Oxidized LDL level is related to gene expression of tumour necrosis factor super family members in children and young adults with familial hypercholesterolaemia.

OBJECTIVE: Familial hypercholesterolaemia (FH) is associated with increased risk of premature atherosclerosis. Inflammation is a key event in atherogenesis, and we have previously reported an inflammatory imbalance between tumour necrosis factor (TNF)α and interleukin-10 in children with FH. Based on the potential role of TNF-related molecules in inflammation, we investigated the regulation of other members of the TNF superfamily (TNFSF)/TNF receptor superfamily (TNFRSF) in children and young adults with FH and matched healthy controls. METHODS: Expression of TNFSF/TNFRSF genes in peripheral blood mononuclear cells (PBMCs) was quantified in children and young adults with FH prior to (n = 42) and after statin treatment (n = 10) and in controls (n = 25) by quantitative real-time polymerase chain reaction. RESULTS: First we found that, compared with controls, the mRNA levels of OX40L, BAFFR and TRAILR1 were significantly higher, whereas TRAIL and TRAILR3 were significantly lower in children and young adults with FH. Secondly, levels of oxidized low-density lipoprotein (oxLDL) were significantly raised in the FH group, and correlated with the expression of OX40L, BAFFR and TRAILR1. Thirdly, oxLDL increased mRNA levels of BAFFR, TRAILR1 and TRAILR4 in PBMCs ex vivo from individuals with FH. Fourthly, OX40, acting through OX40L, enhanced the oxLDL-induced expression of matrix metalloproteinase-9 in THP-1 monocytes in vitro. Finally, after statin treatment in children with FH (n = 10), mRNA levels of OX40L and TRAILR1 decreased, whereas levels BAFF, TRAIL and TRAILR3 increased. CONCLUSION: Our findings suggest the involvement of some TNFSF/TNFRSF members and oxLDL in the early stages of atherogenesis; this may potentially contribute to the accelerated rate of atherosclerosis observed in individuals with FH.

Uptake and degradation of 125I-labelled high density lipoproteins in rat liver cells in vivo and in vitro.

1. The uptake of 125I-labelled high density lipoproteins (HDL) in various organs of the rat was determined after an intravenous injection. The uptake of 125I-labelled polyvinylpyrrolidone in the same organs was determined in order to assess uptake by fluid endocytosis. The uptake/organ was highest for the liver. The adrenals showed the highest uptake/unit weight of the organs studied. The liver, the kidneys and the spleen showed comparable values for uptake/g of tissue. The uptake of 125I-labelled HDL exceeded by far that of 125I-labelled polyvinylpyrrolidone in the liver, the kidneys, the spleen and the adrenals, indicating that the uptake of 125I-labelled HDL was mediated by adsorptive endocytosis. 2. The in vivo uptake of 125I-labelled HDL was determined in purified hepatocytes and non-parenchymal cells prepared by collagenase perfusion of livers from animals after intravenous injections of 125I-labelled HDL. When expressed per cell, the hepatocytes and the non-parenchymal liver cells took up about the same amount of 125I-labelled HDL. 3. The in vitro uptake and degradation of 125I-labelled HDL in isolated rat hepatocytes was studied. The uptake at increasing concentrations of 125I-labelled HDL was saturable indicating uptake mediated through binding sites. 125I-labelled HDL were easily degraded by contaminating proteases from the perfusate. 4. Subcellular fractionation by isopycnic centrifugation indicated that the accumulation of 125I-labelled HDL did not take place in the lysosomes, but rather on the plasma membrane and possibly in the endosomes (phagosomes). 5. 125I-labelled HDL were internalized into the cells and degraded in the lysosomes. Leupetin and chloroquine, inhibitors of the lysosomal function effectively inhibited the formation of 125I-labelled acid-soluble radioactivity by the cells. Chloroquine, but not the protease inhibitor leupeptin, reduced the hydrolysis of the cholesteryl ester moiety of HDL.

The intracellular distribution of high density lipoproteins taken up by isolated rat hepatocytes.

