Hyperlipidemias: Kastelein JJ

Kastelein JJ, Fouchier SW, Defesche JC. · No affiliation provided · J Am Coll Cardiol. · Pubmed #15893177 No free full text.

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Kastelein JJ. · No affiliation provided · BMJ. · Pubmed #11118161 links to  free full text

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Visser ME, Jakulj L, Kastelein JJ, Stroes ES. · Department of Vascular Medicine, Room F4-159.2, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. · Curr Cardiol Rep. · Pubmed #18950563 No free full text.

Abstract: Recent trials have emphasized that more intensive low-density lipoprotein cholesterol (LDL-C) lowering results in a further reduction in cardiovascular disease risk. Uptitration of statins has limited incremental LDL-C-lowering effects and leads to an increased incidence of side effects. Therefore, attention has shifted toward alternative LDL-C-lowering modalities. Several promising compounds have entered the clinical trial arena, although with mixed results. Acyl-coenzyme A: cholesterol O-acyltransferase (ACAT) inhibitors failed to show benefit. Microsomal triglyceride transfer protein and squalene synthase inhibitors, in spite of beneficial lipid profile changes, have shown adverse event profiles. In contrast, inhibitors of intestinal cholesterol absorption have shown LDL-C-lowering efficacy associated with few side effects. The inhibition of apolipoprotein B100 synthesis by antisense oligonucleotides has now been tested in phase 2 clinical trials, with promising results. Finally, compounds modifying protein convertase subtilisin/kexin type 9 levels are currently in the preclinical phase. In the present article, we discuss these LDL-C-lowering strategies.

Huijgen R, Vissers MN, Defesche JC, Lansberg PJ, Kastelein JJ, Hutten BA. · Academic Medical Center, Department of Vascular Medicine, Meibergreef 9 (Room F4-146), 1105 AZ, Amsterdam, The Netherlands. · Expert Rev Cardiovasc Ther. · Pubmed #18402545 No free full text.

Abstract: Heterozygous familial hypercholesterolemia is associated with elevated levels of LDL-cholesterol and the development of premature cardiovascular disease. The condition is considerably under-diagnosed and under-treated. Statins are the first choice treatment for all patients with heterozygous familial hypercholesterolemia. For those patients who do not reach their treatment target or who are unable to use adequate statin dose, several alternative treatment modalities can be used, either as add-on therapy or as monotherapy. In this review the various treatment options are discussed.

El Harchaoui K, van der Steeg WA, Stroes ES, Kastelein JJ. · Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, Room F4-159.2, Meibergdreef 9, Postbus 22660, 1105 AZ Amsterdam, The Netherlands. · Curr Atheroscler Rep. · Pubmed #17877921 No free full text.

Abstract: Cholesteryl ester transfer protein (CETP) inhibitors are currently being investigated because of their ability to increase high-density lipoprotein cholesterol levels. In various metabolic settings, the relationship between CETP and lipoprotein metabolism is complex and may depend largely on the concentration of triglyceride-rich lipoproteins. Two CETP inhibitors, JTT-705 and torcetrapib, are in an advanced phase of development. Following hopeful intermediate results, a large endpoint study using torcetrapib has just been discontinued due to increased mortality in torcetrapib-treated subjects. In this review we summarize clinical data on the use of CETP inhibitors.

Akdim F, Stroes ES, Kastelein JJ. · Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands. · Curr Opin Lipidol. · Pubmed #17620855 No free full text.

