Differential effect of the rs4149056 variant in SLCO1B1 on myopathy associated with simvastatin and atorvastatin.

Statins reduce cardiovascular morbidity and mortality in appropriately selected patients. However, statin-associated myopathy is a significant risk associated with these agents. Recently, variation in the SLCO1B1 gene was reported to predict simvastatin-associated myopathy. The aim of this study was to replicate association of the rs4149056 variant in SLCO1B1 with severe statin-associated myopathy in a cohort of patients using a variety of statin medications and to investigate the association with specific statin types. We identified 25 cases of severe statin-associated myopathy and 84 controls matched for age, gender, statin type and dose. The rs4149056 variant in SLCO1B1 was not significantly associated with myopathy in this group as a whole. However, when subjects were stratified by statin type, the SLCO1B1 rs4149056 genotype was significantly associated with myopathy in patients who received simvastatin, but not in patients who received atorvastatin. Our findings provide further support for a role for SLCO1B1 genotype in simvastatin-associated myopathy, and suggest that this association may be stronger for simvastatin compared with atorvastatin.

Pediatric lipid reference values in the general population: The Dutch lifelines cohort study.

BACKGROUND: Atherosclerosis starts in childhood and its progression is influenced by lifelong low-density lipoprotein cholesterol (LDL-c) exposure, the so-called cholesterol burden. Early identification of children and adolescents with severely elevated LDL-c is thus of major clinical significance. This is especially true for children with familial hypercholesterolemia (FH), a frequent but undertreated genetic disorder. To identify children with possible FH, insight in the distribution of lipid levels in children is a prerequisite. OBJECTIVE: To provide health care professionals with contemporary age- and gender-based pediatric reference values for lipid and lipoprotein levels to help the identification of children with dyslipidemia, especially FH. METHODS: Lifelines is a large prospective population-based Dutch cohort study. Children from 8 till 18 years of age were included and fasting lipid levels were measured. Smoothed reference curves and percentiles (5th, 10th, 25th, 50th, 75th, 90th, and 95th) were generated using the Generalized Additive Models for Location, Scale and Shape package in the statistical software R. RESULTS: A total of 8071 children (3823 boys and 4248 girls) were included. In the total cohort we noted marked dynamic changes in lipid and lipoprotein levels over age, which were in part gender specific. Our data highlight a high and unexpected prevalence of severely elevated LDL-c (>190 mg/dL) in both boys and girls. CONCLUSION: Our cross-sectional data provide contemporary reference ranges for plasma lipids that can assist physicians in identifying children at increased risk of premature atherosclerosis, especially FH.

Prevalence and correction of hypothyroidism in a large cohort of patients referred for dyslipidemia.

BACKGROUND: Treatment of hypercholesterolemia can reduce the risk of developing premature atherosclerosis. The hypercholesterolemia caused by hypothyroidism is potentially reversible by thyroid hormone replacement therapy. We determined the prevalence of hypothyroidism in patients referred to a university lipid research clinic and studied the changes in lipid and lipoprotein levels on restoration of the euthyroid state. METHODS: A retrospective follow-up study was performed. In all 1509 consecutive referrals for severe dyslipidemia, thyrotropin levels were measured. Patients with hypothyroidism were identified by means of a computed database, from January 1, 1989, to July 1, 1993, first by levothyroxine sodium medication and second by serum thyrotropin values greater than 5 mU/L. Twenty-one patients were available to evaluate the effect of restoration of the euthyroid state on plasma lipid and lipoprotein levels. RESULTS: The observed prevalence of hypothyroidism proved to be 4.2% (64/1509). The disorder was previously known in 25 patients and newly diagnosed in 39 patients (11 with overt hypothyroidism and 28 with subclinical hypothyroidism). Significant reductions in total cholesterol and low-density lipoprotein cholesterol levels occurred only in patients with pretreatment thyrotropin values of 10 mU/L or more. CONCLUSIONS: The prevalence of newly diagnosed cases of overt hypothyroidism in patients referred to a lipid clinic is approximately two times that in the general population. The absence of significant reductions in total cholesterol and low-density lipoprotein cholesterol levels on levothyroxine treatment in patients with minor subclinical hypothyroidism (thyrotropin level, < 10 mU/L) does not support the view that this condition is a risk factor for atherosclerosis mediated by an elevated low-density lipoprotein cholesterol level. All patients referred for diagnosis and treatment of dyslipidemia should be screened for hypothyroidism by measurement of thyrotropin values.