The subcellular distribution of 125I-labelled HDL taken up by rat hepatocytes in vivo and in vitro has been studied with subcellular fractionation techniques: differential centrifugation and isopycnic centrifugation in sucrose gradients. 125I-labelled HDL bind to plasma membranes both in vivo and in vitro and part of the membrane-bound 125I-labelled HDL can be dissociated by the addition of unlabelled HDL. The hepatocytes also internalize 125I-labelled HDL. The 125I-labelled HDL accumulate, however, at different intracellular sites in the in vivo and in vitro situation. The subcellular distribution pattern of 125I-labelled HDL taken up by the cells in vivo is similar to that of the lysosomal marker enzyme acid phosphatase. Peak activity was found at a density of 1.20 g/ml. In vitro 125I-labelled HDL accumulate in an organelle with a medium density of about 1.13 g/ml. This distribution was similar to that of the plasma membrane marker 5'-nucleotidase. The subcellular distribution of radioactivity taken up in vivo was changed to lower density by incubating the cells with chloroquine, a drug known to render the lysosomes more boyant. Chloroquine had no effect on the distribution of 125I-labelled HDL taken up by hepatocytes in vitro.

Altered composition of HDL3 in FH subjects causing a HDL subfraction with less atheroprotective function.

BACKGROUND: Subjects with familial hypercholesterolemia (FH) are associated with increased risk of premature atherosclerosis and coronary artery disease (CAD). However, onset of clinically manifested CAD varies widely among subjects with heterozygous FH. The purpose of this study was to investigate whether FH subjects with an identical mutation in the low-density lipoprotein (LDL) receptor gene have a high-density lipoprotein (HDL)3 that is characterized by a less atheroprotective functions than that of healthy controls and within subgroups of FH. DESIGN: Twenty-two adults <75 years of age with FH and 17 healthy sex- and age-matched controls were included. HDL3 was isolated and the composition was characterized from each subject, and its ability to suppress tumor necrosis factor(TNF)-alpha stimulated expression of ICAM-1 on HUVEC was investigated. In addition, plasma level of soluble sICAM-1 and VCAM-1 was measured. RESULTS: Compared to controls, FH subjects had lower content of phospholipids in their HDL3 subfraction and a higher serum ICAM-1 level. No differences in sVCAM-1 were observed. HDL3 isolated from FH with body mass index(BMI)>25 and from FH subjects with premature CAD contained higher content of triglycerides compared to the HDL3 from FH subjects with BMI<25 and without CAD, respectively. Most important, when testing the function of HDL3 in the two FH subgroups characterized by elevated BMI and premature CAD, lower inhibition of ICAM-1 expression on HUVEC was observed. CONCLUSIONS: The altered composition of HDL3 from FH subjects with BMI>25 and FH subjects with premature CAD may be responsible for a HDL3 subfraction with less protective properties assessed as inhibition of ICAM-1 expression on HUVEC consequently leading to more proatherogenic endothelial surface.

Fine mapping of a gene responsible for regulating dietary cholesterol absorption; founder effects underlie cases of phytosterolaemia in multiple communities.

Sitosterolaemia (also known as phytosterolaemia, MIM 210250) is a rare recessive autosomal inherited disorder, characterised by the presence of tendon and tuberous xanthomas, accelerated atherosclerosis and premature coronary artery disease. The defective gene is hypothesised to play an important role in regulating dietary sterol absorption and biliary secretion, thus defining a molecular mechanism whereby this physiological process is carried out. The disease locus was localised previously to chromosome 2p21, in a 15 cM interval between microsatellite markers D2S1788 and D2S1352 (based upon 10 families, maximum lodscore 4.49). In this study, we have extended these studies to include 30 families assembled from around the world. A maximum multipoint lodscore of 11.49 was obtained for marker D2S2998. Homozygosity and haplotype sharing was identified in probands from non-consanguineous marriages from a number of families, strongly supporting the existence of a founder effect among various populations. Additionally, based upon both genealogies, as well as genotyping, two Amish/Mennonite families, that were previously thought not to be related, appear to indicate a founder effect in this population as well. Using both homozygosity mapping, as well as informative recombination events, the sitosterolaemia gene is located at a region defined by markers D2S2294 and Afm210xe9, a distance of less than 2 cM.

