Severe Hypercholesterolemia Research Articles

Whole-Gene Duplication of PCSK9 as a Novel Genetic Mechanism for Severe Familial Hypercholesterolemia

BackgroundFamilial hypercholesterolemia (FH) is a common genetic disorder of severely elevated low-density lipoprotein (LDL) cholesterol, characterized by premature atherosclerotic cardiovascular disease. Although copy number variations (CNVs) are a large-scale mutation-type capable of explaining FH cases, they have been, to date, assessed only in the LDLR gene. Here, we performed novel CNV screening in additional FH-associated genes using a next-generation sequencing–based approach. MethodsIn 704 patients with FH, we sequenced FH-associated genes APOB, PCSK9, LDLRAP1, APOE, STAP1, LIPA, and ABCG5/8 using our LipidSeq targeted next-generation sequencing panel. Bioinformatic tools were applied to LipidSeq data for CNV screening, and identified CNVs were validated using whole-exome sequencing and microarray-based copy number analyses. ResultsWe identified a whole-gene duplication of PCSK9 in 2 unrelated Canadian FH index cases; this PCSK9 CNV was also found to cosegregate with affected status in family members. Features in affected individuals included severely elevated LDL cholesterol levels that were refractory to intensive statin therapy, pronounced clinical stigmata, premature cardiovascular events, and a plasma PCSK9 of approximately 5000 ng/mL in 1 index case. We found no CNVs in APOB, LDLRAP1, APOE, STAP1, LIPA, and ABCG5/8 in our cohort of 704 FH individuals. ConclusionsHere, we report the first description of a CNV affecting the PCSK9 gene in FH. This finding is associated with a profound FH phenotype and the highest known plasma PCSK9 level reported in a human. This finding also has therapeutic relevance, as elevated PCSK9 levels may limit the efficacy of high-dose statin therapy and also PCSK9 inhibition.

IgM autoantibodies against lipoprotein(A) as an “anti-atherogenic” factor in patients with severe hyperlipidemia

Aim: To study the relationship of lipoprotein(a) [Lp(a)], autoantibodies (autoAb) against Lp(a) and lipoprotein subfractions with atherosclerosis of carotid arteries (CA) in patients with severe hypercholesterolemia.

Efficacy and tolerability of long-term lipoprotein apheresis in the management of severe hypercholesterolemia and of elevation of lipoprotein(a): Data from a single center in portugal

Aim: Background: Low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) (Lp(a)) are established causal risk factors for cardiovascular disease (CVD). Lipoprotein apheresis (LA) is often required for treatment of patients with a high risk for CVD due to hypercholesterolemia and/or Lp(a).

Prevalence of severe hypercholesterolemia in Russian acute coronary syndrome registry

Aim: There are gaps in our knowledge of prevalence, awareness and control of severe hypercholesterolemia (low-density lipoprotein-cholesterol cholesterol (LDL-C) cholesterol > 5.0 mmol/l) in the Russian Federation. Increased cardiovascular morbidity and mortality in Russia is related to high prevalence of hypercholesterolemia and low statin use.

Caracterización clínica y molecular en hipercolesterolemia familiar homocigota

Introducción. La hipercolesterolemia familiar homocigota es un desorden genético raro que se caracteriza por niveles muy elevados de colesterol y por una pobre respuesta al tratamiento farmacológico convencional (estatinas, ezetimibe). El estudio molecular es un recurso importante que puede impactar de forma positiva en el tratamiento y pronóstico de estos pacientes; sin embargo, este tipo de estudio no siempre está disponible en todos los centros de atención. El resultado de estas pruebas genéticas permite identificar pacientes que se pueden beneficiar de nuevas opciones terapéuticas asociadas a mayor disminución de colesterol total y LDL.Presentación de casos. Se presentan los casos de dos hermanas con hipercolesterolemia severa y pobre respuesta al tratamiento farmacológico convencional, en quienes el diagnóstico molecular confirmó una mutación en homocigosis del gen del receptor de la lipoproteína de baja densidad. Con base en estos resultados, en ambos casos se adicionó un inhibidor selectivo de proteína microsomal de transferencia de triglicéridos al manejo hipolipemiante convencional, con lo que se logró una reducción de más del 49% en los niveles séricos de colesterol total y LDL.Conclusión. Las pruebas moleculares son una herramienta importante para definir el diagnóstico, pronóstico y tratamiento de los pacientes con hipercolesterolemia familiar homocigota.

