorphism of the CYP7A1 encoding gene (CYP7A1) affects such a response, this pilot study was carried out in healthy men (8 homozygous for the -203A allele and 8 homozygous for the -203C allele of CYP7A1). The subjects were treated for 28 days with colesevelam and blood was drawn for analysis before and on days 1, 3, 7, 14 and 28 of treatment. The response of lipids, BA, fibroblast growth factor-19 (FGF19) and 7a-hydroxy-4-cholesten-3-one (C4) to colesevelam did not differ between carriers of -203A and -203C alleles; their data were then aggregated for further analysis. Colesevelam treatment caused immediate suppression of FGF19 concentration and a fivefold increase in CYP7A1 activity, as assessed from C4 concentration, followed by a 17% decrease in LDL-cholesterol. Although total plasma BA concentrations were not affected, the ratio of cholic acid/total BA rose from 0.25±0.10 to 0.44±0.16 during treatment at the expense of decreases in chenodeoxycholic and deoxycholic acid. [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]

Background--Cardiovascular disease burden and treatment patterns among patients with familial hypercholesterolemia (FH) in the United States remain poorly described. In 2013, the FH Foundation launched the Cascade Screening for Awareness and Detection (CASCADE) of FH Registry to address this knowledge gap. Methods and Results--We conducted a cross-sectional analysis of 1295 adults with heterozygous FH enrolled in the CASCADE-FH Registry from 11 US lipid clinics. Median age at initiation of lipid-lowering therapy was 39 years, and median age at FH diagnosis was 47 years. Prevalent coronary heart disease was reported in 36% of patients, and 61% exhibited 1 or more modifiable risk factors. Median untreated low-density lipoprotein cholesterol (LDL-C) was 239 mg/dL. At enrollment, median LDL-C was 141 mg/dL; 42% of patients were taking high-intensity statin therapy and 45% received >1 LDL-lowering medication. Among FH patients receiving LDL-lowering medication(s), 25% achieved an LDL-C <100 mg/dL and 41% achieved a ≥50% LDL-C reduction. Factors associated with prevalent coronary heart disease included diabetes mellitus (adjusted odds ratio 1.74; 95% confidence interval 1.08-2.82) and hypertension (2.48; 1.92-3.21). Factors associated with a ≥50% LDL-C reduction from untreated levels included high-intensity statin use (7.33; 1.86-28.86) and use of >1 LDL-lowering medication (1.80; 1.34-2.41). Conclusions--FH patients in the CASCADE-FH Registry are diagnosed late in life and often do not achieve adequate LDL-C lowering, despite a high prevalence of coronary heart disease and risk factors. These findings highlight the need for earlier diagnosis of FH and initiation of lipid-lowering therapy, more consistent use of guideline-recommended LDLlowering therapy, and comprehensive management of traditional coronary heart disease risk factors. [ABSTRACT FROM AUTHOR]

This study evaluates in vitro hypocholesterolemic and antioxidant potential of Calotropis procera root extracts and its diterpenoid rich fraction. In vitro hypocholesterolemic activity was determined by measuring cholesterol concentration in the normal and hypercholesterolemic human red blood cells (hRBCs) after incubating with the test extracts (1, 10 and 100 µg/mL) for 24 h. The bioactivity guided fractionation of crude acetone root extract yielded a fraction with EC 50 63.03±1.10 µg/mL in relation to ascorbic acid standard (EC 50 39.95±1.25 µg/mL). In case of isolated erythrocytes of diseased donors, the purified fraction reduced the membrane cholesterol up to 1.62±0.22 µmole CH/mL (52%), whereas it was 1.01±0.75 µmole CH/mL (35%) in case of quercetin standard. The whole blood, when incubated with purified fraction and quercetin standard at 10 µg/mL for 24 h, it showed significant decrease in the cholesterol level of hRBCs of both, healthy ( P <0.001) as well as diseased ( P <0.05) donors. GC-HRMS analysis of the bioactive diterpenoid rich fraction revealed cyclic diterpenoids – Phenol, 2,4 bis (1,1-dimethylethyl) ester and 1,2 benzedenedicarboxylic acid, bis(2-methylpropyl) ester. In conclusion, C. procera root extract and its diterpenoid rich fraction exhibited potential hypocholesterolemic effect possibly by inhibiting membrane cholesterol synthesis and improving antioxidant levels in hypercholesterolemic hRBCs. [ABSTRACT FROM AUTHOR]