Two founder mutations in the LDL receptor gene in Norwegian familial hypercholesterolemia subjects.

DNA from 20 unrelated familial hypercholesterolemia (FH) subjects were studied by analysis of single-strand conformation polymorphisms (SSCP) for mutations in exon 3 of the low density lipoprotein (LDL) receptor gene. Four different SSCP patterns were observed. The underlying mutations were characterized by DNA sequencing. One pattern represented the wild-type sequence. Another pattern represented a C-->G mutation (FH-Svartor) that changes codon 78 into the amber stop codon. The two other patterns represented heterozygosity and homozygosity, respectively, for a G-->A splice donor mutation (FH-Elverum) in intron 3. Based upon two PCR-based assays, the frequencies of FH-Svartor and FH-Elverum among 267 unrelated FH subjects, were 8% and 25%, respectively. FH Svartor was located on a chromosome with haplotype 3 in all five families where haplotype analysis were performed. FH Elverum was located on haplotype 2 in 16 out of 20 families. The two mutations must be considered founder mutations in the Norwegian population, and their existence will be clinically useful in diagnosing FH. The presence of two founder mutations together with previously published data on the prevalence of FH in Norway, indicate that FH may be a more common disease in Norway than previously thought.

Effect of folic acid treatment on endothelium-dependent vasodilation and nitric oxide-derived end products in hyperhomocysteinemic subjects.

PURPOSE: An elevated plasma homocysteine concentration is an independent risk factor for cardiovascular diseases. In this study, we tested the hypothesis that hyperhomocysteinemia induces endothelial dysfunction mediated, at least in part, through nitric oxide-dependent mechanisms and that folic acid supplementation improves endothelial function in hyperhomocysteinemic subjects. SUBJECTS AND METHODS: Endothelial function was evaluated in healthy controls and hyperhomocysteinemic subjects by measuring plasma levels of the nitric oxide-derived end products nitrite and nitrate and by assessing vasodilatory responses in the skin microcirculation and forearm vasculature. In the subjects with hyperhomocysteinemia, these measurements were repeated after 6 weeks and 12 months of folic acid supplementation. RESULTS: Compared with healthy controls, hyperhomocysteinemic subjects had significantly lower median plasma levels of nitric oxide-derived end products (12.1 microM [range 4.4 to 41.8] versus 24.6 microM [13.6 to 53.2]; P <0.001), a significantly lower endothelium-dependent vasodilatory response to acetylcholine (P <0.01), hyperemic response in the microcirculation (P <0.01), and total forearm blood flow during reactive hyperemia (P = 0.01). There was no significant difference in the endothelium-independent response. Folic acid treatment for 12 months increased the plasma level of nitric oxide-derived end products by 121% (95% confidence interval [CI], 72% to 170%), the vasodilatory response to acetylcholine by 124% (95% CI, 36% to 212%), and the ischemia-mediated hyperemic responses in the microcirculation by 60% (95% CI, 25% to 96%) and in the forearm vasculature by 47% (95% CI, 21% to 73%). CONCLUSIONS: Homocysteine appears to induce its atherogenic effect, at least in part, by depressing endothelial function, possibly through nitric oxide-dependent mechanisms. This effect can be reversed by folic acid supplementation.

Results of intensive long-term treatment of familial hypercholesterolemia.