Abstract: PURPOSE OF REVIEW: Antisense oligonucleotides are novel therapeutic agents that reduce the number of specific mRNAs available for translation of the encoded protein. ISIS 301012 is an antisense oligonucleotide developed to reduce the hepatic synthesis of apolipoprotein B-100. Apolipoprotein B-100 is made in the liver, and antisense oligonucleotides preferentially distribute to that organ, so antisense apolipoprotein B-100 may have potential as an efficacious lipid-lowering agent. RECENT FINDINGS: Recently, in healthy volunteers and in mild dyslipidaemic patients, this strategy as monotherapy or in conjunction with statins has shown unparalleled efficacy in reducing apolipoprotein B-100 and LDL-cholesterol. Tolerance for this novel therapy is encouraging and safety concerns currently only relate to mild injection-site reactions and rare liver-function test abnormalities. It should be noted, however, that these safety results were obtained in relatively few individuals. SUMMARY: ISIS 301012 has initially shown promising results in experimental animal models, and in clinical trials in humans. Besides the effect of reducing apolipoprotein B-100 and LDL-cholesterol, this compound also significantly lowers plasma triglycerides. Safety concerns related to the drug include increased liver-function tests. To date no evidence of hepatic steatosis has been reported. Nonetheless, clinical trials of longer duration are required to demonstrate further safety.

Avis HJ, Vissers MN, Stein EA, Wijburg FA, Trip MD, Kastelein JJ, Hutten BA. · Academic Medical Centre, Department of Vascular Medicine, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. · Arterioscler Thromb Vasc Biol. · Pubmed #17569881 links to  free full text

Abstract: OBJECTIVE: Functional and morphological changes of the arterial wall already present in young children with heterozygous familial hypercholesterolemia (HeFH) suggest that treatment should be initiated early in life to prevent premature atherosclerotic cardiovascular disease. The purpose of this study was to assess the efficacy and particularly safety of statin therapy in children with HeFH. METHODS AND RESULTS: We performed a meta-analysis of randomized, double-blind, placebo-controlled trials evaluating statin therapy in children aged 8 to 18 years with HeFH. Six studies (n=798 children) with 12 to 104 weeks of treatment were included. Total cholesterol, LDL cholesterol, and apolipoprotein B were significantly reduced, whereas HDL cholesterol and apolipoprotein A1 were significantly increased by statin therapy. No statistically significant differences were found between statin- and placebo-treated children with respect to the occurrence of adverse events (RR 0.99; 95% CI: 0.79 to 1.25), sexual development (RR of advancing > or = 1 stage in Tanner classification 0.96; 95% CI: 0.79 to 1.17), muscle toxicity (RR of CK > or = 10 times the upper limit of normal [ULN] 1.38; 95% CI: 0.18 to 10.82), or liver toxicity (RR of > or = 3 times the ULN for ASAT 0.98; 95% CI: 0.23 to 4.26 and for ALAT 2.03; 95% CI: 0.24 to 16.95). We found a minimal difference in growth in favor of the statin group (0.33 cm; 95% CI: 0.03 cm to 0.63 cm). CONCLUSION: In addition to the fact that statin treatment is efficacious, our results support the notion that statin treatment in children with HeFH is safe. Thus, even though further studies are required to assess lifelong safety, statin treatment should be considered for all children aged 8 to 18 with HeFH.

van der Graaf A, Hutten BA, Kastelein JJ, Vissers MN. · Academic Medical Centre, Dept.Vascular Medicine, Meibergdreef 9 (room F4-159.2) 1105 AZ, Amsterdam, The Netherlands. · Expert Rev Cardiovasc Ther. · Pubmed #16716095 No free full text.

Abstract: Heterozygous familial hypercholesterolemia is associated with elevated low-density lipoprotein cholesterol levels and the development of premature cardiovascular disease. Despite this general statement, data regarding the incidence of cardiovascular disease in young women with familial hypercholesterolemia are lacking. In this review, information of age-specific incidence, risk factors and therapeutic avenues in women with heterozygous familial hypercholesterolemia are discussed.

Rodenburg J, Vissers MN, Daniels SR, Wiegman A, Kastelein JJ. · Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, the Netherlands, and Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Ohio, USA. · Pediatr Endocrinol Rev. · Pubmed #16456497 No free full text.