Splenectomy had no significant impact on lipid metabolism and atherogenesis in Apoe deficient mice fed on a severe atherogenic diet.

For a long time, our major understanding of the spleen is to function as a blood filter for the removal of aged erythrocytes and circulating microorganisms. Splenectomy, therefore, has been widely performed in case of trauma and a variety of hematologic disorders. Although some studies have indicated an increased rate of developing hyperlipidemia and atherosclerotic cardiovascular diseases in splenectomized patients, our recognition of the splenic regulation on lipid metabolism and atherogenesis is still lacking. Here we explored this issue in Apoe deficient (Apoe-/-) mice fed on an atherogenic diet containing 0.5% cholesterol and 20% fat. 7-week-old male Apoe-/- mice were randomly divided into splenectomy group and sham operation group. After 1-week recovery from the surgery, mice were subjected to the atherogenic diet for the next 8 weeks. The atherogenic diet induced a severe hypercholesterolemia (about 1500 mg/dl), steatohepatitis and accelerated atherogenesis in the Apoe-/- mice. Splenectomy, compared to sham operation, did not alter plasma lipid levels or lipoprotein profiles; it also did not alter hepatic or adipose lipid deposition. Meanwhile, splenectomy did not alter atherosclerotic plaque burden or composition; it also did not alter aortic gene expression associated with macrophage inflammatory responses. Our data suggested that splenectomy had no significant impacts on lipid metabolism and atherogenesis in Apoe-/- mice fed on a severe atherogenic diet.

Lipoprotein Apheresis Acutely Reverses Coronary Microvascular Dysfunction in Patients With Severe Hypercholesterolemia

ObjectivesThis study evaluated whether lipoprotein apheresis produces immediate changes in resting perfusion in subjects with severe hypercholesterolemia, and whether there is a difference in the response between peripheral and coronary microcirculations. BackgroundLipoprotein apheresis is used in patients with severe hypercholesterolemia to reduce plasma levels of low-density lipoprotein cholesterol. MethodsQuantitative contrast-enhanced ultrasound perfusion imaging of the myocardium at rest and skeletal muscle at rest and during calibrated contractile exercise was performed before and immediately after lipoprotein apheresis in 8 subjects with severe hypercholesterolemia, 7 of whom had a diagnosis of familial hypercholesterolemia. Myocardial perfusion imaging was also performed in 14 normal control subjects. Changes in myocardial work and left ventricular function were assessed by echocardiography. Ex vivo ovine coronary and femoral artery ring tension assays were assessed in the presence of pre- and post-apheresis plasma. ResultsApheresis acutely decreased low-density lipoprotein cholesterol (234.9 ± 103.2 mg/dl vs. 67.1 ± 49.5 mg/dl; p < 0.01) and oxidized phospholipid on apolipoprotein B-100 (60.2 ± 55.2 nmol/l vs. 47.0 ± 24.5 nmol/l; p = 0.01), and acutely increased resting myocardial perfusion (55.1 [95% confidence interval: 77.2 to 73.1] IU/s vs. 135 [95% confidence interval: 81.2 to 189.6] IU/s; p = 0.01), without changes in myocardial work. Myocardial longitudinal strain improved in those subjects with reduced pre-apheresis function. Skeletal muscle perfusion at rest and during contractile exercise was unchanged by apheresis. Acetylcholine-mediated dilation of ex vivo ovine coronary but not femoral arteries was impaired in pre-apheresis plasma and was completely reversed in post-apheresis plasma. ConclusionsLipoprotein apheresis produces an immediate improvement in coronary microvascular function, which increases myocardial perfusion and normalizes endothelial-dependent vasodilation. These changes are not observed in the periphery. (Acute Microvascular Changes With LDL Apheresis; NCT02388633)

Frequency of Statin Use in Patients With Low-Density Lipoprotein Cholesterol ≥190 mg/dl from the Veterans Affairs Health System

