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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:1527-1531.)
© 1997 American Heart Association, Inc.

Articles

Atorvastatin: An Effective Lipid-Modifying Agent in Familial Hypercholesterolemia

A. David Marais; Jean C. Firth; Mary E. Bateman; Pam Byrnes; Candice Martens; ; Jean Mountney

From the Department of Medicine, University of Cape Town Medical School, Cape Town, and Parke-Davis Pharmaceuticals (C.M.), South Africa.

Correspondence to Dr A.D. Marais, Department of Internal Medicine, University of Cape Town Medical School, Observatory 7925, Cape Town, South Africa. E-mail dmarais{at}uctgsh1.uCT.ac.za

	Abstract

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Abstract Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are the drugs of choice in heterozygous familial hypercholesterolemia (FH), which has a high risk of ischemic heart disease. An open-label study was conducted to test the efficacy and safety of atorvastatin, a new synthetic HMG-CoA reductase inhibitor in proven FH. After a 4-week placebo phase, 22 subjects were randomized to either 80 mg atorvastatin at night (n=11) or 40 mg twice a day for 6 weeks. The two dosage groups were well matched and had no difference in lipoprotein responses. After 6 weeks, the LDL cholesterol concentration was reduced by 57%, from 8.16±1.15 to 3.53±0.99 mmol/L (P<.001). The total cholesterol concentration decreased from 9.90±1.32 to 5.43 mmol/L (P<.001). HDL cholesterol concentration increased from 1.19±0.31 to 1.49±0.43 mmol/L (P<.001). Triglyceride concentrations decreased from 1.34±0.66 to 0.88±0.36 mmol/L (P<.01). Three subjects had single, transient increases of serum transaminase of up to twice the upper limit of normal. Apolipoprotein B concentration decreased significantly by 42%. Changes in apolipoproteins AI and (a) were not statistically significant. Nondenaturing gradient gel electrophoresis revealed increases in the size of smaller LDL particles in four subjects. Plasma fibrinogen concentration increased by 44%. The drug was well tolerated. One subject withdrew for personal reasons. Ator- vastatin is a powerful and safe lipid-modifying agent for LDL cholesterol; it also modifies HDL cholesterol and triglyceride concentrations, and may suffice as a single agent for many subjects with heterozygous FH.

Key Words: atorvastatin • HMG-CoA reductase inhibitors • familial hypercholesterolemia

	Introduction

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Familial hypercholesterolemia is an autosomal dominant disorder due to dysfunction of the LDL receptor,¹ of which many mutations are known.² FH is associated with a high risk of ischemic heart disease.³ The gene prevalence of this disorder is about 1 in 500, but higher prevalences are recognized in certain founder populations, such as the South African Afrikaner.⁴

In FH, the usually recommended diet and lifestyle modifications do not achieve the target LDL-C concentrations advised by the European Atherosclerosis Society⁵ or the US National Cholesterol Education Program.⁶ The most powerful drugs for lowering plasma cholesterol in FH today are the HMG-CoA reductase inhibitors.⁷ This class of agents acts primarily in the liver where de novo cholesterol synthesis is inhibited. The regulatory response to these agents is to increase LDL receptor expression, which in turn leads to a lower plasma LDL-C concentration. The drugs already in use include lovastatin, simvastatin, pravastatin, and fluvastatin. Despite the efficacy of these agents, patients may still require combination therapy⁷ to achieve the desired cholesterol concentrations.

There is thus still a need for an HMG-CoA reductase inhibitor that could suffice as a single agent. Atorvastatin, a new synthetic and powerful inhibitor of HMG-CoA reductase, was tested in a cohort of heterozygous FH subjects.

	Methods

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The study was conducted according to sound clinical practice guidelines and was approved by the ethics review committee of the university. After they were screened and informed consent was obtained, 22 FH patients discontinued their lipid-modifying treatment. Two weeks later, they commenced a 4-week phase with a placebo. Hereafter the subjects were randomly allocated to the active phase for 6 weeks and took either a single nocturnal dose of atorvastatin (80 mg) or a divided dose of 40 mg twice a day.