Fifty-seven patients with familial hypercholesterolemia (FH) with mean age of 48 years (range 30 to 69), participated in a follow-up examination 5.5 years after the completion of a 1-year trial with lovastatin, cholestyramine, probucol, or omega-3 fatty acids. The goals were to record quality of life, compliance to treatment, adverse effects, and clinical outcome. The quality of life was similar to that in a Norwegian reference population. The factors causing most distress to patients were keeping a diet low in saturated fats, taking medication, and fear of death. The medication was mostly prescribed in maximum dosages. At follow-up, the reduction in total cholesterol was 36% (p < 0.05), low-density lipoprotein (LDL) cholesterol 38% (p < 0.05), triglycerides 20% (p < 0.05) compared with being on diet therapy only. High-density lipoprotein (HDL) cholesterol increased 8% (p < 0.05). Intake of saturated and monounsaturated fat increased 1.5% and 1.7% (p < 0.05), respectively; polyunsaturated fat was unchanged. Three patients experienced myocardial infarction, of whom 2 died and 1 developed angina pectoris. Before the start of lovastatin treatment, 27 coronary events occurred per 1,000 patient-years in this group compared with 12 events per 1,000 patient-years thereafter. Of 28 patients reporting adverse events, 4 discontinued lovastatin and 3 discontinued cholestyramine. Several practical and psychological difficulties were associated with FH. Long-term intensive lipid-lowering therapy was possible in FH outpatients without loss of effect and with good compliance to therapy. Intensive therapy, today is, however, not sufficient for many FH patients to reach a therapeutic goal of LDL cholesterol < 4.0 mmol/L. More potent lipid-lowering agents are needed.

Lipid treatment goals achieved in patients treated with statin drugs in Norwegian general practice.

Statin drug treatment has still not achieved complete acceptance, and titration to recommended target goals is still not used by physicians in Norway.

Clinical efficacy and safety of cerivastatin: summary of pivotal phase IIb/III studies.

Cerivastatin is a new, third-generation 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor ("statin"), which is administered to hypercholesterolemic patients at doses equivalent to 1-3% of the doses of other statins. This report reviews the pivotal Phase IIb/III clinical trials in which the efficacy and safety of cerivastatin was compared with placebo and active comparator statins (lovastatin, simvastatin, and pravastatin) after both short- and long-term administration. Overall, the studies showed that at doses of 0.025-0.4 mg/day, cerivastatin produced dose-dependent reductions in low-density lipoprotein (LDL) cholesterol and total cholesterol, which were significantly greater than placebo. The greatest reductions were achieved with 0.4 mg/day cerivastatin. On this dose, >40% of patients achieved reductions in LDL cholesterol >40% and in a further 9% of patients, LDL cholesterol was decreased by >50%. At higher doses, cerivastatin also demonstrated potent triglyceride-lowering effects in a subgroup of patients with raised plasma triglycerides. Reductions in atherogenic lipids and lipoproteins were accompanied by significant increases in high-density lipoprotein (HDL) cholesterol, apolipoprotein A-I, and antiatherogenic lipoprotein A-I. Long-term administration of cerivastatin for periods of up to 2 years was associated with persistent reductions in LDL cholesterol, total cholesterol, triglycerides, and apolipoprotein B as well as increases in HDL cholesterol similar to those observed after initial administration. Long-term cerivastatin treatment was also well tolerated. There was no significant difference between the incidence of adverse effects with cerivastatin and comparator statins or between cerivastatin and other statins with respect to clinically significant increases in either hepatic enzymes or creatine phosphokinase. In conclusion, these studies indicate that cerivastatin is a safe and effective long-term treatment for patients with primary hypercholesterolemia and also suggest that higher doses should be investigated.

Changes in plasma apolipoprotein B-containing lipoparticle levels following therapy with fluvastatin and cholestyramine. European Fluvastatin Study Group.

