Treatment of Familial Hypercholesterolemia: Is There a Need Beyond Statin Therapy?

Familial hypercholesterolemia (FH) is a genetic lipid disorder that is characterized by severely elevated cholesterol levels and premature cardiovascular disease. Both the heterozygous and homozygous forms of FH require aggressive cholesterol-lowering therapy. Statins alone frequently do not lower these patients’ cholesterol to therapeutic levels, and some patients are intolerant to statins. Combination or monotherapy with other current pharmacotherapies are options, but even with these some FH patients do not meet their low-density lipoprotein (LDL) cholesterol goals. In the cases of statin intolerance, LDL apheresis may be another treatment option. There are currently several novel therapies in development for LDL lowering that target either production or catabolism of LDL, plaque regression, and potentially gene transfer. We conclude that there is a need beyond statins for patients with FH, especially in cases of statin intolerance, and when even the highest doses of statin do not get patients to goal cholesterol levels.     

Recommendations for the use of LDL apheresis

Plasma exchange has been shown to increase life-expectancy in homozygous familial hypercholesterolaemia (FH) but increasingly is being replaced by LDL apheresis. Several methods are now available for undertaking this procedure, which lowers LDL cholesterol and Lp(a) efficiently and safely when performed weekly or bi-weekly and causes only slight decreases in HDL cholesterol. Hitherto the main clinical indication has been homozygous FH, including children and pregnant women, but there are limited data showing that LDL apheresis has effects on the progression of cardiovascular disease in FH heterozygotes which are similar to those of maximal lipid-lowering drug therapy. Hence it has the potential to be beneficial in hypercholesterolaemic patients with overt coronary disease who are refractory to or intolerant of drugs. It is therefore recommended that LDL apheresis should be the treatment of choice for: (1) all FH homozygotes from the age of seven onwards unless their serum cholesterol can be reduced by >50% and/or decreased to 5.0mmol/l or is decreased by <40% with maximal drug therapy. Apheresis may also occasionally be indicated on a case-by-case basis for patients with lower levels of LDL. (3) LDL apheresis should also be considered for patients with aggressive progressing coronary disease and Lp(a)>60mg/l whose LDL cholesterol remains >3.2mmol/l despite maximal drug therapy.     

Long-term effect of low-density lipoprotein apheresis in patients with homozygous familial hypercholesterolemia

Patients that are homozygous for familial hypercholesterolemia (FH) exhibit severe hypercholesterolemia, cutaneous and tendon xanthomas and premature atherosclerosis beginning in childhood. They are resistant to drug therapy and low-density lipoprotein (LDL) apheresis is the practical treatment. Here we review the technique of LDL apheresis treatment, the long-term effects of LDL apheresis, the effect of apheresis on pregnancy, and the drugs that have proven beneficial in patients with homozygous FH. We also record our experiences of treating eight homozygous FH patients using the LDL apheresis treatment. Among the eight patients, one has been free from cardiovascular disease and two patients have each regressed once. In two patients, aortic valve stenosis developed and the other two patients died for acute myocardial infarction. Furthermore, two patients delivered healthy babies in spite of coronary artery disease. Thus, LDL apheresis therapy has the possibility of preventing the progression of atherosclerosis, but the prognosis assessed by long-term observation is still not satisfactory. A recent clinical trial showed some efficacy of the combination therapy of LDL apheresis and atorvastatin for reducing serum cholesterol levels in homozygous FH, suggesting that this combination therapy may be useful for prevention of atherosclerosis in patients homozygous for FH.     

Familial hypercholesterolemia--improving treatment and meeting guidelines

Familial hypercholesterolemia (FH) is a common, inherited disorder that affects around one in 500 individuals in the heterozygous form. By the year 2001, more people in the US had FH than were infected by the human immunodeficiency virus. The disease is caused by mutations within the low-density lipoprotein (LDL) receptor gene. FH is associated with elevated plasma LDL-cholesterol (LDL-C) levels, xanthomatosis, early onset of atherosclerosis and premature cardiac death. Patients with heterozygous FH commonly have plasma LDL-C levels that are two-fold higher than normal, while homozygotes have four- to five-fold elevations in plasma LDL-C. Although FH patients have a high risk of developing premature coronary heart disease (CHD), they remain underdiagnosed and undertreated. Early detection of FH is critical to prolonging the life of these patients. Once identified, patients with heterozygous FH can be placed on a diet and drug management program. As the most efficacious and well-tolerated agents, hydroxy methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are usually the drugs of first choice; bile acid sequestrants, niacin, and occasionally fibrates may be used as supplemental agents. Statins may also provide a realistic option for the treatment of some FH homozygotes with genes that produce partially functional LDL receptors. However, a number of patients are still failing to reach treatment guidelines even with the most effective of the currently available statins. The development of new more efficacious statins or the use of new combination therapies such as statins with the cholesterol absorption inhibitor, ezetimibe may help to reduce the current problem of undertreatment in FH patients.     