Abstract: In the last decades, there has been an important progression in the development and assessment of various cholesterol-lowering agents. Until recently, in children under age 10, the focus of treatment has been on dietary and lifestyle adjustments. For children older than 10 years, bile acid-binding resins were also recommended if LDL-C levels remained high after dietary adjustment. However, the lipid-lowering effect of bile acid-binding resins is modest at best and long-term compliance is often poor. In contrast, HMG-CoA reductase inhibitors (statins) are currently widely used in adults and are considered the first choice in the treatment of hypercholesterolemia. In the last few years, several randomized trials have shown that statins are also effective in reducing LDL cholesterol levels in children and seem safe at least in the short term. Another novel development is the cholesterol-lowering agent, ezetimibe, which inhibits cholesterol absorption in the intestine. Although efficacy and safety data in children are still lacking, ezetimibe has a good safety profile in adults, either as monotherapy or in combination with a statin. Lastly, two other classes of lipid-lowering drugs include fibrates and nicotinic acid, but most agree that the side effect profile precludes their use in children except in extreme circumstances. Overall, therapeutic options to lower cholesterol levels in children are expanding.

Kastelein JJ, Sankatsing RR. · Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef, The Netherlands. · Int J Clin Pract. · Pubmed #16351680 No free full text.

Abstract: Ezetimibe/simvastatin (INEGY), a dual inhibitor of both cholesterol production and absorption, is a new approach to the management of hyperlipidaemia. Recent studies have shown that it produces greater reductions in low-density lipoprotein (LDL) cholesterol than the single inhibition of statin therapy, enabling many more patients to achieve their LDL cholesterol treatment goals. With ezetimibe/simvastatin therapy, reductions of up to 61% from baseline have been seen in LDL cholesterol, with clear improvements in other associated lipid fractions. It has been well tolerated across all studies, with a safety profile similar to that of statin therapy. This article will review clinical experience to date with ezetimibe/simvastatin, commenting upon its place and potential value in the prevention of cardiovascular disease.

Fouchier SW, Rodenburg J, Defesche JC, Kastelein JJ. · Department of Vascular Medicine, Academic Medical Centre at the University of Amsterdam, Amsterdam, The Netherlands. · Eur J Hum Genet. · Pubmed #16189547 links to  free full text

Abstract: Inherited, or autosomal dominant, hypercholesterolaemia, with an average global prevalence of one in 500 individuals, is one of the most frequent inherited metabolic disorders. The disorder is associated with a high risk for premature cardiovascular disease (CVD) and death as a consequence of accelerated atherosclerosis. Although the molecular genetic basis is largely elucidated and effective medical treatment, in the form of inhibitors of intracellular cholesterol synthesis, is available, the disorder is severely underdiagnosed and undertreated. On the other hand, with the well-understood aetiology, the accurate diagnosis, the availability of sensitive predictive makers and efficacious therapy, this disorder can serve as a model for disease management: from early presymptomatic diagnosis, accurate prognosis, optimal treatment and large-scale screening to population-based prevention of CVD.

van Leuven SI, Kastelein JJ. · Department of Vascular Medicine, Academic Medical Center of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. · Expert Opin Pharmacother. · Pubmed #15957972 No free full text.

Abstract: The introduction of statins has drastically changed the treatment and prevention of atherosclerotic vascular disease. By lowering lipid levels and reducing the risk of coronary heart disease, these drugs are among the most effective at reducing morbidity and mortality available to clinical practice. In fact, these compounds have demonstrated the reversible nature of the process of atherosclerosis and can be considered the most useful drugs we currently have in our armamentarium in the prevention of atherosclerosis and its clinical sequelae. Atorvastatin provides pronounced lipid lowering in a broad range of individuals with hypercholesterolaemia and, as such, is an appropriate first-line therapy for patients at low to high risk of coronary heart disease. Reductions in total and low-density lipoprotein cholesterol achieved with atorvastatin have been shown to translate into reductions in risk of cardiovascular morbidity and mortality in both primary and secondary prevention settings. Significant clinical benefits have specifically been observed among patients with Type 2 diabetes and in those with acute coronary syndromes. In common with other members of the statin class, atorvastatin is well tolerated, and adverse events are generally mild and transient in nature. Despite the significant clinical benefits provided by atorvastatin, its full potential in the management of atherosclerotic disease has yet to be wholly explored; however, studies currently ongoing will answer many of the outstanding questions.