Patients with the clinical diagnosis of FH were selected from lipid clinic records. Informed consent was obtained and dietary counseling according to the American Heart Association Step II guidelines⁶ was given. Inclusion criteria for randomization were confirmed heterozygous FH status and TG concentrations that permitted calculation of LDL-C levels, ie, TG<4.5 mmol/L. FH was confirmed by the demonstration of one of the local genotypes or by exclusion of the familial binding-defective apo B genotype in primary hypercholesterolemia with Achilles' tendon xanthomata. The calculated LDL-C⁸ concentration had to exceed 6.4 mmol/L for the subject to be randomized into the study. Criteria that excluded subjects were age >75 or <18 years; concurrent administration of any drugs known to modify plasma lipids; significant liver, renal, or endocrine disease; alcohol consumption >210 g/w; uncontrolled hypertension; risk of conception; a body mass index >32 kg/m²; and poor compliance during the placebo phase. The clinical details of the patients are summarized in Table 1.

View this table: [in this window] [in a new window]   Table 1. Clinical Characteristics of Trial Subjects

Safety monitoring included clinical assessments as well as biochemical tests of liver, renal, muscle, and hematological functions. Plasma cholesterol and TG concentrations were determined after a 10-hour fast by standard commercially available enzymatic kits in a chemical pathology laboratory that practices quality surveillance. HDL-C levels were determined after chemical precipitation of apo B-containing lipoproteins with heparin and MnCl₂. Apo A_I and apo B were assayed by nephelometric kits, and apolipoprotein(a) was assayed by radioimmunoassay.

After DNA was extracted from the blood by the method of Parzer and Mannholter,⁹ the three Afrikaner FH mutations and the Lithuanian mutation were sought by PCR methods as previously described,^{10 11} whereas the Cape Town 2 defect was detected by Southern blotting.¹² The binding defect of apo B was excluded by PCR.¹³

The plasma lipoproteins were examined by nondenaturing GGE before and after drug intervention to evaluate the changes in particle size that occurred during treatment. Plasma was prestained with Sudan black dissolved in ethylene glycol, mixed with sucrose and bromphenol blue, and loaded on a 4% to 8% polyacrylamide minigel. Samples representing the beginning and end of the active phase were placed in adjacent lanes. This technique reproducibly identifies about five species of LDL, which we categorized into A (largest), I (intermediate), or B (smallest). Larger species of lipoprotein corresponding to TG-rich lipoproteins were termed M+ if visible and M- if not visible.

Statistical analysis was performed by ANOVA on commercially available software. Analysis of TG concentrations was done after logarithmic transformation. A two-tailed value of P<.05 was considered significant.

	Results

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Twenty-two subjects (5 men) were randomized into the study. The clinical details are summarized in Table 1. Eleven subjects completed the divided-dose regimen and 10 the single-dose treatment. One subject withdrew for personal reasons toward the end of the active phase, without having experienced any significant clinical or biochemical adverse events.

Because there were no differences in response between the single- and divided-dose groups, the results are reported as a group. The plasma lipid and lipoprotein responses are listed in Table 2. With the exception of the apoprotein values, the baseline value was taken as the mean of the three visits before active therapy was initiated. All of these parameters changed significantly within 14 days and reached their full effect by 4 weeks. At 6 weeks, the average reduction in total cholesterol, LDL-C, and TG concentrations was 45%, 57%, and 31%, respectively. The average apo B concentration decreased by 42%, from 1.77±0.32 to 1.04±0.24 g/L. The average HDL-C level increased by 26%, from 1.19±0.31 to 1.49±0.43 mmol/L (P<.001). Apo A_I increased by 13%, but this latter change was not statistically significant. Lipoprotein(a) did not change significantly. Individual responses in LDL-C are depicted in Fig 1, which shows that 3 individuals responded less well when compared with the remaining subjects.

View this table: [in this window] [in a new window]   Table 2. Lipid, Lipoprotein, and Apolipoprotein Concentrations and Responses in the Entire Group

View larger version (24K): [in this window] [in a new window]   Figure 1. LDL responses in subjects taking atorvastatin. The concentrations of LDL cholesterol (LDLC) are given in mmol/L for the samples taken at commencement of treatment and 6 weeks later.