Clinical experience of scoring criteria for Familial Hypercholesterolaemia (FH) genetic testing in Wales.

BACKGROUND/OBJECTIVE: Familial Hypercholesterolaemia (FH) is caused by mutations in genes of the Low Density Lipoprotein (LDL) receptor pathway. A definitive diagnosis of FH can be made by the demonstration of a pathogenic mutation. The Wales FH service has developed scoring criteria to guide selection of patients for DNA testing, for those referred to clinics with hypercholesterolaemia. The criteria are based on a modification of the Dutch Lipid Clinic scoring criteria and utilise a combination of lipid values, physical signs, personal and family history of premature cardiovascular disease. They are intended to provide clinical guidance and enable resources to be targeted in a cost effective manner. METHODS: 623 patients who presented to lipid clinics across Wales had DNA testing following application of these criteria. RESULTS: The proportion of patients with a pathogenic mutation ranged from 4% in those scoring 5 or less up to 85% in those scoring 15 or more. LDL-cholesterol was the strongest discriminatory factor. Scores gained from physical signs, family history, coronary heart disease, and triglycerides also showed a gradient in mutation pick-up rate according to the score. CONCLUSION: These criteria provide a useful tool to guide selection of patients for DNA testing when applied by health professionals who have clinical experience of FH.

Long-term efficacy and tolerability of simvastatin in a large cohort of elderly hypercholesterolemic patients.

The long-term efficacy and tolerability of simvastatin, a 3-hydroxy-3-methylglutaryl-co-enzyme A (HMG-CoA) reductase inhibitor, was assessed during a 24-month follow-up period in 168 elderly hypercholesterolemic patients. After completing a 4 week double blind dose ranging study with simvastatin, 47 males and 122 females over 62 years of age with type II hyperlipidemia, a total cholesterol level above 6.5 mmol/l and clinically manifest cardiovascular disease were included in this extended study. A total of 159 patients completed the 12-month follow-up period and 141 patients were monitored over the full 24 months. All patients were started on 10 mg simvastatin once daily and the dosage was increased until the target levels of low density lipoprotein (LDL) cholesterol between 2.3 mmol/l (90 mg/dl) and 3.6 mmol/l (140 mg/dl) were reached. Fifty percent of patients reached the targeted LDL cholesterol goal of < 3.6 mmol/l (140 mg/dl) during the study. At study completion, 65 patients (39%) were taking 40 mg simvastatin per day, 56 patients (33%) 20 mg, 42 patients (25%) 10 mg and 5 patients (3%) only used 5 mg per day. Sixteen patients (9%) received concomitant lipid lowering therapy. Over 2 years, the mean decrease in LDL cholesterol ranged from 36% to 38%, the median decrease in triglycerides was 12% to 19% and the mean increase in high density lipoprotein (HDL) cholesterol ranged from 9% to 10%, respectively. Seven patients discontinued simvastatin because of adverse clinical or laboratory events, but only in two (1.1%) was this considered to be drug-related. Side-effects were mild and most frequently gastrointestinal in nature. Mean changes in asparate aminotransferase (AST) were not significantly different from zero and mean changes in alanine aminotransferase (ALT) and creatine phosphokinase (CPK) showed a small increase. We conclude that simvastatin is an efficacious and well-tolerated treatment for hypercholesterolemia in elderly individuals for extended periods.

Analysis of the Afrikaner mutation in exon 9 of the low-density lipoprotein receptor gene in a large Dutch kindred suffering from familial hypercholesterolaemia.