Patients with low-density lipoprotein cholesterol (LDL-C) ≥190 mg/dl have severe hypercholesterolemia and are at markedly increased risk for adverse cardiovascular events. This study sought to examine the prevalence and treatment of patients with uncontrolled severe hypercholesterolemia in the Veterans Affairs (VA) Health System. The study population was comprised of VA outpatients ≥21 years of age without atherosclerotic disease or diabetes mellitus and an index LDL-C ≥190 mg/dl during April 2011 to March 2014. Patients needed to have filled medications at the VA within the past 6 months. Patient and facility-level predictors of statin use, high-intensity statin use, and statin intensification were analyzed using multivariate logistic regressions. There were a total of 63,576 patients meeting inclusion criteria, including 8,553 (13.5%) women and 26,879 (29.0%) nonwhite patients. The mean (±S.D.) age was 55 (±13) years and the mean of the most recent LDL-C values was 207 ± 22 mg/dl. Only 52% of all eligible patients were on any statin therapy and 9.7% received high-intensity statin therapy. High-intensity statin use increased from 8.6% in 2011 to 13.6% in 2014 (p < 0.001). In adjusted analysis, patients <35 or >75 years of age were less likely to be on a statin (p < 0.001). Women were less likely to be treated than men, odds ratio = 0.88; 95% confidence interval (0.83, 0.92). Similar patterns were observed for predictors of high-intensity statin use and statin intensification. In conclusion, only half of high-risk VA patients with uncontrolled severe hypercholesterolemia were treated with statins and a small minority was on high-intensity statin therapy.

Improving Familial Hypercholesterolaemia Diagnosis – Functional in Vitro Analysis of LDLR Missense Variants Found in the Portuguese FH Cohort

Familial hypercholesterolemia (FH) is underdiagnosed in children. We assessed a combination of two screening methods. The first method was to detect hypercholesteraemic children and then study the parents (Ch-P pathway), and the second one was to study the offspring of FH-affected parents (P-Ch pathway).In the Ch-P path, primary care paediatricians were asked to include lipid profiling or, at least, total cholesterol (TC) and then lipid profiling if TC was higher than 5.2 mmol/L in any clinically indicated blood test. Children with LDL-C ≥ 3.5 mmol/L, plus either a family history of early cardiovascular disease or one parent with severe hypercholesterolemia, were referred to the lipid unit where the parents, rather than their children, were studied. In parents with definite, clinical FH, a genetic study was performed. Focused genetic testing was performed on all offspring of genetically positive parents. The P-Ch path consisted of the active study of children from definite FH adults.Fifty-nine paediatricians covering a total population of 63,616 children agreed to participate in the project. Of the 216 children (122 Ch-P and 94 P-Ch) who were ultimately referred to the lipid unit, 87 children with FH (84% genetically positive) were identified. Additionally, 41 parents (from 40 families) were newly diagnosed with FH (63% genetically positive). Forty-nine different mutations were detected: 46 in the LDLR, 2 in the PCSK9 and 1 in APOB gene.The implementation of active strategies to detect FH in children, in close collaboration with primary care paediatricians, provides a high-performance method for early FH detection.

Current Role of Lipoprotein Apheresis in the Treatment of High-Risk Patients.

Lipoprotein apheresis (LA) is a therapeutic approach to save the lives of patients who are at an extremely high risk of developing cardiovascular events (CVE), especially after all other therapeutic options were not tolerated, or appeared not to be effective enough. Homozygous familial hypercholesterolemia represents a clear indication to start LA therapy. Another recognized indication is a severe hypercholesterolemia, which induced CVE, often in association with other risk factors. In the last years, an expressive elevation of lipoprotein(a) (Lp(a)) emerged as an indication for LA. In Germany, progress of atherosclerosis should have been documented before the permission to start LA therapy is given in these patients. Usually, all LA methods acutely decrease both LDL-C and Lp(a). However, specific columns which reduce only Lp(a) are available. Case reports and prospective observations comparing the situation before and during LA therapy clearly show a high efficiency with respect to the reduction of CVE, especially in patients with high Lp(a) levels. PCSK9 inhibitors may reduce the need for LA in patients with heterozygous or polygenetic hypercholesterolemia, but in some patients, a combination of these drugs with LA will be necessary. In the future, an antisense oligonucleotide against apolipoprotein(a) may offer an alternative therapeutic approach.