Epidemiologic studies have demonstrated that apolipoprotein (apo) B-containing lipoparticles (LpE:B, LpC-III:B) are associated with the risk of coronary artery disease whereas apo A-1-containing lipoparticles (LpA-I) are protective against coronary artery disease. The effect on lipoparticle levels of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor fluvastatin, in combination with cholestyramine, was assessed in a double-blind randomized study. A total of 144 patients with primary hypercholesterolemia were recruited, who had successfully completed an original study comparing the effects of fluvastatin and cholestyramine on plasma lipoparticle levels. All subjects fulfilled the following inclusion criteria: plasma low density lipoprotein cholesterol (LDL-C) levels > 160 mg/dL, with premature coronary artery disease and 2 associated risk factors; or LDL-C > 190 mg/dL, no coronary artery disease, and triglycerides < 300 mg/dL, after a lipid-lowering diet. Patients were randomized to 1 of 3 combination therapy groups: fluvastatin 20 mg/day plus cholestyramine 4 g/day; fluvastatin 20 mg/day plus cholestyramine 8 g/day; and fluvastatin 20 mg/day plus cholestyramine 16 g/day. The study length was 6 weeks and patients were examined at 3-week intervals. Fluvastatin plus cholestyramine produced a significant (p < 0.001), dose-dependent reduction in levels of cholesterol (range, -29 to -34%), LDL-C (range, -30 to -44%), apo B (range, -23 to -34%), and apo E (range, -33 to -43%). LpE:B levels were also reduced (range, -19 to -26%), but not significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of high doses of simvastatin and atorvastatin on high-density lipoprotein cholesterol and apolipoprotein A-I.

A randomized, blinded, multicenter clinical trial was performed comparing low- and high-dose simvastatin (40 and 80 mg) with comparable doses of atorvastatin (20 and 40 mg) for effects on plasma concentrations of lipoproteins and apolipoprotein A-I over 12 weeks in 842 patients with elevated low-density lipoprotein cholesterol. The 2 agents reduced low-density lipoprotein cholesterol and triglycerides to a comparable degree, but simvastatin raised high-density lipoprotein cholesterol and apolipoprotein A-I more than atorvastatin, suggesting differences in metabolic effects of the 2 agents on plasma lipids and lipoproteins.

Autosomal dominant partial lipodystrophy associated with Rieger anomaly, short stature, and insulinopenic diabetes.

We describe the clinical findings and natural history of an autosomal dominant form of partial lipodystrophy found in four affected individuals from three generations in the same family. The lipodystrophy was present from infancy/early childhood, involved primarily the face and local areas on the buttocks, and was nonprogressive. Affected individuals also had the Rieger anomaly, midface hypoplasia, short stature, retarded bone age, and hypotrichosis. An affected woman developed insulinopenic diabetes mellitus at 39 yr and another had glucose intolerance at 55 yr.

Disposition of homocysteine in subjects heterozygous for homocystinuria due to cystathionine beta-synthase deficiency: relationship between genotype and phenotype.

We have investigated 31 subjects from five unrelated families with one or more members with cystathionine beta-synthase (CBS) deficiency. On the basis of their CBS genotype, the subjects were grouped as normal (n = 11) or heterozygotes (n = 20). Based on pyridoxine effect in the probands, the heterozygotes were further classified as pyridoxine-responsive (n = 9) or non-responsive (n = 11). Heterozygous subjects had normal fasting total plasma homocysteine (tHcy), but median urinary tHcy excretion rate was significantly elevated compared to healthy controls (0.39 micromol/h vs 0.24 micromol/h, P < 0.05). An abnormal tHcy response after methionine loading identified 73% of the pyridoxine non-responsive heterozygotes, but only 33% of the pyridoxine responsive participants. The increase in cystathionine or the change in tHcy relative to cystathionine did not improve diagnostic accuracy of the methionine loading test. After Hcy loading, the maximal increase in tHcy was significantly elevated, whereas t(1/2) was normal in heterozygotes. In conclusion, a single biochemical test cannot discriminate CBS heterozygotes from controls. Abnormal tHcy response after methionine loading was the most sensitive test. Our data suggest that the urinary tHcy excretion rate is a simple, non-invasive approach for studying mild disturbances in Hcy metabolism.

Comparison of the effect of fluvastatin, an hydroxymethyl glutaryl coenzyme A reductase inhibitor, and cholestyramine, a bile acid sequestrant, on lipoprotein particles defined by apolipoprotein composition.