Treatment of refractory familial hypercholesterolemia by low-density lipoprotein apheresis using an automated dextran sulfate cellulose adsorption system. The Liposorber Study Group.

A subgroup of patients with familial hypercholesterolemia (FH) respond inadequately to standard diet and drug therapy, and are therefore at high risk for the premature development or progression of coronary artery disease. This study evaluated low-density lipoprotein (LDL) cholesterol and lipoprotein (a) removal in a multicenter, controlled trial with a new LDL apheresis procedure (Liposorber LA-15 System). The study comprised patients with FH who had not responded adequately to diet and maximal drug therapy. There were 54 patients with heterozygous FH (45 randomized to treatment and 9 control subjects) and 10 with homozygous FH (all of whom received LDL apheresis). The study included three 6-week treatment phases and a 4-week rebound phase. Treatments were administered at 7- to 14-day intervals. Mean acute reductions in LDL cholesterol were 76% in heterozygous FH patients and 81% in homozygous ones. Time-averaged levels of LDL cholesterol were reduced 41% (243 to 143 mg/dl) in heterozygous FH patients and 53% (447 to 210 mg/dl) in homozygous ones. The substantial acute reduction of lipoprotein (a) (means: 65%, heterozygous FH; 68%, homozygous FH) has not been reported with other therapies. The Liposorber LA-15 System represents an important therapeutic option in FH patients who respond inadequately to diet and drug therapy.     

Homozygous familial hypercholesterolemia and its management

Mutations in the low-density lipoprotein (LDL) receptor gene cause familial hypercholesterolemia. In homozygous familial hypercholesterolemia, both genes for the LDL- receptor are mutated and LDL levels are markedly elevated. High-density lipoprotein cholesterol concentration is often reduced and lipoprotein(a) levels are high when corrected for apolipoprotein(a) isoforms. Cutaneous and tendinous xanthomata develop in childhood and are the most common reason for initial presentation. The diagnosis can be confirmed by analysis of LDL-receptor genes or studies of LDL receptor function in cultured cells. Severe aortic and coronary atherosclerosis usually occurs within the first or second decades of life. Left ventricular outflow tract obstruction may be at the level of the aortic valve or the supravalvar aorta. Treatment for the hyperlipidemia is with plasmapheresis, high-dose statins, and ezetimibe. Liver transplantation reverses the metabolic defect but requires chronic immunosupression, and rejection may still occur. Liver transplantation is indicated if cardiac transplantation becomes necessary. Portocaval shunt may still play a role in patients with coronary artery disease who do not have access to plasmapheresis. Gene therapy is currently not practicable but is being actively developed.     

Identification and treatment of heterozygous familial hypercholesterolemia in children and adolescents

Heterozygous familial hypercholesterolemia (FH) is completely expressed at birth and early in childhood by significant elevations in plasma total and tow density lipoprotein (LDL) cholesterol levels. High density lipoprotein cholesterol can be low in such FH children; the triglyceride levels are usually within the normal range. Screening of children for heterozygous FH using a LDL cholesterol level is reasonably efficient in families with known FH, but for general population screening, the LDL cholesterol level is often too nonspecific. Screening of offspring with a positive family history of premature coronary artery disease will provide a panoply of different lipoprotein phenotypes, reflecting the presence of other genetic conditions, including familial combined hyperlipidemia. Guidelines have been developed by the National Cholesterol Education Program (NCEP) Expert Panel on Blood Cholesterol levels in Children and Adolescents to assist in the evaluation and treatment of children with high LDL cholesterol levels. Although heterozygous FH probably counts for ≤5% of premature coronary artery disease, its identification and treatment are important, because FH often causes marked premature coronary artery disease early in adulthood, and can be successfully treated with a combined dietary and drug approach.     

