0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Contribution |

Efficacy and Safety of Lovastatin in Adolescent Males With Heterozygous Familial Hypercholesterolemia:  A Randomized Controlled Trial FREE

Evan A. Stein, MD, PhD; D. Roger Illingworth, MD, PhD; Peter O. Kwiterovich, Jr, MD; Chris A. Liacouras, MD; Martti A. Siimes, MD; Marc S. Jacobson, MD; Thomas G. Brewster, MD; Paul Hopkins, MD; Michael Davidson, MD; Kevin Graham, MD; Frederick Arensman, MD; Robert H. Knopp, MD; Carlos DuJovne, MD; Christine L. Williams, MD; Jonathan L. Isaacsohn, MD; Carol A. Jacobsen, JD; Peter M. Laskarzewski, PhD; Sharon Ames, BSRD; Glenn J. Gormley, MD PhD
[+] Author Affiliations

Author Affiliations: Medical Research Laboratories, Highland Heights, Ky (Drs Stein and Laskarzewski); Metabolic and Atherosclerosis Research Center, Cincinnati, Ohio (Drs Stein and Isaacsohn and Ms Ames); Oregon Health Sciences University, Portland (Dr Illingworth); Johns Hopkins University Lipid Atherosclerosis Unit, Baltimore, Md (Dr Kwiterovich); Gastroenterology and Nutrition Division, Children's Hospital of Philadelphia, Philadelphia, Pa (Dr Liacouras); University of Helsinki, Helsinki, Finland (Dr Siimes); Division of Adolescent Medicine, Department of Pediatrics, Schneider Children's Hospital, New Hyde Park, NY (Dr Jacobson); Division of Genetics, Maine Medical Center, Portland (Dr Brewster); University of Utah Cardiovascular Genetics Research Clinic, Salt Lake City (Dr Hopkins); Chicago Center for Clinical Research, Chicago, Ill (Dr Davidson); Minneapolis Heart Institute, Minneapolis, Minn (Dr Graham); The Lipid Center, Louisville, Ky (Dr Arensman); Northwest Lipid Research Center, Seattle, Wash (Dr Knopp); University of Kansas Medical Center, Kansas City (Dr DuJovne); American Health Foundation, Valhalla, NY (Dr Williams); and Merck & Co Inc, Rahway, NJ (Ms Jacobsen and Dr Gormley).


JAMA. 1999;281(2):137-144. doi:10.1001/jama.281.2.137.
Text Size: A A A
Published online

Context Heterozygous familial hypercholesterolemia (HeFH) is a common disorder associated with early coronary artery disease, especially in men. The age at which drug therapy should be started is still controversial, as is the use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins).

Objective To assess the lipid-lowering efficacy, biochemical safety, and effect on growth and sexual development of lovastatin in adolescent boys with HeFH.

Design One-year, double-blind, placebo-controlled, balanced, 2-period, 2-arm randomized trial. In the first period (24 weeks), lovastatin was increased at 8 and 16 weeks and the dosage remained stable during the second period (24 weeks). The study was conducted between 1990 and 1994.

Setting Fourteen pediatric outpatient clinics in the United States and Finland.

Patients Boys aged 10 to 17 years with HeFH. Of 132 randomized subjects (67 intervention, 65 placebo), 122 (63 intervention, 59 placebo) and 110 (61 intervention, 49 placebo) completed the first and second periods, respectively.

Intervention Lovastatin, starting at 10 mg/d, with a forced titration at 8 and 16 weeks to 20 and 40 mg/d, respectively, or placebo.

Main Outcome Measures The primary efficacy outcome measure was low-density lipoprotein cholesterol (LDL-C). Primary safety measures were growth and sexual development.

Results Compared with placebo, LDL-C levels of patients receiving lovastatin decreased significantly (P<.001) by 17%, 24%, and 27% receiving dosages of 10, 20, and 40 mg/d, respectively, and remained 25% lower than baseline at 48 weeks. Growth and sexual maturation assessed by Tanner staging and testicular volume were not significantly different between the lovastatin and placebo groups at 24 weeks (P=.85) and 48 weeks (P=.33); neither were serum hormone levels or biochemical parameters of nutrition. However, the study was underpowered to detect significant differences in safety parameters. Serum vitamin E levels were reduced with lovastatin treatment consistent with reductions in LDL-C, the major carrier of vitamin E in the circulation.