Statins [3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase], are wonder drugs that have reshaped the treatment of hypercholesterolemia and associated cardiovascular diseases. However, evidence from various studies indicates existence of many statin-induced side effects such as myopathies, rhabdomyolysis, hepatotoxicity, peripheral neuropathy, impaired myocardial contractility, diabetes, autoimmune diseases, and erectile dysfunction (ED). Physician awareness of these side effects is reported to be very low even for the adverse effects (AEs) most widely reported by patients. This can lead to incorrect treatment decisions, compromised patient care, and an increase in patient morbidity. Therefore, the aim of this article is to highlight the AEs of statin therapy as well as rational management of these complications to further improve safety of these excellent drugs. [ABSTRACT FROM AUTHOR]

Nothing to disclose. None. We reviewed a case of a young man referred for management of severe hypercholesterolemia and bilateral palpebral xanthelasma. This is intended to highlight key features in diagnosis and management of severe hypercholesterolemia due to LpX from biliary obstructive disease. To review clinical management of severe hypercholesterolemia due to LpX. Clinical management at tertiary care lipid program. A 22-year-old slim male with history of Wilson's disease, Crohn's disease, and primary sclerosing cholangitis (PSC) was referred for management of severe hypercholesterolemia and progressive symmetric palpebral xanthelasmas. There is no family history of severe hypercholesterolemia or premature atherosclerotic cardiovascular disease (ASCVD), nor were any other secondary causes identified. He was successfully treated with cholestyramine for pruritis which resulted in marked total cholesterol reduction and increased triglyceride (TG) level. Very severe hypercholesterolemia with total cholesterol levels >500 mg/dL is a rare condition. Levels this high are typically associated with homozygous familial hypercholesterolemia (FH) due to an increased level of atherogenic LDL cholesterol (LDL-C). However, other causes need to be considered in the right clinical context, such as lipoprotein fraction lipoprotein X (LpX) in an individual with obstructive biliary disease. LpX is a consequence of ''spillover'' of hepatic free cholesterol (FC)/phospholipid complexes in disc- shaped lipoproteins which do not contain apoB. Consequently, there is wide discordance between apoB and the calculated LDL-C and high serum FC levels. The diagnosis is typically made in the right clinical context without FC measurement since this test is not commercially available. Hypercholesterolemia due to LpX is not associated with increased ASCVD risk, but its presence can be a marker of the severity of liver disease and cause other medical complications including hyperviscosity syndrome, pulmonary embolism and cholesteroloma.Our patient's marked increase in total cholesterol without severe increase in apoB suggested progression of PSC and prompted referral back to his primary Hepatology team. Additional cholesterol-lowering pharmacotherapy is not indicated for hypercholesterolemia due to LpX without hyperviscosity. [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]