Familial hypercholesterolaemia (FH) is the most common genetic metabolic disorder, affecting about 1 in 500 persons in the general population. With novel techniques, it is possible to identify the molecular defects underlying FH in the gene coding for the low-density lipoprotein (LDL) receptor, thereby confirming the diagnosis of FH. In this study we present a large family with a specific mutation in exon 9 of the LDL-receptor gene (an Afrikaner mutation) and we demonstrate that by a large-scale case-finding study in this family, carriers of such a mutation can be detected. Of 63 family members, 13 were shown to be at risk for cardiovascular disease as judged by their lipoprotein profile or the presence of the Afrikaner mutation. Two persons were detected, affected with a dyslipidaemia other than FH. Medical management was initiated in order to reduce the high cardiovascular risk associated with this disorder.

[Genetic screening of patients with familial hypercholesterolemia and insurability for life insurance policies and disability cover policies]. / Actieve opsporing van patiënten met familiaire hypercholesterolemie en verzekerbaarheid voor levens- en arbeidsongeschiktheidsverzekeringen.

In the Netherlands, people with familial hypercholesterolaemia (FH) have been actively screened since 1994 by means of DNA analysis. Recently, the Stichting Opsporing Erfelijke Hypercholesterolemie (Foundation for the Detection of Familial Hypercholesterolaemia) initiated a large scale-screening programme aimed at finding all 40,000 people. The Dutch ministry of Health, Welfare and Sport is providing the financial support. Genetic screening has social implications and raises questions on insurability. The Dutch Medical Examination Act prohibits insurers from posing questions about untreatable, serious inheritable conditions for insured sums under a certain value: for life-insurance policies < [symbol: see text] 150,000 and for disability-cover policies < [symbol: see text] 30,000 in the 1st year and < [symbol: see text] 20,000 in the 2nd year and following years. The Health Council of the Netherlands has defined FH as a serious disease, but one which responds well to treatment. Therefore insurers can request information for the purpose of an accurate risk classification. Insurance contracts can be accepted at normal rates if the target value of LDL-cholesterol < 4 mmol/l and additional risk factors such as smoking and an abnormal BMI are absent; the risk is determined by the phenotype and clinical factors and not by the genotype.

[Familial hypercholesterolemia: recognition and prevention of cardiac complications at a young age]. / Familiaire hypercholesterolemie: cardiovasculaire complicaties op jonge leeftijd te verwachten en te voorkomen.

A man aged 35 and a woman aged 30 visited a lipid clinic because of a raised total cholesterol level, which was also present in a number of first-degree relatives. Apart from the lipid abnormalities they had no risk factors for coronary disease. Both proved to have familial hypercholesterolaemia. The man had vague angina pectoris symptoms and a high dose of cholesterol synthesis inhibitors was prescribed. Coronary angiography showed severe stenoses; a coronary balloon angioplasty was successfully performed. The woman, however, died at age 33 suddenly from myocardial infarction. Familial hypercholesterolaemia may cause unexpected cardiovascular complications and sudden death of young persons. Timely diagnosis of the condition on the basis of adequate anamnesis and thorough physical examination, more rapid administration of cholesterol-lowering agents and alertness for anginous complaints may prevent myocardial infarctions and save lives in these patients.

[Higher prevalence of familial hypercholesterolemia than expected in adult patients of four family practices in Netherlands]. / Prevalentie van familiaire hypercholesterolemie onder volwassenen in vier huisartsenpraktijken hoger dan werd aangenomen.