Rodenburg J, Vissers MN, Trip MD, Wiegman A, Bakker HD, Kastelein JJ. · Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. · Semin Vasc Med. · Pubmed #15861313 No free full text.

Abstract: The recommended therapy of hypercholesterolemia in children consists of dietary modification and bile acid-binding resins. Unfortunately, the lipid-lowering efficacy of bile acid-binding resins is modest, and moreover, long-term compliance is poor because of side effects. In contrast, hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) are widely used in adults and are considered to be the first choice in the treatment of hypercholesterolemia in that age category. In the last few years, several randomized trials have been conducted to evaluate the efficacy, safety, and tolerability of statin therapy in both children and adolescents. In this article, we review statin therapy in hypercholesterolemic children in terms of efficacy, safety, pharmacokinetics, and psychosocial functioning. Statins are not only effective in reducing low-density lipoprotein cholesterol levels in children with familial hypercholesterolemia but also improve endothelial function and reduce the progressive thickening of the intima media complex of the carotid arteries. Statins seem safe at the longer term in children in terms of plasma levels of liver enzymes and liver function, creatine kinase levels, and muscle function, as well as growth and sexual development. Long-term follow-up studies are needed to assess whether statin treatment started early in children with familial hypercholesterolemia can prevent future cardiovascular events.

Nierman MC, Rip J, Twisk J, Meulenberg JJ, Kastelein JJ, Stroes ES, Kuivenhoven JA. · Department of Vascular Medicine (G1-113), Academic Medical Centre, University of Amsterdam, The Netherlands. · Neth J Med. · Pubmed #15719847 links to  free full text

Abstract: Lipoprotein lipase (LPL) deficiency is a rare, hereditary disorder of lipoprotein metabolism characterised by severely increased triglyceride levels, and associated with an increased risk for pancreatitis. Since no adequate treatment modality is available for this disorder, we set out to develop an LPL gene therapy protocol. This paper focuses on the clinical presentation of LPL deficiency, summarises the preclinical investigations in animal models and describes the rationale to evaluate gene therapy for this monogenetic disorder of lipid metabolism in humans.

van der Steeg WA, Kuivenhoven JA, Klerkx AH, Boekholdt SM, Hovingh GK, Kastelein JJ. · Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands. · Curr Opin Lipidol. · Pubmed #15529021 No free full text.

Abstract: PURPOSE OF REVIEW: This review summarizes novel human data on cholesteryl ester-transfer protein (CETP) and atherosclerosis and the possible use of CETP inhibitors in the treatment of dyslipidemia. In addition, it will underline that therapeutic targeting of the high-density lipoprotein (HDL) metabolism entails more than simply observing changes in cholesterol levels of this lipoprotein. RECENT FINDINGS: Two pharmacological small-molecule inhibitors of CETP, JTT-705 and torcetrapib, have recently been shown to effectively raise HDL cholesterol in humans without serious side effects when either used as a monotherapy or combined with statins that lower low-density lipoprotein cholesterol. Importantly, prospective data from the Epic-Norfolk study furthermore indicate that elevated CETP concentration in conjunction with elevated triglyceride levels are associated with increased odds for cardiovascular events. Data from the Diabetic Atherosclerosis Intervention Study furthermore show that elevated CETP concentration is associated with increased progression of coronary atherosclerosis in patients with type 2 diabetes who use fenofibrate. SUMMARY: Long-term studies will have to show whether CETP inhibition decreases the risk of atherosclerotic disease in dyslipidemic patients. Increased CETP activity might be detrimental under hypertriglyceridemic conditions which is of importance when considering that a large proportion of patients at increased risk from coronary artery disease exhibit elevated triglyceride levels. Studies into the effects of CETP inhibition in hypertriglyceridemic patients therefore seem warranted. Awaiting the first data on the effect of CETP inhibition on surrogate endpoints for atherosclerosis, this review furthermore outlines that the complexity of HDL metabolism will necessitate a wide variety of studies on many aspects of this intriguing lipoprotein.