Abstract: Objective: To explore the effect of alcoholic extract of Bacopa monniera (AEBM) on high cholesterol diet-induced rats. Methods: The shade-dried and coarsely powdered whole plant material (Bacopa monniera) was extracted with 90% ethanol, finally filtered and dried in vacuum pump. The experimental rats were divided into 4 groups: control (group-I), Rats fed with hypercholesterolemic diet (HCD) for 45 days [4% cholesterol (w/w) and 1% cholic acid], Rats fed with HCD for 45 days+AEBM (40mg/kg, body weight/day orally) for last 30 days (group-III) and AEBM alone (group-IV). Blood and tissues (Aorta) were removed to ice cold containers for various biochemical and histological analysis. Results: AEBM treatment significantly decreased the levels of TC, TG, PL, LDL, VLDL, atherogenic index, LDL/HDL ratio, and TC/HDL ratio but significantly increased the level of HDL when compared to HCD induced rats. Activities on liver antioxidant status (SOD, CAT, GPx, GR, GST) were significantly raised with concomitant reduction in the level of LPO were obtained in AEBM treated rats when compared to HCD rats. Treatment with AEBM significantly lowered the activity of SGOT, LDH and CPK. Histopathology of aorta of cholesterol fed rat showed intimal thickening and foam cell deposition were noted. Conclusions: These results suggests that AEBM extended protection against various biochemical changes and aortic pathology in hypercholesterolemic rats. Thus the plant may therefore be useful for therapeutic treatment of clinical conditions associated hypercholesterolemia. [Copyright &y& Elsevier]

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Abstract: Patients with familial hypercholesterolemia (FH) are not always able to achieve target levels of low-density lipoprotein (LDL) cholesterol with currently available medications. A number of novel pharmaceutical approaches to LDL cholesterol-lowering have been in development. Antisense oligonucleotides are molecules that are injected subcutaneously and cause decreased release of apolipoprotein B-containing lipoproteins from the liver. Microsomal transfer protein inhibitors block the accumulation of triglyceride into apolipoprotein B precursors. Squalene synthase inhibitors partially block a late step in cholesterol biosynthesis. Proprotein convertase subtilisin kexin type 9 inhibitors can lead to increased LDL cholesterol receptor functioning and thereby decrease LDL cholesterol levels. Thyroid hormone analogues lower LDL cholesterol and other lipoproteins by a selective effect on certain thyroid hormone receptors, avoiding the adverse effects of excessive thyroid hormone levels. Several of these classes of lipid-modifying agents are currently in clinical trials. Long-term safety data will be needed before any are available to be used clinically, but some hold significant potential for improving treatment options for patients with FH. [ABSTRACT FROM AUTHOR]

Abstract: Options for treatment of severe heterozygous and homozygous familial hypercholesterolemia prior to the statin era were limited by significant side effects and morbidity. The advent of both the statins and technology for the selective removal of LDL via apheresis have revolutionized management but challenges remain. [ABSTRACT FROM AUTHOR]

Background: Familial hypercholesterolemia (FH) is associated with an increased risk of premature atherosclerosis. Central in this aspect is enhanced inflammation and endothelial dysfunction. Objective: We sought to examine inflammatory cytokines and endothelial dysfunction in patients with FH treated with statins (n = 14) compared with healthy control patients (n = 11). Methods: Endothelial function was evaluated by the use of the Endo-PAT® system which measured mean reactive hyperemia index. Fasting blood samples were drawn, and 27 biomarkers in addition to standard laboratory tests were analyzed. Results: There were no statistically significant differences between the FH group and the control group regarding age, weight, blood pressure, or body mass index. Endothelial function given as RHI was 1.58 and 1.93 (P = NS) in the control and FH groups, respectively. There were no differences between the groups in tumor necrosis factor-alpha, interleukin (IL-1) beta, IL-1 receptor antagonist, IL-6, IL-10, monocyte chemoattractant protein 1, high-sensitivity C-reactive protein, or any of the other inflammatory markers tested. Furthermore, no significant differences between the groups in high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, apolipoprotein A, apolipoprotein B, lipoprotein (a), homocysteine, HbA1c, platelets, and fibrinogen were found. Conclusion: Endothelial function assessed by reactive hyperemia index-peripheral arterial tonometry or inflammatory state assessed by soluble inflammatory biomarkers were not different in FH patients on statins compared with healthy control patients. [ABSTRACT FROM AUTHOR]

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]