The association of LDL receptor activity, LDL cholesterol level, and clinical course in homozygous familial hypercholesterolemia

Patients with homozygous familial hypercholesterolemia (FH), reveal a marked heterogeneity in plasma cholesterol levels, response to diet as well as drug treatment, and clinical course. Low-density lipoprotein (LDL) receptor activities were assessed by the rate of 14C-oleate cholesteryl ester biosynthesis in fibroblasts from 13 FH homozygotes in tissue culture. The receptor activity of the individual patients was highly correlated with initial pretreatment plasma cholesterol and LDL cholesterol levels (P less than .001, r = -0.89). In addition, the LDL receptor activity was positively correlated with the age of onset of angina based on the Cox model (P less than .035, likelihood ratio = 6.71). An association was also noted between LDL receptor activity and cholesterol reduction with drugs. These data provide direct evidence for the correlation between the heterogeneity of the LDL receptor and the expression of the clinical manifestations of homozygous FH. The determination of pretreatment plasma cholesterol level and LDL receptor activity in patients with homozygous FH provide useful parameters on which to base predictions of the clinical progression of cardiovascular disease. These parameters may also influence the selection of a program for diet and drug therapy. Patients with markedly elevated plasma cholesterol levels and very low LDL receptor activity should be considered to be candidates for multiple drug therapy, and portacaval shunt, and/or periodic plasma exchanges.     

Plant sterols lower LDL cholesterol without improving endothelial function in prepubertal children with familial hypercholesterolaemia

In adults with familial hypercholesterolaemia (FH), cholesterol lowering with statins has been shown to improve the endothelial function, a hallmark of early atherogenesis. Currently, therapeutic options for treating high cholesterol levels in FH children are limited. Plant sterols safely and effectively reduce serum cholesterol concentrations by inhibiting cholesterol absorption. Therefore, we evaluated the effect of plant sterols on cholesterol and vascular function in prepubertal children with FH. We included 41 children (5–12 years old) with FH in a double-blind crossover trial using spreads containing 2.3 g of plant sterols (mainly sitosterol and campesterol) per 15 g spread and a placebo spread for a 4-week period, separated by a 6-week washout period. Lipid levels and endothelial function were assessed after both 4-week treatment periods. Endothelial function was assessed as flow-mediated dilation (FMD) of the brachial artery using a wall tracking system. Data were compared to those of 20 healthy controls. Intake of 2.3 g plant sterols per day decreased total cholesterol (-11%) and low-density cholesterol (-14%) as compared to placebo spread in FH children. FH children treated with placebo spread were characterized by an impaired FMD compared to healthy control children (7.2 %± 3.4% versus 10.1%±4.2%, p < 0.005). However, the reduction of LDL in FH children did not improve FMD (placebo: 7.2% ± 3.4% versus plant sterols: 7.7% ± 4.1%). In conclusion, the present study shows a clear reduction of LDL cholesterol by plant sterol treatment. However, short-term plant sterol treatment does not improve the endothelial function in FH children. This revised version was published online in August 2006 with corrections to the Cover Date.     

Effect of low-density lipoprotein receptor mutation on lipoproteins and cardiovascular disease risk: a parent-offspring study

Studies on the clinical consequences of different low-density lipoprotein (LDL) receptor genotypes in adult patients have yielded conflicting results. We hypothesized that children with familial hypercholesterolemia (FH) provide a better model to perform genotype-phenotype analyses than adults. We tested this hypothesis and assessed the effect of LDL receptor genotypes on lipoprotein levels and on parental risk of cardiovascular disease (CVD) in a pediatric FH cohort. We identified 75 different LDL receptor mutations in 645 children with heterozygous FH; in these children, null alleles were clearly associated with more elevated LDL cholesterol levels compared to receptor-defective mutations. Familial factors explained 50.4% of the variation in LDL cholesterol levels of this pediatric cohort compared to only 9.5% in adults. Parental CVD risk was not significantly different between carriers of null alleles and receptor-defective mutations (RR, 1.22; 95% CI, 0.76-1.95; p=0.4). The N543H/2393del9 mutation was associated with a less deteriorated lipid profile and the parents had less often CVD relative to parents with other mutations (RR, 0.39; 95% CI, 0.20-0.78; p=0.008). We could confirm that children with FH provide a better model to perform genotype-phenotype analyses. In particular, children with null alleles had significantly more elevated LDL cholesterol levels than carriers of other alleles but this was not associated with higher risk of CVD in the parents. Nonetheless, a specific LDL receptor mutation was associated with less deteriorated lipoprotein levels and a milder CVD risk.     