No serious adverse events were reported in the study. Constipation may have been related to the drug in three subjects but was mild and self-limiting. The hematological and biochemical safety monitoring revealed 3 subjects whose transaminases rose to twice the upper limit of normal but decreased without discontinuing the drug. Statistically significant differences were detected in serum enzyme assays, when the last studies done on placebo and atorvastatin were compared. These changes were similar for the single- and divided-dose groups. The alanine aspartate amino transferase activity increased from 11±2.8 to 16.1±8.7 IU/L (46%, P<.001), the alanine pyruvate amino transferase activity from 9.6±4.5 to 16.1±8.7 IU/L (67%, P<.001), and the glutamyl transpeptidase activity from 14.2±6.4 to 19.4±8.1 IU/L (36%, P<.0001). Alkaline phosphatase activity increased from 118±37 to 133±39 IU/L (13%, P<.001) whereas creatine kinase activity increased from 64±32 to 71±23 IU/L (11%, P<.001). Albumin concentration increased slightly but significantly, from 44±3 to 45±2 g/L (a 2% increase; P<.03). Further analysis revealed significant changes in plasma fibrinogen and uric acid levels. The average plasma fibrinogen concentration increased significantly from 2.6±0.5 g/L at baseline to a concentration of 3.6±0.5 g/L, by 46%. Subgroup analysis revealed that there was a statistically significant difference in these changes between the single- and divided-dose groups: 28±7% compared with 60±6%, respectively (P<.05). The change in concentration for each individual in each dosage group is indicated in Fig 2. In the group taking the divided dose, fibrinogen changes were correlated with the decrease in fasting plasma TG levels (R²=.50, P<.02) and the increase in HDL-C (r²=.49, P<.02), although the changes in TG were not related to the changes in HDL-C. The changes in fibrinogen concentration did not correlate with the changes in total cholesterol or LDL-C and were also unrelated to the changes in plasma liver enzyme activity. Serum uric acid concentration was slightly but significantly reduced by nearly 10%, from 0.29±0.08 to 0.26±0.08 mmol/L (P<.01).

View larger version (17K): [in this window] [in a new window]   Figure 2. Changes in fibrinogen concentration in subjects taking atorvastatin. The baseline concentration and the concentration after 6 weeks on atorvastatin are indicated for subjects taking 80 mg as a single dose (A) or twice a day (B). The increase in fibrinogen was statistically significant only for the divided-dose group (see text).

The GGE findings are summarized in Table 3. There was a heterogeneity of LDL particle size in FH. In four cases the particle size increased noticeably, and two cases had a change in size class. The M band became invisible in four cases. Changes in M status and LDL particle size were observed for both dosage regimens and were not interdependent.

View this table: [in this window] [in a new window]   Table 3. Nondenaturing GGE of LDL

	Discussion

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Atorvastatin is a powerful new synthetic HMG-CoA reductase inhibitor. Like other drugs in its class, it is a powerful competitive inhibitor of the enzyme. It is also selectively taken up by the liver, where the inhibition of cholesterol synthesis results in an upregulation of de novo cholesterol synthesis enzymes as well as of LDL receptor synthesis. The duration of activity of atorvastatin appears to be longer than that of other HMG-CoA reductase inhibitors (data on file at Parke-Davis), and this may induce greater LDL receptor upregulation.

Atorvastatin significantly reduced LDL-C levels, but some individual variation was observed. This cohort was too small to determine the factor(s) responsible for the variation in response. These factors could be related to differences in lipid, lipoprotein, or drug metabolism but do not appear to be related to body mass and baseline concentration. The percent reduction of LDL-C in this cohort of FH subjects is appreciably higher than the reported 42% reduction with 80 mg of simvastatin in FH.¹⁴ Simvastatin has approximately twice the potency of lovastatin and pravastatin¹⁵ on a per-mass basis. The greater magnitude of cholesterol reduction with ator- vastatin appears to be due to greater or more prolonged inhibition of HMG-CoA reductase,¹⁶ since fasting plasma mevalonic acid concentrations in FH subjects taking pravastatin, simvastatin, or atorvastatin revealed a corresponding progressive suppression. Most of the reduction in LDL-C occurred during the first 2 weeks and a new equilibrium was reached within 4 weeks. This same time course was observed for the other lipid-modifying effects. Atorvastatin also caused significant increases in plasma HDL-C and reductions in TG levels. These changes are also more marked than those previously reported for simvastatin in FH.¹⁴ If one notes both the potency of atorvastatin to lower LDL-C concentrations and the significant effect on TG levels, it is tempting to speculate that lipoprotein secretion as well as uptake are modified by this agent. While there is evidence for increased LDL turnover during simvastatin treatment of FH,¹⁷ there is no precedent in human metabolism that the secretion of lipoproteins is retarded. A single 80-mg dose was as effective as a divided 80-mg dose in producing the lipid modifications. For reasons of compliance with drug therapy, it is therefore suggested that future use of this agent be as a single dose. It remains to be proved whether this drug, with its longer intracellular activity compared with other HMG-CoA reductase inhibitors, will demonstrate greater efficacy at night.