Conclusions This study in adolescent boys with HeFH confirmed the LDL-C–reducing effectiveness of lovastatin. Comprehensive clinical and biochemical data on growth, hormonal, and nutritional status indicated no significant differences between lovastatin and placebo over 48 weeks, although further study is required.

Figures in this Article

Familial hypercholesterolemia (FH) is a dominant genetic disorder first described by Muller1 nearly 60 years ago. The elevated circulating low-density lipoprotein cholesterol (LDL-C) levels found in FH are caused by a defect in receptor-mediated LDL clearance2 and are the underlying cause of the marked increase in early coronary artery disease (CAD).3 In men with untreated heterozygous FH (HeFH), the risk of clinically overt CAD is approximately 5% by age 30 years, 20% by age 40 years, and 50% by age 50 years.3,4 Only about 15% of men with HeFH reach age 65 years without experiencing an ischemic coronary event.4 If left untreated, 23% of men experience fatal coronary events by age 50 years. Furthermore, the location and extent of coronary lesions in patients with HeFH suggest a prognosis worse than that of patients without FH; in 1 study, 70% of patients with HeFH had triple-vessel CAD and 32% had left main vessel disease.5

In the vast majority of patients, a diet low in saturated fat and cholesterol has only a small effect on reduction of LDL-C levels.6,7 Lipid-lowering treatment in select children with HeFH is considered medically appropriate,8 although there is no consensus on the age at which drug therapy should be started. The US National Cholesterol Education Program Pediatric Treatment Panel recommended drug therapy be considered if, after diet, LDL-C level remains higher than 4.2 mmol/L (160 mg/dL) with a family history of premature CAD or 4.9 mmol/L (190 mg/dL) without such history.8 Bile-acid sequestrants have been considered the drugs of choice and have been used in children with FH for more than 20 years.9,10 These sequestrants appear safe, but their LDL-C–lowering effects are modest and long-term compliance is a major problem.9,10 The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been in widespread clinical use in adults for more than a decade11 and have been shown to be safe and effective therapy for the reduction of total cholesterol and LDL-C levels. Recent large, end point–based clinical trials have demonstrated significant reductions in cardiovascular mortality and/or morbidity in trials assessing both primary12 and secondary13 prevention of morbidity.

Information on the effect of statins in a pediatric population has been limited to small observational reports14,15 and short-term placebo-controlled studies.16,17 The present article describes a 1-year, double-blind, placebo-controlled, randomized study of 132 adolescent boys with severe HeFH, designed to assess the lipid-lowering efficacy of lovastatin and its effect on growth, sexual maturation, and biochemical, nutritional, and endocrine parameters.

Eligibility Criteria

The study was reviewed and approved by each local center's institutional review board. Written parental or guardian consent was obtained for each subject prior to his entry into the study at each of the 14 centers. Adolescent boys aged 10 to 17 years who followed the American Heart Association (AHA) pediatric diet18 for at least 4 months were considered to have HeFH if their LDL-C values were at least 4.9 mmol/L (189 mg/dL) and no more than 13.0 mmol/L (503 mg/dL) and at least 1 parent had an LDL-C value of at least 4.9 mmol/L (189 mg/dL) not associated with a disorder known to cause secondary LDL-C elevation, or if their LDL-C values were at least 5.7 mmol/L (220 mg/dL) and no more than 13.0 mmol/L (503 mg/dL) and a parent had died of CAD with no available lipid values. These LDL-C entry criteria were to be met at both week −4 and week −2 (prebaseline).

To follow sexual maturation, patients were prepubertal or pubertal (Tanner stage I-IV) on recruitment. Subsequently, the US Food and Drug Administration (FDA) requested that subjects who had not reached Tanner stage II at entry discontinue the trial. This request resulted in the discontinuation of 8 subjects (7 in the placebo group and 1 in the lovastatin group). Subjects with a testicular volume of no more than 3 cm3 after age 12 years were excluded for delayed puberty, as were those weighing less than 32 kg or whose weight was less than the 10th or more than the 95th weight percentiles for age. Additional exclusion criteria were homozygous FH, underlying disorders known to produce secondary LDL-C elevations, or disorders primarily affecting triglyceride-rich lipoproteins (chylomicrons, very low-density lipoprotein, or intermediate-density lipoprotein).