Comparison of apolipoprotein B metabolism in familial defective apolipoprotein B and heterogeneous familial hypercholesterolemia

Both defective LDL receptors (familial hypercholesterolaemia, FH) and mutations in apolipoprotein B (apoB) on LDL (familial defective apoB, FDB) give rise to a phenotype of elevated LDL cholesterol. We sought to compare the metabolic basis of the two conditions by examining apoB turnover in FDB and FH subjects. A group comprising three heterozygous and one homozygous FDB subjects were compared with five FH heterozygotes and 17 control subjects using a deuterated leucine tracer. Kinetic parameters were derived by multicompartmental modelling. FH heterozygotes had a reduced delipidation rate for VLDL, which led to a moderate increase in plasma triglyceride. Compared with controls and FH, the FDB subjects converted 44% less IDL to LDL. The LDL FCR was reduced to a similar extent in FDB and FH. In all subjects LDL plasma levels appeared to be regulated by the LDL FCR and the rate of production of small VLDL. We conclude that disturbances in IDL metabolism provide the basis for understanding why FDB is less severe than FH. Our findings suggest that an apoB-LDL receptor interaction is important in the IDL to LDL conversion.     

Mechanisms of disease: genetic causes of familial hypercholesterolemia

Familial hypercholesterolemia (FH) is characterized by raised serum LDL cholesterol levels, which result in excess deposition of cholesterol in tissues, leading to accelerated atherosclerosis and increased risk of premature coronary heart disease. FH results from defects in the hepatic uptake and degradation of LDL via the LDL-receptor pathway, commonly caused by a loss-of-function mutation in the LDL-receptor gene (LDLR) or by a mutation in the gene encoding apolipoprotein B (APOB). FH is primarily an autosomal dominant disorder with a gene-dosage effect. An autosomal recessive form of FH caused by loss-of-function mutations in LDLRAP1, which encodes a protein required for clathrin-mediated internalization of the LDL receptor by liver cells, has also been documented. The most recent addition to the database of genes in which defects cause FH is one encoding a member of the proprotein convertase family, PCSK9. Rare dominant gain-of-function mutations in PCSK9 cosegregate with hypercholesterolemia, and one mutation is associated with a particularly severe FH phenotype. Expression of PCSK9 normally downregulates the LDL-receptor pathway by indirectly causing degradation of LDL-receptor protein, and loss-of-function mutations in PCSK9 result in low plasma LDL levels. Thus, PCSK9 is an attractive target for new drugs aimed at lowering serum LDL cholesterol, which should have additive lipid-lowering effects to the statins currently used.     

A case of heterozygous familial hypercholesterolemia associated with hyperthyroidism: Effects of triiodothyronine on low-density lipoprotein receptor and cholesterol synthesis

A 58-year-old patient with heterozygous familial hypercholesterolemia (FH) showed normal levels of serum cholesterol (193 mg/dL) in coexistence with hyperthyroidism. After hyperthyroidism therapy with radioiodine and methimazole, the patient's lipid profile showed high concentrations of cholesterol (whole serum 318 mg/dL, VLDL 35 mg/dL, LDL 217 mg/dL, HDL 44 mg/dL). There was a significant inverse correlation between serum cholesterol levels and serum thyroxine levels (r = -0.815, p less than 0.01). Effects of triiodothyronine on LDL degradation and cholesterol synthesis from 14C-labeled acetate were studied in cultured skin fibroblasts. Triiodothyronine (T3) stimulated both LDL degradation and cholesterol synthesis in the cells from normal subjects and patients with heterozygous FH. The T3 increased cellular cholesterol synthesis markedly in the cells from patients with homozygous FH but did not increase LDL receptor activity. These results suggest that normal serum cholesterol levels in our case result in part from an enhancement of LDL receptors by thyroid hormone.     