Specific targets are set for the management of dyslipoproteinemia by the European Atherosclerosis Society⁵ and the US National Cholesterol Education Program.⁶ In this study of FH subjects, atorvastatin reduced LDL-C levels to the target of <4.2 mmol/L in 14 subjects. A target LDL-C level of <3.5 mmol/L, which may apply to high-risk cases, was reached in 10 subjects, and the target of <2.6 mmol/L set for those with existing ischemic heart disease was reached in 5 cases. Although its prospects as a single agent seem favorable, combination therapy may still be required in the treatment of some patients with FH. It is likely that LDL-C levels will be reduced even further when bile acid sequestrants are added to this drug, but there is yet no published experience with this or other combination therapy. Like other HMG-CoA reductase inhibitors, atorvastatin may be less efficacious in homozygous FH since there is very little, if any, LDL receptor activity.

Although atorvastatin greatly modified lipids and lipoproteins, its toxicity did not appear to be enhanced compared with other HMG-CoA reductase inhibitors. Skeletal muscle toxicity¹⁵ when combined with erythromycin or a fibrate is likely to occur with atorvastatin as well, and caution with such combination therapy is thus advised. It has been shown that FH phenotype can vary with the LDL receptor mutation:¹⁸ The Afrikaner 1 mutation (defective receptor status, class 2B) has a lower LDL-C concentration than the Afrikaner 2 mutation (null receptor status, class 5). Our experience with FH is that the LDL-C concentration is generally <6.4 mmol/L after dietary modification. The patients in this study were especially selected from a large cohort (>500) to satisfy the criterion of an elevated LDL-C concentration while on a strict lipid-modifying diet. This study is indeed biased toward the less-common receptor-negative mutation in the LDL receptor, with a ratio reciprocal to that expected in the clinic cohort. A greater percent response to simvastatin was previously found¹⁹ in FH Afrikaner 2 compared with FH Afrikaner 1. The present study is too small to resolve any differences in response to genotype or sex. The response of familial binding-defective apol B to the HMG-CoA reductase inhibitors may be slightly less than that for FH,²⁰ but a powerful response to atorvastatin can nevertheless be anticipated for this disorder as well.

This study demonstrates heterogeneity in LDL particle size for FH, in which it is generally held that large, buoyant species of LDL predominate. Denser, smaller LDL particles have been linked with a higher risk of ischemic heart disease,²¹ but it is not clear whether this association is true for FH. In this study, only a few individuals had larger LDL particles as a result of atorvastatin treatment. The two subjects whose LDL class changed had relatively high plasma TG concentrations, which were reduced by >50% after treatment. It can be calculated that the number of LDL particles decreased as well as the cholesterol content of each particle (apo B). Other studies^{22 23} with HMG-CoA reductase inhibitors also have not demonstrated a uniform change in LDL size by GGE analysis. In contrast, gemfibrozil significantly increased LDL particle size in hypertriglyceridemia but not in primary hypercholesterolemia.²⁴ The B pattern of LDL particle size also persisted in familial combined hyperlipidemia after treatment with gemfibrozil.²⁵ It would therefore appear that in a subset of individuals, the B pattern can be modified by drug therapy, presumably by changes in the metabolism of the TG-rich lipoproteins. However, neither the implications nor the mechanisms of this apparently desirable change are known. The observed changes may be related to intrinsic properties of TG-rich particles and/or secondary changes in lipases and transfer/exchange proteins. HDL particle size was also studied by GGE, but these responses varied widely. There was no consistent change in the ratio of small to large HDL species. The ratios of HDL-C to apo A₁ also did not change uniformly.