de Grooth GJ, Klerkx AH, Stroes ES, Stalenhoef AF, Kastelein JJ, Kuivenhoven JA. · Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands. · J Lipid Res. · Pubmed #15342674 links to  free full text

Abstract: Although the atheroprotective role of HDL cholesterol (HDL-c) is well documented, effective therapeutics to selectively increase plasma HDL-c levels are not yet available. Recent progress in unraveling human HDL metabolism has fuelled the development of strategies to decrease the incidence and progression of coronary artery disease (CAD) by raising HDL-c. In this quest for novel drugs, cholesteryl ester transfer protein (CETP) represents a pivotal target. The role of this plasma protein in HDL metabolism is highlighted by the discovery that genetic CETP deficiency is the main cause of high HDL-c levels in Asian populations. The use of CETP inhibitors to effectively increase HDL-c concentration in humans was recently published and data with regard to the effect on human atherosclerosis are expected shortly. This review discusses the potential of CETP inhibitors to protect against atherosclerosis in the context of the current knowledge of CETP function in both rodents and humans.

Rodenburg J, Vissers MN, Wiegman A, Trip MD, Bakker HD, Kastelein JJ. · Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands. · Curr Opin Lipidol. · Pubmed #15243213 No free full text.

Abstract: PURPOSE OF THIS REVIEW: This review provides an update on recent advances in the diagnosis and management of children with familial hypercholesterolemia. RECENT FINDINGS: A large cross-sectional cohort study of paediatric familial hypercholesterolemia demonstrated that affected children had a 5-fold more rapid increase of carotid arterial wall intima-media thickness during childhood years than their affected siblings. This faster progression led to a significant deviation in terms of intima-media thickness from the age of 12 years and onwards. Low-density lipoprotein cholesterol was a strong and independent predictor of carotid artery intima-media thickness in these children, which confirms the pivotal role of low-density lipoprotein cholesterol for the development of atherosclerosis. In this condition lipid lowering by statin therapy is accompanied by carotid intima-media thickness regression in familial-hypercholesterolemic children, which suggests that initiation of low-density lipoprotein cholesterol-reducing medication in childhood already can inhibit or possibly reduce the faster progression of atherosclerosis. Furthermore, these trials demonstrated that statins are safe and do not impair growth or sexual development in these children. Conversely, products containing plant sterols reduced low-density lipoprotein cholesterol levels by 14%, but did not improve endothelial dysfunction as assessed by flow-mediated dilatation. SUMMARY: Children with familial hypercholesterolemia clearly benefit from lipid-lowering strategies. Statins are safe agents and have been proven to reduce elevated low-density lipoprotein cholesterol levels significantly. In addition, statins improve surrogate markers for atherosclerosis. Therefore these agents should become the pivotal therapy in children with familial hypercholesterolemia.

Defesche JC, Lansberg PJ, Umans-Eckenhausen MA, Kastelein JJ. · Department of Vascular Medicine, Academic Medical Center at the University of Amsterdam, The Netherlands. · Semin Vasc Med. · Pubmed #15199434 No free full text.