Clinical features of familial hypercholesterolemia in Japan in a database from 1996-1998 by the research committee of the ministry of health, labour and welfare of Japan

Familial hypercholesterolemia (FH) is one of the most common primary hyperlipidemias, characterized by a heterozygous or homozygous phenotype for a severe serum low-density lipoprotein (LDL)-cholesterol level and advanced atherosclerosis, leading to coronary artery diseases (CAD). Various kinds of mutations in the LDL receptor gene responsible for the genetic disease have been identified since the human LDL receptor gene has been identified. In this study, the clinical features of FH were investigated using a database based on nationwide surveillance for primary hyperlipidemia and related disorders by the Research Committee on Primary Hyperlipidemia. The clinical features and the frequencies of accompanying vascular diseases in 660 cases of FH homozygotes and heterozygotes showed that the incidence of CAD was negatively associated with plasma HDL-cholesterol levels, but not with plasma LDL-cholesterol levels, in 641 FH heterozygotes. Risk factor analyses revealed that hypertension, male, smoking, low HDL-cholesterol levels, age > 50 y, diabetes mellitus, and hypertriglyceridemia were positive risk factors for CAD. The summarized gene analysis in FH heterozygotes showed at least 4 mutations in the LDL receptor gene as common mutations in Japan. The average serum lipids and frequency of CAD based on each common mutation suggested that their clinical features are in part determined by responsive mutations in the LDL receptor gene.     

Treatment of dyslipidemia: how and when to combine lipid lowering drugs

Familial combined hyperlipidemia (FCH) is a frequent familial lipid disorder associated with insulin resistance, low HDL cholesterol, high triglycerides and cholesterol levels with variable phenotypes within the same family. FCH is linked to a high risk for cardiovascular diseases. Treatment goals for lipid abnormalities are changing in recent years. Lowering elevated levels of LDL e Non HDL-cholesterol levels are primary targets of therapy. Lower LDL-C than 70 mg/dL seems to be useful to lower cardiovascular risk in patients with very high risk. Many statins are available, with different potencies and drug interactions. Combination therapy of statins and bile acid sequestrants or ezitimibe may be necessary to further decrease LDL cholesterol levels in order to meet guideline goals. High triglycerides and low HDL cholesterol are also important goals in the treatment of these patients, and frequently statins alone are insufficient to normalize the lipid profile. Combination therapy with fibrates will further lower triglycerides and increase HDL cholesterol levels; this combination is also associated with higher incidence of myopathy and liver toxicity; appropriate evaluation of patients' risk and benefits is necessary. Association of statin/niacin seems be very useful in patients with FCH, especially as niacin is the best drug to increase HDL cholesterol; this association is not linked to a higher frequency of myopathy. Niacin causes flushing, that can in part be managed with use of aspirin and extended release forms (Niaspan); niacin also may increase plasma glucose and uric acid levels. Evaluation of risks and benefits for each patient is needed.     

Low-density lipoprotein cholesterol bulk is the pivotal determinant of atherosclerosis in familial hypercholesterolemia

This study's aim was to determine whether biochemical risk factors such as lipoprotein(a), fibrinogen, homocysteine, and insulin, as well as low-density lipoprotein (LDL) particle size, were predictive of carotid intimamedia thickness (IMT), an early marker of atherosclerosis, in subjects with familial hypercholesterolemia (FH). We also determined whether plasma 8-isoprostane, as a marker of in vivo lipid oxidation, correlated with carotid IMT. Twenty-two homozygous and 20 heterozygous subjects with FH were compared with 20 normocholesterolemic controls. On univariate analysis, plasma total and LDL cholesterol, the cholesterol-years score (CYS), lipoprotein(a), and fibrinogen, but not homocysteine or insulin, were positively related, and high-density lipoprotein (HDL) cholesterol was negatively related to carotid IMT. However, on multivariate analysis, only LDL cholesterol and the CYS predicted carotid IMT (multiple r = 0.82; r2 = 0.68; p <0.0001). The subjects with FH had large rather than small dense LDL particles, and plasma 8-isoprostane levels were not increased. LDL cholesterol and the CYS, or "cholesterol bulk" are the pivotal determinants of atherosclerosis and are the strongest predictors of carotid IMT in FH.     