Abstract 032: Somatic Editing of Ldlr with AAV-CRISPR for Atherosclerosis Studies

Background: Current methods to study genetic contributions to atherosclerosis are time-consuming and expensive. The Ldlr and Apoe knockout (KO) models are currently the gold-standard, but require extensive backcrossing to homozygosity and congenic status on the C57BL6/J background. More rapid and efficient methods are needed to investigate the ever-growing list of candidate genes identified through human genetics.The C lustered R egularly- I nterspaced S hort P alindromic R epeats/Cas9 (CRISPR/Cas9) genome editing system is a powerful new tool for gene disruption. Hypothesis: Liver-directed somatic disruption of Ldlr using an all-in-one AAV-CRISPR vector can generate atherosclerotic lesions in adult mice, thereby avoiding the need to cross to Ldlr KO mice. Methods: An Adeno-Associated Viral (AAV) vector based on serotype 8 was used to deliver Staphylococcus aureus Cas9 (SaCas9) and small guide RNA (gRNA) targeting the Ldlr gene (AAV-CRISPR). This vector was compared head-to-head with AAV-mediated overexpression of a human gain-of-function variant of PCSK9 , a recent model that mimics Ldlr KO through promoting degradation of the Ldlr protein. Adult C57BL6/J mice received either: 1 ) saline, 2 ) AAV-CRISPR, or 3 ) AAV-hPCSK9, versus 4 ) germline Ldlr KO mice. Animals were placed on a Western diet for twenty weeks and followed for changes in plasma lipids, atherosclerotic lesion burden, and editing efficiency. Results and Conclusion: Disruption of Ldlr with AAV-CRISPR vector was robust, resulting in severe hypercholesterolemia and atherosclerosis on a standard western diet. AAV-hPCSK9 also produced atherosclerotic lesions as expected from previous reports. Lesion burden was slightly lower with AAV-CRISPR and AAV-hPCSK9 relative to germline Ldlr KO mice. Unexpected sexual dimorphism was also observed with AAV-CRISPR, with the greatest effects seen in male mice. In summary, our all-in-one AAV-CRISPR vector is a rapid and efficient alternative to the use of Ldlr KO mice to study atherosclerosis.

New data on the use of rosuvastatin and acetylsalicyl acid for the prolongation of human life

This review deals with the necessary and relevant measures for primary and secondary prevention of cardiovascular diseases in Russia. The latest European and American guidelines emphasize that statins are the main class of drugs to be used to improve prognosis. The use of rosuvastatin is justified among the categories of moderate and high risk of developing cardiovascular complications, especially in severe hypercholesterolemia. The use of acetylsalicylic acid is undoubtedly useful for the secondary and, which is more controversial, for the primary prevention of cardiovascular diseases. Over the last few years, major clinical studies on the prevention of cardiovascular, hemorrhagic and oncological complications enable to rely on the expediency of combined, safe use of rosuvastatin and acetylsalicylic acid in individuals over 50 years of age with moderate and high cardiovascular risk. The use of both drugs in one tablet (the original drug Rosulip ASA®, EGIS Pharmaceuticals PLC, Hungary) will significantly increase the compliance with the vital therapy and significantly expand the use of rosuvastatin in clinical practice, which means further reduction in morbidity and mortality from atherosclerotic cardiovascular diseases.

Pharmacokinetic interactions and tolerability of rosuvastatin and ezetimibe: an open-label, randomized, multiple-dose, crossover study in healthy male volunteers.

PurposeRosuvastatin is a synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor that effectively reduces low-density lipoprotein cholesterol levels. However, statin monotherapy does not always achieve acceptable low-density lipoprotein cholesterol levels in patients with severe hypercholesterolemia. Ezetimibe, a selective cholesterol-absorption inhibitor, is approved for use as a monotherapy or combination therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors for patients with hypercholesterolemia. The aim of this study was to examine the pharmacokinetics (PKs) of drug interactions between rosuvastatin and ezetimibe, and the tolerability of combined administration in healthy Korean male volunteers.Subjects and methodsHealthy subjects (n=24) were randomly allocated to 3 treatment groups: rosuvastatin (20 mg) alone, ezetimibe (10 mg) alone, and rosuvastatin (20 mg) plus ezetimibe (10 mg). The drugs were taken once every 24 hours over a period of 10 days. Blood samples were collected to analyze steady-state PKs.ResultsAll adverse events observed during the study were mild, and the frequency was no higher for combined administration than for mono administration. For rosuvastatin, the steady-state mean ratios (90% CI) of the combined over the single dose were 1.076 (1.019–1.136) for AUCτ,ss and 1.099 (1.003–1.204) for concentration at steady-state, respectively. In the case of free and total ezetimibe, the steady-state ratios of AUCτ,ss and concentration at steady-state were 1.131 (1.051–1.218) and 1.182 (1.038–1.346), and 1.055 (0.969–1.148) and 0.996 (0.873–1.135), respectively.ConclusionCombined administration of rosuvastatin and ezetimibe was well tolerated. No clinically significant PK interactions between rosuvastatin and ezetimibe were observed when the 2 drugs were administered concomitantly.