Background: Low-density lipoprotein cholesterol (LDL-C) can either be calculated or measured directly. Clinical guidelines recommend the use of calculated LDL-C (C-LDL-C) to guide therapy because the evidence base for cholesterol management is derived almost exclusively from trials that use C-LDL-C, with direct measurement of LDL-C (D-LDL-C) being reserved for those patients who are nonfasting or with significant hypertriglyceridemia. Objective: Our aim was to determine the clinical equivalence of directly measured-LDL-C, using a Siemens Advia Chemistry System, and fasting C-LDL-C. Methods: Eighty-one subjects recruited for two cholesterol treatment studies had at least one C-LDL-C and D-LDL-C performed simultaneously; 64 had a repeat lipid assessment after 4 to 6 weeks of therapy, resulting in 145 pairs of C-LDL-C and D-LDL-C. Results: There was significant correlation between D-LDL-C and C-LDL-C (r2 = 0.86). Correlation was significantly better in those with lower total cholesterol, triglycerides, and high-density lipoprotein. In 60% of subjects, the difference between D-LDL-C and C-LDL-C was more than 5 mg/dL and greater than 6%. Clinical concordance between D-LDL-C and C-LDL-C was present in 40% of patients, whereas clinical discordance was noted in 25%. One-third had greater than a 15 mg/dL difference between D-LDL-C and C-LDL-C, whereas 25% had a greater than 20 mg/dL difference. In 47% of subjects, the difference between D-LDL-C and C-LDL-C at baseline and follow-up changed by a minimum of 10% or 10 mg/dL. Conclusions: Our findings suggest that D-LDL-C is not clinically equivalent to C-LDL-C. This puts into question the current recommendation of using D-LDL-C in situations in which C-LDL-C would be inaccurate. [ABSTRACT FROM AUTHOR]

Abstract: Patients with high low-density lipoprotein cholesterol (LDLC) and asymptomatic high creatine kinase (CK) (≥250 but <2500 IU/L, 10× the laboratory upper normal limit [UNL]) are often not started on statins or have statins stopped because of concern about myositis-rhabdomyolysis. In the current report, we prospectively examined the hypothesis that asymptomatic patients with high CK (≥250 but <2500 IU/L) tolerate statins well at doses reducing LDLC to target, less than 100 mg/dL, without development of myalgia-myositis. We assessed outcomes of 3 groups of patients referred to us because of asymptomatic high CK (≥250 but <2500 IU/L)—1 group (n = 29) on statins at referral and continued on statins, 1 group (n = 20) not on statins and started on statins, and 1 group (n = 19) not on statins and not given statins—all restudied 1 month after entry and then every 3 months. Of the 68 patients, 59 (87%) had CK greater than 1 to 3 times the UNL, 7 (10%) had CK greater than 3 to 5 times the UNL, and 2 (3%) had CK greater than 5 to 10 times the UNL. After 1.2 months of follow-up in 29 statin→statin patients, median CK fell from 353 to 301 (P = .0018) and was 287 (P = .015) after 4 months. After 1.3 months of follow-up in 20 no statin→statin patients, median CK fell from 397 to 292 (P = .0094) and was 419 after 4.1 months. After 1.1 months of follow-up in 19 no statin→no statin patients, median CK fell from 392 to 323 (P = .14) and was 271 (P = .029) after 4.2 months. By repeated-measures analysis, there were no differences in entry CK among the 3 treatment groups; CK fell (P = .04) in the no statin→no statin patients. Despite high baseline CK (48 patients with CK 1-5× the UNL, 1 with CK 5-10× UNL), no patients during follow-up on statins developed CK greater than 10 times the UNL (2500 IU/L), none discontinued statins or reduced statin dose because of myalgia-myositis, and there was no rhabdomyolysis. High pretreatment CK, particularly 1 to 5 times the UNL, should not be an impediment to start or continue statins to lower LDLC. [Copyright &y& Elsevier]