OBJECTIVE: To determine the prevalence of familial hypercholesterolaemia (FH). DESIGN: Patient record screening, questionnaire and if necessary, case finding. METHODS: Over the period mid-1990-mid-1992 (approximately 2.5 years) 8,800 adult individuals (age 18 years and over) in 4 general practices in Hoofddorp, the Netherlands, were screened for risk factors for coronary artery disease and invited for further analysis. Of the 3,289 selected and invited individuals 2,719 (83%) were investigated. Total cholesterol concentrations were investigated 3 times and if the mean value was above 8.0 mmol/l patients were referred to a lipid clinic to investigate the possible existence of FH. RESULTS: 114 patients were eligible for referral to a lipid clinic of whom 92 (81%) were indeed referred. Of these, 38 patients were diagnosed with FH: 23 men and 15 women, with a mean age of 47.7 years (range: 21-74). CONCLUSION: The prevalence of FH in this investigated population was at least 1:232. This is more than 1:500, the estimated number of FH patients in the Dutch population.

[Statins: possibly more than just lowering of the lipid level]. / Statinen: mogelijk meer dan alleen verandering van de lipideconcentratie.

Clinical trials have demonstrated that treatment of hypercholesterolemia with HMG-CoA reductase inhibitors (statins) is beneficial in primary and secondary prevention of vascular diseases. The observed reduction in cardiovascular morbidity and mortality cannot only be explained by lipid-lowering only. Apart from lowering cholesterol, statins conceivably also exert effects on the vascular wall that may directly contribute to decrease of vascular incidents: (a) a favourable influence on endothelial dysfunction through stimulation of nitrous oxide synthetase: (b) stabilization of plaques by reducing influx of macrophages into the vascular wall and decreasing the production of matrix metalloproteinases, that may affect the connective tissue cover of the plaque: (c) inhibition of the initiation and progression of atherosclerosis by reducing adhesion of leukocytes to the vascular wall: (d) reducing the haemorrhagic diathesis by increasing the fibrinolytic capacity and inhibiting tissue factor expression on macrophages. All these effects of statins independent of the lowering of the cholesterol level might contribute to primary and secondary prevention of vascular incidents. While most nonlipid mechanisms of statins are being studied in vitro and in animals, the clinical relevance is still to be determined.

Safety of statins in the new millennium.

Looking at the world today and six months ago in retrospect, it becomes clear that things have changed dramatically. Not only are global economic forecasts in turmoil, other certainties have also been proven to be not as steadfast as we had hoped and expected. Safety in the world has gained a different perspective since the assault on the twin towers of the World Trade Centre in New York and the Pentagon. The safety of medicine and especially statins has also become an issue since the withdrawal of cerivastatin because of its possible association with an increased rate of rhabdomyolysis under certain circumstances.

[A patient with the homozygote form of familial hypercholesterolemia]. / Een patiënt met de homozygote vorm van familiaire hypercholesterolemie.

The history of an 11 year old boy with homozygous familial hypercholesterolemia with therapeutic response to cholesterol lowering drugs is presented. Symptoms, laboratory diagnosis and therapeutic problems are discussed.

Treatment of primary hypercholesterolaemia. Short-term efficacy and safety of increasing doses of simvastatin and pravastatin: a double-blind comparative study.

OBJECTIVES: To compare the efficacy and safety of increasing doses (0, 10, 20 and 40 mg day-1, each dose for 6 weeks) of the inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, simvastatin and pravastatin, in the treatment of primary hypercholesterolaemia. DESIGN: Randomized, double-blind study with two parallel groups. SETTING: Two specialist lipid clinics in the Netherlands. SUBJECTS: Forty-eight patients aged 25-66 years with primary hypercholesterolaemia (mean serum cholesterol 10.2 mmol-1). MAIN OUTCOME MEASURES: Total serum cholesterol, triglycerides, lipoproteins, apolipoproteins A-I and B, laboratory safety parameters and sleep questionnaires. RESULTS: Both drugs induced a dose-dependent reduction in the mean total and low-density lipoprotein cholesterol concentration (P < 0.001); low-density lipoprotein cholesterol decreased from 32 to 43% by simvastatin and from 23 to 33% by pravastatin. There was an overall difference in the mean relative change from baseline in favour of simvastatin (total cholesterol, P < 0.01; LDL cholesterol P < 0.001). Both drugs reduced serum triglycerides by 10-15%. The changes in apolipoprotein B and the differences in efficacy between the two drugs paralleled those of total and low-density lipoprotein cholesterol. Adverse experiences were mild and did not differ between treatment groups; in each group, one subject discontinued medication because of complaints of dizziness. Sleep questionnaires revealed different degrees of sleep problems, unaffected by active treatment. CONCLUSIONS: Simvastatin appeared to be more potent than pravastatin in lowering total cholesterol, low-density lipoprotein cholesterol and apolipoprotein B, whereas both drugs had the same short-term safety profile.