In a double-blind, parallel-group, randomized study, the effects of fluvastatin (FLUV) 20 and 40 mg/d on lipoprotein particle levels were compared with those of cholestyramine (CME) 16 g/d. Lipoparticles were defined by apolipoprotein composition as either those containing both apolipoprotein (apo) B and apo E or CIII (lipoprotein [Lp] E-B or Lp CIII-B) or those containing apo AI alone (Lp AI) or in association with apo AII (Lp AI-AII). After an 8-week dietary stabilization period, 100 hypercholesterolemic patients were treated with FLUV 20 mg/d for 6 weeks and 40 mg/d for an additional 6 weeks and were compared with 48 hypercholesterolemic subjects treated with CME 16 g/d. Treatment with FLUV (40 mg/d) or CME (16 g/d) for 12 weeks was associated with a significant reduction in plasma cholesterol and low-density lipoprotein (LDL) cholesterol and a significant increase in high-density lipoprotein (HDL) cholesterol. However, plasma triglyceride levels decreased following FLUV treatment, whereas they increased with CME. These changes were associated with a significant reduction in the levels of apo B (FLUV, -24%, P < .001; CME, -26%, P < .001), apo E (FLUV, -36%, P < .001; CME, -32%, P < .001), and apo CIII (FLUV, -21%, P < .001; CME, -6%, NS).(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of growth hormone on low-density lipoprotein cholesterol and lipoprotein (a) levels in familial hypercholesterolemia.

Severe elevations of low-density lipoprotein (LDL) cholesterol are not always normalized with conventional drugs. Growth hormone decreases LDL cholesterol levels, in part by augmenting liver LDL receptor activity. This increase may be on the order of magnitude of the increase induced by statins. We investigated the effect of growth hormone in familial hypercholesterolemia (FH) in a randomized, double-blind, placebo-controlled study. Thirty-one men with FH aged 20 to 48 years, of whom 81% had a known LDL receptor gene mutation, discontinued all lipid-lowering drugs 6 weeks before the study. Dietary stabilization continued for 5 more weeks, followed by single-blind placebo injections for 1 week. Thereafter, 16 subjects were allocated to recombinant growth hormone 0.05 IU/kg/d and 15 to placebo injected subcutaneously for 12 weeks. Baseline lipid levels were similar in both groups. One subject in the growth hormone group withdrew after 8 weeks due to shoulder pain. Mean compliance among the rest of the subjects was 98%. The mean change in LDL cholesterol was -0.46 mmol/L (95% confidence interval [CI], -1.00 to 0.09 mmol/L) in the growth hormone group versus 0.08 mmol/L (95% CI, -0.55 to 0.71 mmol/L) in the placebo group (difference not significant). No changes occurred in the levels of other lipids, lipoprotein particles, or apolipoproteins, with the exception of lipoprotein(a) [Lp(a)]. The median changes in Lp(a) were 33% (interquartile range, 2% to 53%) and -15% (interquartile range, -22% to 18%) in the growth hormone and placebo groups, respectively (P = .02). We conclude that the effect of growth hormone on LDL cholesterol levels in FH is less than expected, based on its LDL-catabolic effects, and is counteracted by profound increases in Lp(a) levels, resulting in unchanged levels of apolipoprotein B. Thus, growth hormone is probably not useful as adjunctive therapy in FH.

Cerivastatin gender effect: sub-analyses of results from a multinational, randomised, double-blind study. Cerivastatin Study Group.