Atherogenesis involves the migration of leukocytes into vascular subendothelial space, a process mediated by endothelial and leukocyte cell adhesion molecules. Endothelial molecules are assessed indirectly via serum levels, but leukocyte molecules canbe assessed directly. We have therefore hypothesized that leukocyte adhesion molecules are altered to a greater degree in hypercholesterolemia than serum endothelial adhesion molecules. We examined 29 subjects with hypercholesterolemia and 27 controls at baseline and after 12 weeks of atorvastatin treatment (20 mg/day). Expression of leukocyte integrins CD11a, CD11b, CD18, and CD49d and of L-selectin was measured by flow cytometry. Serum ICAM-1, E-selectin and von Willebrand factor were measured by ELISA. Expression of leukocyte adhesion molecules was significantly higher in patients at baseline than in the controls, except for CD11a. Expression significantly decreased after atorvastatin in most adhesion molecules except for CD11b. In contrast, there was no effect of hypercholesterolemia and/or atorvastatin on the serum endothelial molecules. Leukocyte but not endothelial adhesion molecules were influenced by hypercholesterolemia and by lipid lowering treatment. Leukocyte molecules may therefore be a more sensitive marker of atherogenesis than endothelial molecules. Our results support the role of increased leukocyte adhesiveness in atherogenesis. [ABSTRACT FROM AUTHOR]

Background: Lipid lowering through statin therapy significantly reduces the risk of cardiovascular events. The ENHANCE study is an international 2-year, randomized, double-blind, controlled trial designed to test the hypothesis that treatment of hypercholesterolemia by use of 2 complementary agents, ezetimibe (a specific cholesterol absorption inhibitor) and simvastatin (a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor), will result in larger beneficial effects on carotid artery intima-media thickness (CA IMT) than simvastatin monotherapy. Methods: The study will recruit 725 men and women with heterozygous familial hypercholesterolemia. After a placebo washout period, participants are randomized to receive daily administration of either simvastatin 80 mg and ezetimibe 10 mg or simvastatin 80 mg and placebo. The ENHANCE trial uses novel state-of-the-art single-frame digital image acquisition and rigorous quality assurance and control. Results: The primary end point is mean change from baseline to 2 years in CA IMT, using composite measures from the right and left far wall common carotid artery, carotid bulb, and internal carotid artery. Secondary end points include (1) the proportion of participants who exhibit reductions in CA IMT, (2) the change in maximum far wall IMT, (3) the proportion of participants who develop new carotid artery plaques, and (4) the changes in carotid plus common femoral artery IMT. Conclusions: This study addresses the question of whether a regimen that uses drugs with different mechanisms of action will be of further benefit in terms of atherosclerosis reduction compared to statin monotherapy. [ABSTRACT FROM AUTHOR]

The statins (3-hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors) represent drugs of first choice for treatment of hypercholesterolemia. The safety and efficacy of atorvastatin (CAS 134523-00-5), simvastatin (CAS 79902- 63-9), lovastatin (CAS 75330-75-7), pravastatin (CAS 81093-37-0) and fluvastatin (CAS 93957-54-1) has been well documented. Statins decrease dose-dependently low-density lipoprotein (LDL) cholesterol as well as coronary events and total mortality. Clinical outcome data indicate that for simvastatin the lowest number of treated patients is needed to prevent one major coronary event (NNT 15). Based on an approximately 30 % reduction of LDL (valid surrogate parameter) atorvastatin (5 mg/day) and simvastatin (10 mg/day) are the most potent agents whereas 40 mg of lovastatin or pravastatin and 60 mg of fluvastatin are needed to reach this "therapeutic target". While all statins share the same mode of action their pharmacokinetic properties and their susceptibility to drug interactions differ slightly. Agents inhibiting CYP3A4 (e.g. grapefruit juice, itraconazole, cyclosporine) should be discouraged if a patient is on atorvastatin, lovastatin or simvastatin. Likewise, fluconazole interferes with the CYP2C9-mediated hepatic elimination of fluvastatin. Moreover, coadministration of gemfibrozil should be avoided because it seems to increase the very low risk for statin-induced rhabdomyolysis. Several statins are available and their equieffective doses have been defined. Selection of a particular drug should be primarely based on clinical outcome data. However, costs and in certain situations the pharmacokinetic profile including the interaction potential of the statins should be taken into account. [ABSTRACT FROM AUTHOR]