Abstract: Familial hypercholesterolemia (FH) has a prevalence of 1 in 500 in Western society and predisposes for premature cardiovascular disease. Lipid-lowering treatment of affected individuals is widely advocated. Maximum health benefit can be obtained in FH if treatment is started as early as possible, as the World Health Organization has recently recommended. In 1994 we initiated an active case-finding program for individuals with FH, based on family investigation and DNA-testing. In an initial pilot study we established that active family screening supported by DNA diagnostics resulted in the identification of substantial numbers of FH heterozygotes and determined that diagnosis by DNA analysis was superior to conventional cholesterol measurement. Since its initiation, the program has led to the identification of more than 6000 individuals with FH, of whom the greatest part was not adequately treated at the time of identification. Our findings indicate not only that this case-finding approach is effective in identifying FH patients who otherwise would not have been identified but also that the vast majority of these patients seek treatment and are successfully started on cholesterol-lowering therapy to reduce their risk of premature cardiovascular disease. Here we describe an effective model to identify and bring under treatment large numbers of individuals affected by FH.

van Aalst-Cohen ES, Jansen AC, de Jongh S, de Sauvage Nolting PR, Kastelein JJ. · Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. · Semin Vasc Med. · Pubmed #15199431 No free full text.

Abstract: Heterozygous familial hypercholesterolemia (FH) is a common inherited disorder of lipoprotein metabolism. FH is characterized by elevated levels of low-density lipoprotein cholesterol, the presence of tendon xanthomas, and premature cardiovascular disease. The underlying molecular defect of FH consists of mutations in the gene coding for the low-density-lipoprotein-receptor protein, detection of which provides the only unequivocal diagnosis. Although the cause of FH is monogenic, there is wide variation in the onset and severity of atherosclerotic disease in these patients. Additional atherogenic risk factors of environmental, metabolic, and genetic origin are presumed to influence the clinical phenotype in FH. Criteria used to identify individuals with FH include a combination of clinical characteristics, personal and family history of early coronary artery disease, and biochemical parameters. Since the introduction in 1989 of statins, which have been shown to be effective and to delay or prevent the onset of cardiovascular disease, drug treatment of FH has greatly improved. New lipid-lowering agents are presently being developed for clinical use. This review provides an update on the clinical, diagnostic, and therapeutic aspects of heterozygous familial hypercholesterolemia.

de Groot E, Hovingh GK, Wiegman A, Duriez P, Smit AJ, Fruchart JC, Kastelein JJ. · Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, The Netherlands. · Circulation. · Pubmed #15198964 links to  free full text

Abstract: Large observational studies and atherosclerosis regression trials of lipid-modifying pharmacotherapy have established that intima-media thickness of the carotid and femoral arteries, as measured noninvasively by B-mode ultrasound, is a valid surrogate marker for the progression of atherosclerotic disease. To exploit fully the potential of ultrasound imaging in atherosclerosis research, standardized and strictly implemented imaging protocols should be used in both observational studies and applied clinical research. This article describes such a protocol developed at the Academic Medical Center of the University of Amsterdam, the Netherlands. Results are presented from a study that estimated atherosclerosis progression from childhood into old age by measuring intima-media thickness in subjects with familial hypercholesterolemia compared with healthy controls.

Fruchart JC, Nierman MC, Stroes ES, Kastelein JJ, Duriez P. · Departement de Recherche sur les Lipoproteines et l'Atherosclerose,Pasteur de Lille, Inserm U545 et Faculté de Pharmacie, Université du Droit et de la Santé de Lille 2, Lille, France. · Circulation. · Pubmed #15198961 links to  free full text

Abstract: Advances in our understanding of the ways in which the traditional cardiovascular risk factors, including standard lipid (eg, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol) and nonlipid (eg, hypertension) risk factors, interact to initiate atherosclerosis and promote the development of cardiovascular disease have enhanced our ability to assess risk in the individual patient. In addition, the ongoing identification and understanding of so-called novel risk factors may further improve our ability to predict future risk when these are included along with the classic risk factors in assessing the global risk profile. This review briefly summarizes the evidence that some newer risk factors, including impaired fasting glucose, triglycerides and triglyceride-rich lipoprotein remnants, lipoprotein(a), homocysteine, and high-sensitivity C-reactive protein, contribute to an increased risk of coronary and cardiovascular diseases.