Prevalence and significance of cardiovascular risk factors in a large cohort of patients with familial hypercholesterolaemia.

OBJECTIVE: Patients with familial hypercholesterolaemia (FH) vary widely in terms of onset of cardiovascular disease (CVD). DESIGN: The association between cardiovascular risk factors and prevalent CVD was examined in a cross-sectional study in order to elucidate their contribution to atherogenesis. SETTING AND SUBJECTS: Patients were recruited from 37 Dutch Lipid Clinics. The diagnosis of FH was based on a uniform diagnostic protocol, confirmed by DNA analysis in 62% of the cases. All patients were investigated free from any lipid-lowering drug for at least 6 weeks. MAIN OUTCOME MEASURES: Differences in lipids, lipoproteins and other risk factors for CVD were analysed in FH patients with and without CVD. RESULTS: A total of 526 patients were assessed and more than 37% had a history of CVD with a mean age of onset of 46.8 years. Mean LDL cholesterol (LDL-C) levels were severely elevated (8.38 +/- 2.13 mmol L-1). In univariate analysis, age, presence of hypertension or diabetes, body mass index, triglycerides (TG) and low HDL cholesterol (HDL-C) were all significantly associated with CVD. Also in multivariate analysis, all these risk factors, except TG and diabetes, were significantly linked to CVD. CONCLUSION: A high CVD risk in this large well-documented characterized sample of FH patients is not only conferred by elevated LDL-C but also by low HDL-C.

South African founder mutations in the low-density lipoprotein receptor gene causing familial hypercholesterolemia in the Dutch population.

In South African Afrikaners, three point mutations in the gene coding for the low-density lipoprotein (LDL)-receptor are responsible for more than 95% of the cases of familial hypercholesterolemia (FH). To investigate whether one or more of these mutations originated in The Netherlands, a large group of Dutch heterozygous FH patients was screened for the presence of these three mutations. Of these, a missense mutation in exon 9 of the LDL-receptor gene, resulting in a substitution of Met for Val408, responsible for 15% of FH in Afrikaners, was found in 19 (1.5%) of 1268 FH patients of Dutch descent. Nine of the patients carrying the exon 9 mutation on one allele shared the LDL-receptor DNA haplotype with an FH patient from South Africa, who was homozygous for the same mutation. This would suggest that the mutation in these patients and in the South African patient have a common ancestral background. The remaining ten FH patients all shared a common haplotype, partly identical to the Afrikaner haplotype, which could have arisen from a single recombinational event. This mutation has not been described in persons other than of Dutch ancestry and supports the hypothesis that this mutation in exon 9 originated in The Netherlands and, in all likelihood, was introduced into South Africa by early Dutch settlers in the seventeenth century.

Long term efficacy and safety of atorvastatin in the treatment of severe type III and combined dyslipidaemia.