Abstract: Heterozygous familial hypercholesterolemia is an autosomal dominant disorder characterized by half the normal number of low density lipoprotein (LDL) receptors and markedly elevated LDL cholesterol levels. FH is a very common disorder, affecting about one in 500 in the general population and occurring more frequently in certain ethnic groups. Untreated, roughly 50% of men and 25% of women who have FH will have had their first myocardial infarction or other cardiovascular event by the age of 50. Since roughly half of an affected individual''s first degree relatives will also have FH, Cascade Screening represents an important tool for patient identification. Although treating FH represents a clinical challenge, most affected patients can be managed with currently available treatment modalities including statins, resins, cholesterol absorption inhibitors, and niacin. LDL apheresis is an option for individuals who fail currently available oral prescription therapies. And mipomersen is an antisense therapy designed to inhibit apolipoprotein B (apo B) synthesis. This agent is currently being studied in FH patients who fail to achieve target LDL cholesterol levels with the aforementioned prescription therapies. [Copyright &y& Elsevier]

Background and study aims: Cardiovascular diseases (CVD) are the leading cause of death worldwide. Among all CVDs, coronary heart disease (CHD) is the most common. While data for CHD and its risk factors are available for different regions and countries, the Middle East lacks such reliable data. The CEPHEUS-MIDDLE EAST study (ClinicalTrials.gov ID: NCT 01031277) was performed to gain a unique perspective on the potential undertreatment of hypercholesterolemia in this area. Patients and methods: This multi-centric, non-interventional study recruited a total of 5457 consecutive patients by 177 specialists and general practitioners in Saudi Arabia, United Arab Emirates, Kuwait, Qatar, Bahrain and Oman between 22 November 2009 and 07 July 2010. Data collection (Investigator and Patient Questionnaires, Patient Record Form and a fasting blood sample) occurred at a single visit. Results: Subjects were 58.16% male (n =3060) with a mean age of 55.56years. The reasons for being pharmacologically treated were primary (71.54%; n =3773), secondary prevention (27.27%; n =1438) and familial hypercholesterolemia (1.19%; n =63). The most frequent treatments were with statins (94.43%; n =5260) or fibrates (3.12%; n =174). According to the Patient Questionnaire, only 43.91% (2304) of patients had been informed about their cholesterol levels, even though, according to the Investigator Questionnaire, physicians set individual target cholesterol levels for 70.00% of their patients. The majority of physicians (87.57% ; n =155), reported to use guidelines to establish target cholesterol levels, with the NCEP ATP III being the most used frequently used (46.53%; n =67). ▪ Conclusions: Although the risk of mortality for patients with CHD is well-known and a number of guidelines exist to reduce this risk, the hypercholesterolemia of patients in the Middle-Eastern countries surveyed is still being undertreated. [ABSTRACT FROM AUTHOR]

Abstract: Aim: To investigate the effect of pitavastatin on the ratio of serum high-molecular weight (HMW) adiponectin to total adiponectin. Methods: Twenty-four type 2 diabetic patients with hypercholesterolemia were studied before and 12 weeks after pitavastatin treatment (2mg/day). Results: Treatment with pitavastatin significantly increased the ratio of serum HMW adiponectin to total adiponectin. Conclusions: This data showed the pleiotropic effect of pitavastatin on the serum active form of adiponectin. [Copyright &y& Elsevier]

The author reflects on the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) study in patients with hypercholesterolemia. He cites several accounts based on trial results such as inefficacy of ezetimibe in vasculature despite its substantial reduction of lipoprotein cholesterol (LDL-C) levels and insufficient methods used to calculate femoral intima-media thickness (IMT). He adds that significant regression was seen in patients receiving simvastatin.