We previously reported the results of a multicentre, randomised, double-blind, parallel-group study comparing the efficacy and safety of cerivastatin 0.4 mg/day and cerivastatin 0.2 mg/day in patients with primary hypercholesterolaemia. Exploratory analysis in this study suggested a gender difference in the 0.4 mg group: mean low-density lipoprotein cholesterol (LDL-C) decreased by 44.4 +/- 8.9% in women, compared with a mean decrease of 37.0 +/- 0.9% in men (p < 0.046). This paper reports the results of further sub-analyses from this study. Overall in the per-protocol (PP) population, 71.5% (n = 73) of women taking cerivastatin 0.4 mg had an LDL-C decrease of > 40%, compared with 38.0% (n = 76) of men taking the same dose. In the cerivastatin 0.2 mg PP population, 34% (n = 17) of women had an LDL-C decrease of > 40%, compared with 19% (n = 18) of men. Mean LDL-C/HDL-C ratio decreased by 43% from baseline to the end of the study in the cerivastatin 0.4 mg PP group: -41.3% in males vs. -48.3% in females. In the cerivastatin 0.2 mg group, the decrease in LDL-C/HDL-C ratio from baseline to endpoint did not markedly differ between genders: -37.0% for males vs. -37.3% for females. Categorial analysis of the LDL-C/HDL-C ratio found that 90% of PP patients taking cerivastatin 0.4 mg, and 84% of PP patients taking cerivastatin 0.2 mg, had a low CHD risk (defined as a LDL-C/HDL-C ratio < or = 3) after 8 weeks of treatment. The 6th and 95th percentiles of the distribution of LDL-C reduction from baseline revealed that 90% of PP patients taking cerivastatin 0.4 mg had an LDL-C reduction of between 22% and 56%. The mean LDL-C reduction for this 90% subset of patients was 40.1%. The same analysis for PP patients taking cerivastatin 0.2 mg found that 90% had an LDL-C reduction of between 13% and 49%. The mean LDL-C reduction in this 90% subset of patients was 31.5%. Of the patients taking cerivastatin 0.4 mg and valid for treatment according to National Cholesterol Education Program (NCEP) criteria, 71% (149/211) achieved NCEP targets for LDL-C at Week 16.

Efficacy and safety of cerivastatin, 0.2 mg and 0.4 mg, in patients with primary hypercholesterolaemia: a multinational, randomised, double-blind study. Cerivastatin Study Group.

Elevated serum cholesterol level is a key risk factor for cardiovascular morbidity and mortality. Cerivastatin is a highly effective lipid-lowering agent currently licensed at doses of 0.1, 0.2, 0.3 and 0.4 mg. This was a multicentre, randomised, double-blind, parallel-group study comparing the efficacy and safety of cerivastatin 0.4 mg/day with that of cerivastatin 0.2 mg/day in patients with primary hypercholesterolaemia. There was a six-week placebo run-in phase followed by a 24-week active treatment phase. A total of 494 patients were randomised to receive cerivastatin 0.4 mg (n = 332) or 0.2 mg (n = 162). Per-protocol (PP) analysis revealed that mean low-density lipoprotein cholesterol (LDL-C) level decreased by 38.4 +/- 0.7% from baseline in the 0.4 mg group, compared with a decrease of 31.5 +/- 0.9% in the 0.2 mg group (p < 0.0001). There was a significant gender difference in the 0.4 mg group: LDL-C decreased by 44.4 +/- 8.9% in women, compared with a decrease of 37.0 +/- 0.9% in men (p < 0.046). In the PP group as a whole, total cholesterol decreased by 26.0 +/- 0.5% from baseline in the 0.4 mg group, compared with a decrease of 21.6 +/- 0.7% in the 0.2 mg group (p < 0.0001). Both doses were well tolerated; only eight (2.4%) patients in the 0.4 mg group and five (3.1%) patients in the 0.2 mg group withdrew owing to adverse events. Cerivastatin 0.2 mg/day and 0.4 mg/day was found to lower low-density lipoprotein cholesterol and total cholesterol levels in a dose-dependent manner, with both doses exhibiting a good safety profile.

Long-term compliance and changes in plasma lipids, plant sterols and carotenoids in children and parents with FH consuming plant sterol ester-enriched spread.