Homsma SJ, Lansberg PJ, Kastelein JJ. · Nationale-Nederlanden N.V., Weena 505, 3013 AL Rotterdam. · Ned Tijdschr Geneeskd. · Pubmed #15042898 No free full text.

Abstract: 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.

Kastelein JJ. · Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam-Zuidoost, The Netherlands. · Neth J Med. · Pubmed #12918548 links to  free full text

Abstract: Several lipid-lowering intervention studies published in 2002 shed light on the current status and the future of cardiovascular risk reduction by drug therapy. The Heart Protection Study has demonstrated that simvastatin reduces heart attack, stroke and revascularisation risk by about one-third irrespective of total cholesterol, LDL cholesterol, patient's age or sex, or the nature of pre-existing cardiovascular disease. Coronary heart disease death and myocardial infarction risk reduction in elderly patients by pravastatin in the PROSPER study was similar to the benefit of statins in middle-aged populations in other studies. The ALLHAT-LLT study has failed to demonstrate a benefit of pravastatin on all-cause mortality, CHD death or nonfatal myocardial infarction, illustrating that too modest cholesterol lowering does not result in clinical benefit under all circumstances. The cholesterol absorption inhibitor ezetimibe has demonstrated significant LDL and total cholesterol lowering, and induced an additional 21% LDL cholesterol lowering when added to ongoing statin therapy. The cholesteryl ester transfer protein inhibitor JJT-705 produced a dose-dependent increase in HDL cholesterol concentrations of up to 34% and improved the total cholesterol/HDL cholesterol ratio in healthy individuals while having very mild side effects. Cholesterol absorption inhibitors and HDL cholesterol enhancers may become useful tools to achieve further improvements in cardiovascular risk reduction in the future.

van Dam M, van Wissen S, Kastelein JJ. · Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. · J Cardiovasc Risk. · Pubmed #12006916 No free full text.

Abstract: Few things are better understood within the medical community than the relationship between elevated total and low-density lipoprotein cholesterol (LDL-C) levels, cardiovascular disease and death. There is consensus in the treatment guidelines of numerous national and international bodies that cholesterol levels in at-risk patients should be reduced to target levels that have been shown in population studies to be associated with low rates of coronary heart disease (CHD). However, dyslipidaemia continues to be underdiagnosed and undertreated. The 'landmark' statin trials have demonstrated unequivocally that effective lipid-lowering therapy significantly decreases CHD morbidity and mortality. Furthermore, these benefits of lipid-lowering therapy are not limited to middle-aged men, but extend across a broad range of patient populations. Recent trial data suggest that lowering LDL-C to target levels is possible in a substantial proportion of patients when statins are administered aggressively and results in a greater reduction in the risk of major coronary events. This reduction in events is seen in patients with stable coronary disease as well as those treated immediately after an acute coronary syndrome. Although strong clinical and angiographic evidence shows that intensive treatment prevents morbidity and saves lives, indications are that clinicians are still waiting too long to treat dyslipidaemia and when treatment is initiated it is often at inadequate dosages. Undertreatment of dyslipidaemia is an issue that the healthcare community can no longer ignore.

Jansen AC, van Wissen S, Defesche JC, Kastelein JJ. · Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. · Curr Opin Lipidol. · Pubmed #11891419 No free full text.

Abstract: Heterozygous familial hypercholesterolaemia is among the most common inherited dominant disorders, and is characterized by severely elevated LDL-cholesterol levels and premature cardiovascular disease. Although the cause of familial hypercholesterolaemia is monogenic, there is a substantial variation in the onset and severity of atherosclerotic disease symptoms. Additional atherogenic risk factors of environmental, metabolic and genetic origin, in conjunction with the LDL receptor defect, are presumed to influence the clinical phenotype in familial hypercholesterolaemia. The present review discusses recent developments in this field.