BACKGROUND: Fibric acid derivatives and HMG-CoA reductase inhibitors are effective in combination for treating patients with familial dysbetalipoproteinaemia and severe combined dyslipidaemia, but combination therapy affects compliance and increases the risk of side effects. AIM: To evaluate the efficacy and safety of monotherapy with atorvastatin, an HMG-CoA reductase inhibitor with superior efficacy in lowering low density lipoprotein cholesterol and triglyceride concentrations, in patients with dysbetalipoproteinaemia and severe combined dyslipidaemia. METHODS: Atorvastatin was tested as single drug treatment in 36 patients with familial dysbetalipoproteinaemia and 23 patients with severe combined dyslipidaemia. RESULTS: After 40 weeks of 40 mg atorvastatin treatment decreases in total cholesterol, triglycerides, and apolipoprotein B of 40%, 43%, and 41%, respectively, were observed in the combined dyslipidaemia group, and of 46%, 40%, and 43% in the dysbetalipoproteinaemic patients. Target concentrations of total cholesterol (< 5 mmol/l) were reached by 63% of the patients, and target concentrations of triglycerides (< 3.0 mmol/l) by 66%. Treatment with atorvastatin was well tolerated and no serious side effects were reported. CONCLUSIONS: Atorvastatin is very effective as monotherapy in the treatment of familial dysbetalipoproteinaemia and severe combined dyslipidaemia.

The contribution of classical risk factors to cardiovascular disease in familial hypercholesterolaemia: data in 2400 patients.

OBJECTIVE: To determine the contribution of classical risk factors to the development of cardiovascular disease (CVD) in patients with heterozygous familial hypercholesterolaemia (FH). DESIGN: A retrospective, multi-centre, cohort study. Extensive data were collected by scrutinizing medical records and the use of questionnaires. Multivariate Cox regression was used to study the relationship between potential risk factors and the occurrence of CVD. SETTING AND SUBJECTS: We included 2400 FH patients from 27 Dutch lipid clinics. The diagnosis of FH was based upon the presence of a low-density lipoprotein receptor mutation or upon strict clinical criteria. MAIN OUTCOME MEASURES: Cardiovascular mortality and CVD. RESULTS: During 112.943 person-years, 782 (32.6%) patients had had at least one cardiovascular event. Male gender (RR 2.82, 95% CI 2.37-3.36), smoking (RR 1.67, 95% CI 1.40-1.99), hypertension (RR 1.36, 95% CI 1.06-1.75), diabetes mellitus (RR 2.19, 95% CI 1.36-3.54), low HDL-C (RR 1.37, 95% CI 1.15-1.63) and elevated lipoprotein(a) levels (RR 1.50, 95% CI 1.20-1.79) proved to be independent CVD risk factors. These six risk factors explained 18.7% of the variation in the occurrence of CVD. CONCLUSIONS: Male gender, smoking, hypertension, diabetes mellitus, HDL cholesterol and lipoprotein(a) levels proved to be important risk factors for CVD in FH patients. In addition to the routine institution of statin therapy, controlling these factors needs special attention in the management of this disorder.

A frequent mutation in the lipoprotein lipase gene (D9N) deteriorates the biochemical and clinical phenotype of familial hypercholesterolemia.

The D9N substitution is a common mutation in the lipoprotein lipase (LPL) gene. This mutation has been associated with reduced levels of HDL cholesterol and elevated triglycerides (TG) in a wide variety of patients. We investigated the influence of this D9N mutation on lipid and lipoprotein levels and risk for cardiovascular disease (CVD) in patients with familial hypercholesterolemia (FH). A total of 2091 FH heterozygotes, all of Dutch extraction, were screened for the D9N mutation using standard polymerase chain reaction techniques, followed by specific enzyme digestion. A total of 94 FH subjects carried the D9N mutation at a carrier frequency of 4.5%. Carriers of other common LPL mutations, such as the N291S and the S447X were excluded. Clinical data on 80 FH individuals carrying the D9N were available and were compared with a FH control group matched for age, sex, and body mass index (n=203). Analysis revealed significantly higher TG (P=0.01) and lower HDL-cholesterol levels (P=0.002). Dyslipidemia was more pronounced in D9N carriers with higher body mass index. Moreover, FH patients carrying this common LPL mutation were at higher risk for CVD, (odds ratio=2.8; 95% CI, 1.43 to 5.32; P=0.002). The common D9N LPL mutation leads to increased TG and decreased HDL plasma levels in patients with FH. These effects are most apparent in those FH heterozygotes with an increased body mass index. Furthermore, this mutation, present in 4.5% of Dutch FH heterozygotes, leads to increased risk for CVD.