OBJECTIVE: To study the compliance and changes in plasma lipids, plant sterols, fat-soluble vitamins and carotenoids in children and parents with familial hypercholesterolemia (FH) consuming a plant sterol ester-enriched (PSE) spread. DESIGN: A 26-week open-label follow-up of children who had previously been studied in a controlled cross-over design. The parents were also included in the open-label arm of the study. SETTING: Outpatient clinic for treatment of hyperlipidemia. SUBJECTS: A total of 37 children (7-13 y) and 20 parents (32-51 y) diagnosed with 'definite' or 'possible' heterozygous FH. In all, 19 of the parents, but no children, used statins. All were patients at the Lipid Clinic, National Hospital in Oslo. INTERVENTIONS: Subjects were recommended to eat 20 g/day of PSE spread as part of their lipid-lowering diet. RESULTS: The mean intake of PSE spread was 13.7 and 16.5 g/days in the children and parents, respectively, corresponding to 1.2 and 1.5 g of plant sterols. Plasma total cholesterol decreased by 9.1% in both children (P<0.001) and parents (P=0.002). The corresponding decreases in LDL cholesterol were 11.4% (P<0.001) and 11.0% (P=0.012). Increases in serum lathosterol, campesterol and sitosterol, adjusted for total cholesterol, were observed in the children (31, 96, 48%, respectively, P<0.001) at the end of the controlled cross-over period. In the parents, serum campesterol and sitosterol, adjusted for total cholesterol, increased by 92 and 39%, respectively (P< 0.001). Lipid-adjusted serum alpha- and beta-carotene decreased by 17.4% (P=0.008) and 10.9% (P=0.018), respectively, in the children at the end of the controlled PSE period, but increased again during the follow-up. In the parents, serum alpha- and beta-carotene concentrations were unchanged, while serum lutein and lycopene decreased by 7.3% (P=0.037) and 14.6% (P=0.044), respectively. CONCLUSIONS: Sustained efficacy of cholesterol reduction and long-term compliance of PSE intake were demonstrated in this study.

Lipid-altering efficacy and safety of simvastatin 80 mg/day: long-term experience in a large group of patients with hypercholesterolemia. World Wide Expanded Dose Simvastatin Study Group.

BACKGROUND: Elevated levels of low-density lipoprotein (LDL) cholesterol promote the development of atherosclerosis and coronary heart disease. HYPOTHESIS: Simvastatin 80 mg/day will be more effective than simvastatin 40 mg/day at reducing LDL cholesterol and will be well tolerated. METHODS: Two similar, randomized, multicenter, controlled, double-blind, parallel-group, 48-week studies were performed to evaluate the long-term lipid-altering efficacy and safety of simvastatin 80 mg/day in patients with hypercholesterolemia. One study conducted in the US enrolled patients meeting the National Cholesterol Education Program (NCEP) LDL cholesterol criteria for pharmacologic treatment. In the other multinational study, patients with LDL cholesterol levels > or = 4.2 mmol/l were enrolled. At 20 centers in the US and 19 countries world-wide, 1,105 hypercholesterolemic patients, while on a lipid-lowering diet, were randomly assigned at a ratio of 2:3 to receive simvastatin 40 mg (n = 436) or 80 mg (n = 669) once daily for 24 weeks. Those patients completing an initial 24-week base study were enrolled in a 24-week blinded extension. Patients who had started on the 80 mg dose in the base study continued on the same dose in the extension, while those who had started on the 40 mg dose were rerandomized at a 1:1 ratio to simvastatin 40 or 80 mg in the extension. RESULTS: There was a significant advantage in the LDL cholesterol-lowering effect of the 80 mg dose compared with that of the 40 mg dose, which was maintained over the 48 weeks of treatment. The mean percentage reductions (95% confidence intervals) from baseline in LDL cholesterol for the 40 and 80 mg groups were 41% (42, 39) and 47% (48, 46), respectively, for the 24-week base study, and 41% (43, 39) and 46% (47, 45), respectively, after 48 weeks of treatment (p < 0.001 between groups). Larger reductions in total cholesterol and triglycerides were also observed with the 80 mg dose compared with the 40 mg dose at Weeks 24 and 48. Both doses were well tolerated, with close to 95% of patients enrolled completing the entire 48 weeks of treatment. Myopathy (muscle symptoms plus creatine kinase increase > 10 fold upper limit of normal) and clinically significant hepatic transaminase increases (> 3 times the upper limit of normal) occurred infrequently with both doses. There was no significant difference between the groups in the number of patients with such increases, although there were more cases for both with the 80 mg dose. CONCLUSIONS: Compared with the 40 mg dose, simvastatin 80 mg produced greater reductions in LDL cholesterol, total cholesterol, and triglycerides. Both doses were well tolerated.