IDENTIFICATION OF PATIENTS WITH FAMILIAL HYPERCHOLESTEROLEMIA IN THE RUSSIAN POPULATION USING THE EXAMPLE OF MOSCOW CITY AND MOSCOW REGION

Aim . To estimate the prevalence of familial hypercholesterolemia (FH) in a sample of Moscow city and Moscow region patients with hypercholesterolemia (HCh) based on lipid spectrum and instrumental methods. Material and methods . The study included two samples of patients (age >18 years), with total cholesterol (TCh) level ≥7.5 mmol/l and/or low-density lipoprotein (LDL) cholesterol level ≥4.9 mmol/l. First sample (n=60) was included to determine secondary hyperlipidemia frequency in newly diagnosed HCh, with measurement of thyroid hormone, glucose and glycated hemoglobin (HbA1c) levels. Patients of the second sample (n=432) from Russian registry of FH (RuFH) were studied by drug therapy assessment, lipid profile measurements, calculation of FH probability according to Dutch and British criteria, carotids duplex scanning (CDS), cardiac perfusion single-photon emission computed tomography (SPECT/CT) using rest/stress protocol. Results . The incidence of secondary dyslipidemia due to diabetes or hypothyroidism in patients with severe HCh was 18.3%. Monotherapy with atorvastatin (34.2%) or rosuvastatin (31.8%), combined therapy with statins and other lipid-lowering drugs (24.4%) prevails in the structure of lipidlowering therapy in patients with severe HCh. The frequency of FH according to Dutch criteria in HCh patients was 15.3%, – 18.1%. Patients with definite FH diagnosis showed higher level of TCh (p<0.001), LDL cholesterol (p<0.001), proprotein convertase subtilisin/kexin type 9 (p<0.001), lower high-density lipoprotein (HDL; p=0.02), and triglycerides (p<0.001). At that HDL cholesterol levels differed only in patients treated with lipid-lowering drugs. Patients with lipid-lowering therapy had significantly higher values of total stenosis percent, the number of plaques, intima-media complex thickness (p<0.001). Patients with lipid-lowering therapy with a definite and probable FH diagnosis had significantly worse values of CDS parameters. CDS parameters correlated with age in both therapeutic groups, and with maximal TCh levels in history in lipid-lowering therapy group (p<0.01). Patients with HCh and established ischemic heart disease showed higher frequency of positive exercise test result, higher values of left ventricle myocardial perfusion heterogeneity and defect severity parameters according to SPECT. Conclusion . Patients with severe HCh and suspected FH in Moscow city and region demonstrate satisfactory awareness, but low adherence to therapy, which is also extremely rarely sufficient to achieve target LDL levels and reduce coronary risks. This leads to early manifestations of atherosclerosis, including characteristic progressive impairments of myocardial perfusion. Despite the ongoing work on primary prevention, it is advisable to recommend sending such patients to specialized clinics for more qualified consultations and selection of optimal lipid-lowering therapy with mandatory further monitoring of its effectiveness.

Statin-related Lichenoid Dermatosis: An Uncommon Adverse Reaction to a Common Treatment.

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are generally safe and well-tolerated drugs that are extensively used for the primary and secondary prevention of atherosclerotic cardiovascular events. Muscle and liver adverse reactions are the best recognized, while cutaneous side effects are exceedingly rare. We present the case of a 65-year-old woman with severe hypercholesterolemia, who developed generalized erythematous cutaneous lesions with pruritus, resembling lichen planus, months after starting treatment with simvastatin. The symptoms disappeared on withdrawal of simvastatin and reappeared within 3 months upon rechallenge with rosuvastatin. In addition to describing a rare adverse effect of statins, the authors also discuss the nutraceutical approach to the management of a statin-intolerant patient.LEARNING POINTSLichenoid drug eruption is an uncommon cutaneous adverse effect of several drugs, with very few cases associated with statins.A temporal relationship, dechallenge/rechallenge information, and the lack of confounding factors or alternative explanations support the suggestion of causality.Due to the lack of optimized alternative treatment options for statin-intolerant patients, the nutraceutical approach should be considered.