Familial hypercholesterolaemia

Familial hypercholesterolaemia (FH) is a common (1 in 500) autosomal dominant group of syndromes associated with early onset coronary artery disease or sudden death in heterozygotes. Clinical signs are not universal but the family history is often a good indicator for initial screening. Prognosis without treatment is dependent on family history and the presence of other cardiovascular risk factors. Family screening is necessary but treatment of affected children is usually postponed until puberty. Treatment of adults is primarily with statins but removal of lipoproteins by apheresis is used in severe refractory cases or in patients with homozygous FH. FH is an easily diagnosed disorder with a reasonable prognosis after treatment and therefore cases should be identified and treated.     

Low-density lipoprotein apheresis as a treatment option for hyperlipidemia

Opinion statement  Data support the relevance of blood cholesterol levels, particularly high levels of low-density lipoprotein (LDL), in the pathogenesis and progression of atherosclerosis. A strong and continuous relationship between dyslipidemia and vascular morbidity and mortality has been established. The initial approach to treating dyslipidemia consists of lifestyle modifications followed by pharmacologic therapy, usually beginning with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Some patients with familial hypercholesterolemia (FH) fail to achieve their LDL goal despite aggressive pharmacologic therapy. In certain cases, LDL apheresis may be an effective therapeutic option. In the United States, LDL apheresis is approved for homozygous FH patients with an LDL cholesterol level ≥ 500 mg/dL. For patients with heterozygous FH, LDL apheresis may be offered if their LDL is ≥ 300 mg/dL, or ≥ 200 mg/dL with known coronary artery disease, despite maximum medical treatment. This review focuses on the principles and methods of LDL apheresis, its potential benefit in clinical care, and its current indications.     

Long-term effects of LDL apheresis on carotid arterial atherosclerosis in familial hypercholesterolaemic patients

OBJECTIVES: To assess the long-term effect of LDL apheresis on carotid arterial atherosclerosis in severe familial hypercholesterolaemic (FH) patients. DESIGN: Changes in existing plaque, new plaque formation and annual progression rate of carotid early plaque were evaluated by B-mode ultrasonography. SUBJECTS: LDL apheresis group: two homozygous FH and nine heterozygous FH patients received a combination of LDL apheresis and cholesterol-lowering drug therapy for a mean of 7.8 years. Control group: 10 heterozygous FH patients were maintained by medication only for a mean of 5.5 years. RESULTS: As a result of LDL apheresis treatment, LDL cholesterol levels reduced from 16.0+/-3.60 to 6.43+/-0.07 mmol L(-1) in homozygous FH patients and from 11.5+/-2.46 to 4.32+/-1.2 mmol L(-1) in heterozygous FH patients. During the long-term treatment period, the existing plaque tended to progress and new plaque formation in carotid arteries was also observed in both groups. The annual progression rate of mean maximum intima-media thickness in the common carotid artery was a mean of -0.0023+/-0.0246 mm year(-1) in heterozygous FH patients in the LDL apheresis group, suggesting regression. This was significantly lower when compared with the control group, which had a mean of 0.0251+/-0.0265 mm year(-1) CONCLUSION: The results suggest that the long-term treatment with combined LDL apheresis and drugs may delay the progression of the atherosclerotic process and prompt the stabilization of atheromatous plaque in severe FH patients.     

Effectiveness of mevinolin on plasma lipoprotein concentrations in type II hyperlipoproteinemia

Patients with low-density lipoprotein (LDL) concentrations in the top 10th percentile of the population (type II hyperlipoproteinemia [HLP]) are at increased risk for premature cardiovascular disease; however, the incidence of myocardial infarction and death can be decreased by LDL cholesterol reduction. Mevinolin, an inhibitor of endogenous cholesterol synthesis, has been shown to reduce LDL cholesterol concentrations in a subset of type II patients with heterozygous familial hypercholesterolemia (FH). Using a double-blind, randomized, crossover, placebo-controlled trial, the safety and efficacy of mevinolin were compared in 24 patients with type II HLP with heterozygous FH (n = 6) or without FH type II HLP (n = 18). Compared with placebo treatment, both apolipoprotein B and LDL cholesterol levels were reduced (p less than 0.01) in both FH and non-FH patients by 28 to 34% with mevinolin treatment. In addition, high-density lipoprotein cholesterol levels were significantly increased (p less than 0.001) in both patients with FH (16%) and those with non-FH type II HLP (14%). Patients had no serious or clinically significant adverse effects. Thus, mevinolin is a useful drug for treatment of most patients with elevated plasma LDL cholesterol concentrations.