Study Design. Eligible subjects as described herein received formal dietary reinstruction, were monitored, and were determined to be stable following an AHA pediatric diet18 for at least 8 weeks prior to randomization. Placebo was administered during the final 4 weeks (week −4 to week 0). Subjects were then randomized (Figure 1) to either active treatment (arm 1) or placebo (arm 2). Within the active treatment group, the dosage of lovastatin was started at 10 mg/d and increased at 8-week intervals (weeks 8 and 16) to 20 and 40 mg/d, respectively. Subjects in the placebo arm received matching placebo tablets throughout the first 24 weeks (period 1). During the next 24 weeks (weeks 25-48; period 2), subjects in the active treatment arm received 40 mg/d of lovastatin while those in the placebo group continued to receive placebo. All subjects continued to receive diet instruction, monitoring, and evaluation throughout the study. Quantitative dietary analysis was carried out at a central facility (Metabolic and Atherosclerosis Research Center, Cincinnati, Ohio).

Figure. Profile of Patient Allocation and Participation
Graphic Jump Location
FDA indicates US Food and Drug Administration.

Clinical Monitoring. Subjects were seen every 4 weeks throughout the first 24-week period and every 6 weeks during the second 24-week period for clinical assessment and blood lipid and laboratory measurements, including hepatic transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) and creatine kinase (CK). Sexual maturation was evaluated using Tanner staging19 at entry (week 0) and after 24 and 48 weeks of treatment. Testicular volume was assessed by comparison with a standardized set of wooden beads (Orchidometer, Kabi, Japan). Height was measured using a stadiometer (University of Iowa, Iowa City) and weight was monitored by regularly calibrated scales.

Dietary review and reinforcement by a registered dietitian was carried out at weeks −8, −4, 0, 8, 16, 24, 30, 36, 42, and 48. Lovastatin or matching placebo was taken immediately prior to the evening meal. Compliance was assessed by tablet count at every visit.

Laboratory Testing. At each visit, blood was obtained after an overnight fast. Serum chemistry (including hepatic transaminases and CK) and plasma lipids were measured at each visit. Routine hematology was assessed at baseline and every 12 weeks thereafter. At weeks 0, 24, and 48, values were determined for the following parameters: blood coagulation; urinalysis; thyroid function; blood nutrients (ferritin and vitamins A, D, and E); adrenal (cortisol and dehydroepiandrosterone sulfate [DHEAS]), gonadal (testosterone), and pituitary (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]) hormones; and apolipoproteins (apo) A-I, A-II, B, and lipoprotein(a) (Lp[a]). All laboratory measurements were carried out at a central laboratory (Medical Research Laboratories, Highland Heights, Ky).

Blood samples were centrifuged immediately after collection to isolate plasma or serum. Samples were transported overnight at 4°C and analyzed immediately on receipt, except for coagulation and special hormone testing, for which samples were frozen (−20°C) at the clinics and transported at regular intervals on dry ice to the central laboratory for analysis. Total cholesterol and triglycerides were analyzed by enzymatic methods on a Hitachi 737 analyzer (Boehringer Mannheim Diagnostics, Indianapolis, Ind) as previously described.20 The laboratory participated in and remained certified by the National Heart, Lung, and Blood Institute–Centers for Disease Control and Prevention Part III program21 throughout the study. High-density lipoprotein cholesterol (HDL-C) was isolated using heparin-2M manganese chloride.22 Apolipoprotein A-I, A-II, B, and Lp(a) analyses were performed using competitive enzyme-linked immunosorbent assay procedures.2325

Routine hematology and serum chemistries and enzymes were analyzed on a Coulter STKS (Coulter Corp, Hialeah, Fla) and Hitachi 747 (Boehringer Mannheim Diagnostics), respectively, by well-standardized procedures in the College of American Pathologists–accredited central laboratory. Retinol, tocopherols, and carotene were analyzed by high-performance liquid chromatography as previously described,26 with the laboratory participating in an external monitoring program by the National Institutes of Standards and Technology. 25-Hydroxyvitamin D was measured by radioimmunoassay (Nichols Institute Diagnostics, Los Angeles, Calif); ferritin, thyroxine, and triiodothyronine resin uptake by microparticle enzyme immunoassay (IMx, Abbott Diagnostics, North Chicago, Ill); and thyrotropin, DHEAS, cortisol, testosterone, FSH, and LH by radioimmunoassay (Diagnostics Products Corp, Los Angeles).