Genetics, Lifestyle, and Low-Density Lipoprotein Cholesterol in Young and Apparently Healthy Women

Atherosclerosis starts in childhood but low-density lipoprotein cholesterol (LDL-C), a causal risk factor, is mostly studied and dealt with when clinical events have occurred. Women are usually affected later in life than men and are underdiagnosed, undertreated, and understudied in cardiovascular trials and research. This study aims at a better understanding of lifestyle and genetic factors that affect LDL-C in young women. We randomly selected for every year of age 8 women with LDL-C ≤1st percentile (≤50 mg/dL) and 8 women with LDL-C ≥99th percentile (≥186 mg/dL) from 28 000 female participants aged between 25 to 40 years of a population-based cohort study. The resulting groups include 119 and 121 women, respectively, of an average 33 years of age. A gene-sequencing panel was used to assess established monogenic and polygenic origins of these phenotypes. Information on lifestyle was extracted from questionnaires. A healthy lifestyle score was allocated based on a recently developed algorithm. Of the women with LDL-C ≤1st percentile, 19 (15.7%) carried mutations that are causing monogenic hypocholesterolemia and 60 (49.6%) were genetically predisposed to low LDL-C on the basis of an extremely low weighted genetic risk score. In comparison with control groups, a healthier lifestyle was not associated with low LDL-C in women without genetic predispositions. Among women with LDL-C ≥99th percentile, 20 women (16.8%) carried mutations that cause familial hypercholesterolemia, whereas 25 (21%) were predisposed to high LDL-C on the basis of a high-weighted genetic risk score. The women in whom no genetic origin for hypercholesterolemia could be identified were found to exhibit a significantly unfavorable lifestyle in comparison with controls. This study highlights the need for early assessment of the cardiovascular risk profile in apparently healthy young women to identify those with LDL-C ≥99th percentile for their age: first, because, in this study, 17% of the cases were molecularly diagnosed with familial hypercholesterolemia, which needs further attention; second, because our data indicate that an unfavorable lifestyle is significantly associated with severe hypercholesterolemia in genetically unaffected women, which may also need further attention.

Alirocumab in high-risk patients: Observations from the open-label expanded use program

The alirocumab expanded use program provided open-label access to alirocumab before its commercial availability to patients with severe hypercholesterolemia not controlled with maximally tolerated doses of standard-of-care lipid-lowering therapy. To describe the safety and lipid-lowering efficacy of alirocumab in high-risk patients who were likely to be early users of proprotein convertase subtilisin/kexin type 9 inhibitors after approval. Patients with heterozygous familial hypercholesterolemia (HeFH) and/or coronary heart disease (CHD) and baseline low-density lipoprotein cholesterol (LDL-C) of ≥160mg/dL on maximally tolerated lipid-lowering therapy were enrolled and received alirocumab 150mg every 2weeks for 24weeks. Patients were permitted use of all available statins; those not taking any dose of statin could also be enrolled. Of 100 enrolled patients, 93 were white, 62 were women, and overall mean age was 58years; 61 had HeFH, 3 had unknown type of familial hypercholesterolemia, 66 had CHD, and 30 had both familial hypercholesterolemia and CHD. Sixty-four patients were identified by their providers to have some level of statin intolerance; of these, 47 were not on statin. Alirocumab reduced LDL-C on average from 221mg/dL at baseline to 102mg/dL by week 24 (-55%). Treatment-emergent adverse events were experienced in 61% of patients and treatment-emergent adverse events leading to permanent treatment discontinuation in 3% of patients; no deaths occurred. Safety and efficacy observations from the open-label alirocumab expanded use program of very high-risk patients with HeFH and/or CHD and baseline LDL-C of ≥160mg/dL uncontrolled by maximally tolerated lipid-lowering therapy were consistent with those in the placebo/ezetimibe-controlled ODYSSEY trials.

Treatment Preferences in Germany Differ Among Apheresis Patients with Severe Hypercholesterolemia.