The clinical significance of an increase in plasma fibrinogen concentration is not clear. If this is an undesirable feature, its effect may still be outweighed by the desirable changes in lipoproteins. Studies with other HMG-CoA reductase inhibitors in the setting of FH have reported increases²⁶ or insignificant changes²⁷ in fibrinogen concentration. It is not known how or why the divided dose should elicit a different response in fibrinogen metabolism, nor whether the effect is sustained beyond the study period. It is also possible that the fibrinogen response is linked to the metabolism of TG-rich lipoproteins. It appears unlikely that the increase in fibrinogen concentration is related to liver cell injury, as it was not correlated with the change in liver enzyme activity. The change in plasma uric acid concentration is also unexplained and, like the change in fibrinogen concentration, requires more careful evaluation in the future.

We conclude that atorvastatin induces the greatest cholesterol reduction yet published for a single agent and that it is well tolerated in the short term. Its long-term effects still need evaluation. It has apparently favorable effects on plasma LDL-C and HDL-C as well as TG concentrations. It may suffice as single-drug therapy in many cases of severe genetic hypercholesterolemia.

	Selected Abbreviations and Acronyms

 

apo = apolipoprotein FH = familial hypercholesterolemia GGE = gradient gel electrophoresis HDL-C = HDL cholesterol HMG-CoA = hydroxymethylglutaryl coenzyme A LDL-C = LDL cholesterol PCR = polymerase chain reaction TG = triglyceride

	Acknowledgments

 
This study was supported by Parke-Davis Pharmaceuticals. We would like to acknowledge the assistance of M. Moodie and B. Ratanjee in laboratory procedures. We also thank Prof D.R. van der Westhuyzen of Medical Biochemistry for assistance with the genetic diagnoses.

Received March 31, 1996; accepted November 18, 1996.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Brown MS, Goldstein JL. A receptor mediated pathway for cholesterol homeostasis. Science.. 1986;232:34-47.[Free Full Text]

2. Hobbs HH, Brown MS, Goldstein JL. Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Human Mutat.. 1992;1:445-446.[Medline] [Order article via Infotrieve]

3. Slack J. Risks of ischaemic heart disease in familial hyperlipoproteinemic states. Lancet.. 1969;2:1380-1382.[Medline] [Order article via Infotrieve]

4. Seftel HC, Baker SG, Sandler MP, Forman MB, Joffe BI, Mendelsohn D, Jenkins T, Mieny CJ. A host of hypercholesterolemic homozygotes in South Africa. Br Med J.. 1980;281:633-636.

5. Recommendations of the European Atherosclerosis Society prepared by the International Task Force for Prevention of Coronary Heart Disease. Prevention of coronary heart disease: scientific background and new clinical guidelines. Nutr Metab Cardiovasc Dis.. 1992;2:113-156.

6. Summary of the Second Report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel II). JAMA.. 1993;269:3015-3023.[Abstract/Free Full Text]

7. Grundy SM. HMG-CoA reductase inhibitors for treatment of hypercholesterolemia. N Engl J Med.. 1988;319:24-32.[Medline] [Order article via Infotrieve]

8. Friedewald WT, Levy RI, Frederickson DS. Estimation of the concentration of low density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem.. 1972;18:499-502.[Abstract]

9. Parzer S, Mannholter S. A rapid method for the isolation of genomic DNA from citrated whole blood. Biochem J.. 1991;273:229-231.

10. Graadt van Roggen JF, van der Westhuyzen DR, Marais AD, Gevers W, Coetzee GA. Low density lipoprotein receptor founder mutations in Afrikaner familial hypercholesterolemic patients: a comparison of two geographical areas. Ann Hum Genet.. 1991;88:204-208.

11. Meiner V, Landsberger D, Berkman N, Reshef A, Segal P, Seftel HC, van der Westhuyzen DR, Coetzee GA, Leitersdorf E. A common Lithuanian mutation causing familial hypercholesterolemia in Ashkenazi Jews. Am J Hum Genet.. 1991;49:443-449.[Medline] [Order article via Infotrieve]

12. Henderson HE, Berger GMB, Marais AD. A new LDL receptor gene deletion mutation in the South African population. Hum Genet.. 1988;80:371-374.[Medline] [Order article via Infotrieve]

13. Kotze MJ, Langenhoven E, Peeters AV, Theart L, Oosthuizen CJJ. Detection of two point mutations causing familial binding defective apolipoprotein B100 by heteroduplex analysis. Mol Cell Probes. 1994 In press.