Statistics. For efficacy analysis, participants with a baseline value who had completed at least one 8-week phase of the study were included. Patients needed to complete subsequent 8-week phases to be included in the associated summary statistics.

For safety, analysis was carried out on an intent-to-treat basis, in which all subjects randomized to double-blind therapy were included. Means and SEs were computed for each parameter at each point (baseline and weeks 8, 16, 24, and 48). Median, first-quartile, and third-quartile values were determined for all endocrine function parameters (testosterone, DHEAS, cortisol, FSH, and LH). Percentage changes from baseline were also calculated for each treatment group for the parameters of efficacy, safety (ALT, AST, CK), growth (height), and sexual development (testicular volume). The Wilcoxon rank sum statistic27 was used to test for treatment differences between treatment groups for the following efficacy parameters: total cholesterol, triglycerides, LDL-C, HDL-C, apo B, apo A-I, apo A-II, and Lp(a), as well as the endocrine function and nutritional parameters. Analysis of variance was used to examine the growth parameters (height, weight, testicular volume, and Quetelet index). The Cochran-Mantel-Haenszel test statistic28 was used for testing for treatment differences in Tanner staging between lovastatin and placebo. Differences in new or worsening adverse experiences were compared using the Fisher exact test29 on both the total number of patients and by organ systems. The power to detect a difference in the safety parameters was not a primary consideration in the design of the study. Low power was observed for almost all of the safety parameters and ranged from 5% to 88%.

Patient Characteristics and Demographics

Family history was obtained in 97 (74%) of the 132 randomized subjects. The parent with FH was the mother in 54 cases (56%) and the father in 43 cases (44%). Evidence of CAD was present in 36 parents (37%; 59% of fathers with FH and 19% of mothers with FH). The mean age of onset of CAD of the affected parents was 37 years. Eight fathers with FH (20% of FH carriers) had died due to CAD; the mean age of death was 39 years. No mothers with FH had died due to CAD.

Table 1 shows baseline demographic features at entry and indicates balance between the randomized groups. One hundred twenty-three (93%) of 132 randomized subjects were white. One hundred twenty-two (92%) completed period 1 and 110 (83%) completed the entire 48-week study; there were 6 and 16 discontinuations in the lovastatin and placebo groups, respectively. These were due to withdrawal of consent (lovastatin, 4; placebo, 5), FDA request (lovastatin, 1; placebo, 7), deviation from protocol (placebo, 2), and adverse events (lovastatin, 1; placebo, 2).

Table Graphic Jump LocationTable 1. Demographic Characteristics and Lipid and Apolipoprotein Values of Patients at Randomization*
Lipids and Apolipoproteins

Baseline lipid and apolipoprotein concentrations are shown in Table 1. Levels of total cholesterol, LDL-C, and apo B were markedly elevated, consistent with the stringent entry criteria. Mean HDL-C values were between the 25th and 50th percentiles by age and sex, while mean triglyceride values were at the 95th percentile.30 Apolipoprotein A-I concentrations tended to be slightly low31 and apo A-II values were average. Lipoprotein(a) levels were elevated (>0.2 g/L [20 mg/dL]) in concentration in almost half the subjects and were higher than 0.3 g/L (30 mg/dL) in more than 25% of the subjects.

Period 1 (0-24 Weeks).Table 2 shows lipid and apolipoprotein changes after 8 weeks of treatment with dosages of 10, 20, and 40 mg/d of lovastatin or matching placebo. Lovastatin produced reductions in LDL-C and total cholesterol levels at all dosages (P<.001 vs placebo; Table 2), and in apo B at 40 mg/d (apo B was not measured during treatment with the lower dosage). An approximate 6% additional LDL-C lowering occurred with each doubling of lovastatin dosage. Minimal and nonsignificant (P>.05) increases occurred in HDL-C and triglycerides compared with placebo and were not dose-related. No changes were seen in Lp(a) in either group.