Severe hypercholesterolemia is a major risk factor of death in patients with coronary heart disease. New adjunctive drug therapies (proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors) have gained approval in Europe and the USA. In this empirical study, we documented preferences regarding adjuvant drug therapy in apheresis-treated patients with severe familial hypercholesterolemia. We conducted a systematic literature search to identify patient-relevant outcomes in patients with severe hypercholesterolemia currently undergoing apheresis. Data were used to generate a semi-structured qualitative interview that enabled seven patient-relevant characteristics with three levels each to be identified. For the discrete choice experiment, an experimental design (7×3) was generated using NGene Software that consisted of 96 choices divided into eight blocks. The survey was conducted between November 2015 and April 2016 using computer-assisted personal interviews. The survey was completed by 348 patients (64.9% male). The random parameter logit estimation showed predominance for the attribute 'reduction of LDL-C (low-density lipoprotein cholesterol) level'. 'Risk of myopathy' and 'frequency of apheresis' dominated next. Within the random parameter logit estimation, all coefficients were significant (P≤0.01). The latent class analysis identified three patient groups. The first group (126 patients) found 'reduction of LDL-C levelin blood' to be most important. This group focused solely on this treatment outcome independently of apheresis frequency or additional injections. The second group (106 patients) focused on three attributes: 'frequency of apheresis', 'risk of myopathy', and 'reduction of LDL-C levelin blood'. Respondents clearly considered a high frequency of apheresis to have a negative impact. The third group (116 patients) demonstrated the highest preference for apheresis. These patients have adjusted to apheresis for>10years. Regarding patient preference, clinical efficacy seems to dominate. Hence, 'reduction of LDC-C in blood' was ranked highest above patient-relevant modes of administration and adverse effects. In the patient groups identified, reduction of apheresis was important for only a subsegment (30%) of patients. Another 30% wanted effective LDL-C reduction by whatever means necessary. Most strikingly, another 30% preferred higher frequencies of apheresis.

PATIENT PRIORITIES FOR TREATMENT ATTRIBUTES IN ADJUNCTIVE DRUG THERAPY OF SEVERE HYPERCHOLESTEROLEMIA IN GERMANY: AN ANALYTIC HIERARCHY PROCESS.

Severe hypercholesterolemia is a major cause of death in coronary heart disease. New adjunctive drug therapies have passed authorization processes and been launched recently. So far it is not known which properties of the new treatment options generate the highest benefit for patients. The aim was to evaluate patient priorities in the field of adjunctive drug therapy with apheresis. Therapy characteristics were examined as to their relevance to hypercholesterolemia patients. To identify all potential patient-relevant treatment characteristics, a systematic literature review and ten interviews with patients were conducted. Seven key characteristics were identified from the patient perspective. Patients' priorities were elicited using an analytic hierarchy process (AHP). In total, N = 61 patients diagnosed with severe hypercholesterolemia and undergoing apheresis participated in the study. The analysis showed predominance for the attribute "reduction of LDL-C level in blood" (Wglobal:0.362). The "risk of myopathy" (Wglobal:0.164), "risk of neurocognitive impairment" (Wglobal:0.161) and "frequency of apheresis" (Wglobal:0.119) were ranked second, third and fourth. Subgroup analyses revealed that "frequency of apheresis" is of greater importance to younger patients, men and/or patients who indicated a reduction in quality of life due to apheresis. The essential decision criteria for optimal therapy from the patients' perspective were obtained. "Reduction of lipoprotein in blood" was ranked highest compared with the "mode of administration" and "side effects" characteristics. The study offers a transparent approach for the identification of patient priorities for adjunctive PCSK9-inhibitor therapy in apheresis-treated hypercholesterolemia. The project can be used by healthcare decision makers to understand the importance of each patient-relevant endpoint.

Therapeutic approach to dyslipidemias, the main cause of atherosclerosis

Cardiovascular diseases kill more than 4 million people annually in Europe. Atherosclerosis is the main cause of fatal cardiovascular events. The risk of atherosclerosis is higher as the plasma cholesterol level increases. In order to reduce the cardiovascular risk, the decrease in the LDL-C fraction is the main objective of therapeutic intervention in lipid metabolism. Statins are the first choice medication for lowering LDL-C. Other newer therapeutic options may be added to statins in severe hypercholesterolemia such as familial hypercholesterolemia. Fibrates are used in high-triglyceride dyslipidemias.