14. Mol MJTM, Erkelens DW, Gevers Leuven JA, Schouten JA, Stalenhoef AFH. Effects of synvinolin (MK-733) on plasma lipids in familial hypercholesterolemia. Lancet. 1986;2:936-939.[Medline] [Order article via Infotrieve]

15. Illingworth RI. HMG CoA reductase inhibitors. Curr Opin Lipidol.. 1991;2:24-50.

16. Naoumova RP, Marais AD, Mountney J, Firth JC, Rendell NB, Taylor GW, Thompson GR. Plasma mevalonic acid, an index of cholesterol synthesis in vivo, and responsiveness to HMG-CoA reductase inhibitors in familial hypercholesterolaemia. Atherosclerosis.. 1996;119:203-213.[Medline] [Order article via Infotrieve]

17. Hagemenas FC, Pappu AS, Illingworth DR. The effects of simvastatin on plasma lipoproteins and cholesterol homeostasis in patients with heterozygous familial hypercholesterolemia. Eur J Clin Invest.. 1990;20:150-157.[Medline] [Order article via Infotrieve]

18. Kotze MJ, de Villiers WJS, Steyn K, Kriek JA, Marais AD, Langenhoven E, Herbert JS, Graadt van Roggen JF, van der Westhuyzen DR, Coetzee GA. Phenotypic variation among familial hypercholesterolemics heterozygous for either one of two Afrikaner founder LDL receptor mutations. Arterioscler Thromb.. 1993;13:1460-1468.[Abstract/Free Full Text]

19. Jeenah M, September W, Graadt van Roggen F, de Villiers W, Seftel H, Marais D. Influence of specific mutations at the LDL-receptor gene locus on the response to simvastatin therapy in Afrikaner patients with heterozygous familial hypercholesterolemia. Atherosclerosis.. 1993;98:51-58.[Medline] [Order article via Infotrieve]

20. Illingworth DR, Vakar F, Mahley RW, Weisgraber KH. Hypocholesterolemic effects of lovastatin in familial defective apolipoprotein B-100. Lancet.. 1992;339:598-600.[Medline] [Order article via Infotrieve]

21. Austin MA. Genetics of low density lipoprotein subclasses. Curr Opin Lipidol.. 1993;4:125-132.

22. Yuan J, Tsai MY, Hegland J, Hunninghake DB. Effects of fluvastatin (XU 62-320), an HMG-CoA reductase inhibitor, on the distribution and composition of low density lipoprotein subspecies in humans. Atherosclerosis.. 1991;87:147-157.[Medline] [Order article via Infotrieve]

23. Cheung MC, Austin MA, Moulin P, Wolf AC, Cryer D, Knopp RH. Effects of pravastatin on apolipoprotein-specific high density lipoprotein subpopulations and low density lipoprotein subclass phenotypes in patients with primary hypercholesterolemia. Atherosclerosis.. 1993;102:107-119.[Medline] [Order article via Infotrieve]

24. Yuan J, Tai MY, Hunninghake DB. Changes in composition and distribution of LDL subspecies in hypertriglyceridemic and hypercholesterolemic patients during gemfibrozil therapy. Atherosclerosis.. 1994;110:1-10.[Medline] [Order article via Infotrieve]

25. Hokanson JE, Austin MA, Zambon A, Brunzell JD. Plasma triglyceride and LDL heterogeneity in familial combined hyperlipidemia. Arterioscler Thromb.. 1993;13:427-434.[Abstract/Free Full Text]

26. Beigel Y, Fuchs J, Snir M, Lurie Y, Green P, Djaldetti M. Lovastatin therapy in heterozygous familial hypercholesterolemic patients: effect on blood rheology and fibrinogen levels. J Intern Med.. 1991;230:23-27.[Medline] [Order article via Infotrieve]

27. Illingworth RI, Bacon S, Pappu AS, Sexton GJ. Comparative hypolipidemic effects of lovastatin and simvastatin in patients with heterozygous familial hypercholesterolemia. Atherosclerosis.. 1992;96:53-64.[Medline] [Order article via Infotrieve]

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This Article Abstract Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Marais, A. D. Articles by Mountney, J. Search for Related Content PubMed PubMed Citation Articles by Marais, A. D. Articles by Mountney, J.