Table Graphic Jump LocationTable 2. Changes in Lipid and Apolipoprotein Levels During Treatment*

Period 2 (24-48 Weeks). Continued therapy with lovastatin, 40 mg/d, produced reductions in levels of LDL-C and apo B of 25% and 22%, respectively (P<.001 vs placebo for both; Table 2). There were no significant changes in the other lipids and apolipoproteins.

Growth and Development

Lovastatin had no significant effect on the growth parameters at 24 and 48 weeks (Table 3). Furthermore, compared with expected individual growth rates monitored on percentile growth charts, neither group showed significant deviations.

Table Graphic Jump LocationTable 3. Growth and Development During Treatment*

Sexual maturation was assessed clinically by changes in both testicular volume and Tanner staging. During 24 and 48 weeks of observation, subjects treated with lovastatin progressed to more advanced Tanner staging and larger testicular volumes at rates not significantly different from those of the placebo group (P=.85 and P=.33 for 24 and 48 weeks, respectively).

Baseline and 4-week hormone values are shown in Table 4. As anticipated, substantial increases in testosterone and LH levels compared with baseline occurred in both treatment groups over 48 weeks, with no significant between-group differences. For DHEAS, the median increase for the lovastatin group was 18% compared with 5% for the placebo group (P=.03).

Table Graphic Jump LocationTable 4. Baseline Endocrine Function and Effects of Treatment After 48 Weeks*
Nutritional Assessment

A number of biochemical measurements to assess nutritional status are shown in Table 5. No differences were found at baseline or after 48 weeks of treatment between groups, except for tocopherol. The reduction of tocopherol (P=.002) with lovastatin is consistent with the decrease in LDL-C, the major transport vehicle for tocopherol in the circulation.

Table Graphic Jump LocationTable 5. Baseline Serum Nutritional Parameters and Effects of Treatment After 48 Weeks*
Serum Transaminases and CK

A gradual upward trend from baseline levels in ALT was noted in both placebo and lovastatin groups (Table 6). However, there were no significant differences (P=.20) between groups at week 48, although the increase from baseline for both groups reached statistical significance (lovastatin, P<.001; placebo, P=.008). No consistent changes in AST or CK values were seen. There was no significant difference either from baseline or between the treatment groups in either of these parameters at any of the points. No subject experienced a clinically significant increase in transaminase levels (>3 × the upper limit of normal) or CK level (>10 × the upper limit of normal). There were infrequent, sporadic, and nonsustained CK elevations that exceeded 5 × the upper limit of normal throughout the study, with 3 such occurrences in the lovastatin group and 1 in the placebo group. These were generally associated with vigorous or unusual exercise, and no associated muscle pain was reported. No subject discontinued treatment for biochemical adverse experiences.

Table Graphic Jump LocationTable 6. Hepatic Transaminase and Creatine Kinase Levels During Treatment*
Clinical Events

One subject taking lovastatin and 2 subjects taking placebo discontinued the study because of adverse clinical experiences. The lovastatin-treated subject reported increased bruising and purpura and the placebo-treated subjects reported skin rash and myalgia. No abnormal results in the hematological indices or basic coagulation testing were found in the lovastatin-treated subject. None of these reasons for discontinuation were considered clinically significant or definitely related to study drug by the investigators. All new or worsening adverse events were recorded and summarized according to organ systems (Table 7). No significant difference between placebo and lovastatin groups was found for observation of any body-system parameter or for clinical adverse events.

Table Graphic Jump LocationTable 7. New or Worsening Adverse Experiences*

Heterozygous FH is a common genetic disorder associated with early death or devastating morbidity due to CAD. Although the homozygous condition unquestionably requires aggressive lipid-lowering therapy, treatment for HeFH is often postponed until later in life. However, as exemplified by the parents of the participants in this study, HeFH is far from benign; 1 in 5 fathers with HeFH were already dead and nearly 3 in 5 had experienced symptoms of CAD. Although the prevalence of CAD was less in mothers with HeFH, almost 1 in 5 had clinical evidence of CAD. Furthermore, the early onset of clinically manifest CAD, sometimes in the 30s age range, highlights the need to treat patients with HeFH, especially boys, early and aggressively. To delay effective lipid-lowering therapy in these high-risk groups until late adolescence or early adulthood can easily result in their being lost to the medical system until they present with CAD or sudden death.