Introduction: La majorité (2/3) des hypercholestérolémies familiales (HF) est due à des mutations du gène du récepteur aux LDL. Ce gène comprend 18 exons, qui codent pour 5 domaines où peuvent siéger les mutations. Les domaines principaux sont celui de la liaison du LDL (exons 2 à 6) et celui de l’homologie au précurseur de l’EGF (exons 7 à 14). Par ailleurs, les mutations observées peuvent être à l’origine soit d’un allèle défectif, soit d’un allèle nul, ce dernier entraînant un phénotype clinique et biologique plus sévère. Nous avons voulu étudier les liens entre domaine de mutation et type de mutation dans une population de patients HF. Patients et méthodes: Nous avons inclus 135 patients avec HF génétiquement identifiée (mutation du gène du récepteur aux LDL), et nous avons comparé (par test du chi2) la répartition entre allèle défectif (D)/nul (N) selon que la mutation touche le domaine de liaison du LDL (groupe L) ou celui de l’homologie au précurseur de l’EGF (groupe E). Résultats: Parmi les 135 patients, le groupe L regroupait 53 patients (39 %), le groupe E 66 patients (49 %), 16 patients présentaient une mutation autre. Dans le groupe L, 27 patients (51 %) avaient un allèle N, 26 (49 %) un allèle D, vs 16 N (24 %) et 50 D (76 %) dans le groupe E Conclusion: Dans une population de patients avec HF génétiquement identifiée, une mutation touchant le domaine de liaison du LDL entraîne 2 fois plus de phénotypes sévères (allèle nul) qu’une mutation touchant le domaine d’homologie au précurseur de l’EGF. [Copyright &y& Elsevier]

Introduction: Le traitement médicamenteux actuel de l’hypercholestérolémie familiale (HF) repose sur les statines. Mais compte tenu d’un taux de cholestérol-LDL (C-LDL) de départ élevé, une association thérapeutique est parfois nécessaire, pouvant alors inclure l’ézétimibe, selon le taux-cible de C-LDL souhaité. Nous avons voulu évaluer le pouvoir hypocholestérolémiant de cette molécule ajoutée aux statines chez des patients porteurs d’une HF. Patients et méthodes: Nous avons inclus 71 patients avec HF génétiquement identifiée (mutation du gène du récepteur aux LDL), et nous avons comparé (par test t de Student) la variation du taux de C-LDL sous traitement selon que les patients étaient traités par statine seule (groupe S), ou par statine + ézétimibe (groupe E). Le taux-cible de C-LDL était de 1,60g/l pour les patients en prévention primaire, et de 1,00g/l en prévention secondaire. Résultats: Le groupe S comprenait 24 patients, le groupe E 47 patients. Les taux de C-LDL avant traitement et le pourcentage de baisse sous traitement étaient pour le groupe S vs le groupe E : 2,74±0,66 vs 3,08±0,57g/l (p<0,05) et 39,0±11,9 vs 57,0±10,6 % (p<0,05). Conclusion: Dans une population de patients avec HF génétiquement identifiée, l’ajout d’ézétimibe à un traitement par statine entraîne une baisse supplémentaire du C-LDL de 18 %, soit un effet cohérent avec l’efficacité revendiquée de ce médicament. Il reste à déterminer si des facteurs génétiques préexistants tels le génotype de l’ApoE pourraient moduler cette réponse. [Copyright &y& Elsevier]

The article discusses research on the therapeutic use of red yeast rice for hypercholesterolemia. It references a study published in the 2009 issue of "Annals of Internal Medicine." The study included 31 patients with a history of statin-associated myalgias, who were randomized to either receive red yeast rice or placebo. It concluded that red yeast rice and therapeutic lifestyle change decrease low-density lipoproteins (LDL)-cholesterol without increasing creatine phosphokinase (CPK) or pain levels.