Bile-acid sequestrants have generally been accepted as the drugs of choice in this age group.8 However, as was the case with most of the participants prior to their entry into this study, resins are poorly tolerated, are generally ineffective unless taken in large dosages, and result in only a modest LDL-C reduction in patients with severe HeFH.9,14

Furthermore, despite their availability for more than 20 years, bile-acid sequestrants have never been evaluated in placebo-controlled trials in children for long periods or in a large number of subjects and have yet to receive FDA approval for lowering cholesterol in children. The longest and largest resin study, by Tonstad et al,32 was only recently published. They studied 72 subjects for 1 year in a randomized placebo-controlled study and concluded that modest LDL-C reductions (17%-19%) were achievable. Although growth was not adversely affected, they noted that folate deficiency may occur and recommended vitamin D supplementation.

Alternative therapy includes nicotinic acid and fibrates. Nicotinic acid has rarely been used in childhood and adolescence14,33 because it is poorly tolerated and has not been adequately evaluated in terms of long-term safety in this population. Fibric acid derivatives (fenofibrate34 and bezafibrate35) have been used in children with HeFH with moderate success in terms of LDL-C reduction. However, these studies have been either uncontrolled or were performed with an inadequate number of subjects to yield meaningful data on safety, including growth and development. Furthermore, both fibrates were associated with significant transaminase elevations in 5% to 25% of pediatric subjects.34,35

Of all the systemic agents, statins have been the most widely used and reported in children and adolescents. Early reports in the late 1980s involved small numbers of children with severe HeFH treated in observational or uncontrolled studies.14,15 However, in the last few years, 2 statin studies in children and adolescents, 1 placebo-controlled and 1 uncontrolled (8-12 weeks), have been reported.16,17 In a placebo-controlled study with pravastatin sodium,16 72 children (66% female) ranging in age from 8 to 16 years were treated with dosages ranging from 5 to 20 mg/d. After 12 weeks, LDL-C reductions ranging from 23% to 32% were obtained. No safety concerns were reported in the 3 months of treatment. Lambert and colleagues17 recently reported using lovastatin in 69 adolescent boys who were randomized to receive 10 to 40 mg/d for 8 weeks. Low-density lipoprotein cholesterol reductions of 21% to 36% were observed and no safety concerns were reported. However, there was no placebo control. Although both of these studies confirm the efficacy of statins in children, they were both of short duration and inadequate sample size and neither adds significantly to the important issue of safety or the effect on growth and development.

To our knowledge, the present study is the largest and longest placebo-controlled trial of any lipid-lowering drug in an adolescent population. Boys were carefully evaluated at a critical stage in their growth and development, and a number of clinical and biochemical parameters not previously reported in this population were examined. Nevertheless, with approximately 60 patients in each group studied for 48 weeks, there is limited ability to detect adverse effects. Because the prevalence of HeFH is only approximately 0.2%, it is difficult to study large numbers of patients.

The number of subjects who discontinued because of an adverse experience was small. The lack of evidence for symptomatic adverse effects, together with the clinical and biochemical data, supports the tolerability of lovastatin in boys. Although there was no specific evaluation of psychological development or behavior, no adverse effects on mental (eg, school) performance or the central nervous system were reported by the boys or their parents, except for insomnia in 1 patient taking lovastatin. Insomnia with lovastatin has been reported anecdotally in adults by Schaefer.36 However, better-controlled and larger surveys and smaller placebo-controlled sleep laboratory studies have failed to elicit differences from either placebo or other statins or lipid-lowering agents in sleep patterns with lovastatin.37,38 Muldoon et al39 reported decreased attention and psychomotor speed in adults receiving lovastatin, with the degree of impairment apparently correlating with the amount of LDL-C reduction. However, numerous measurements of cognitive performance were made without adjustment for multiplicity, and other studies in adults with lovastatin or other inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors have found no such effects.38,4042

The only significant difference in biochemical measurements between the 2 treatment groups was the reduction in tocopherol observed with lovastatin. This was anticipated and explained by the reduction in LDL-C, which is the major transport vehicle for tocopherol in the circulation. Even with this reduction, tocopherol levels remained well within the accepted reference range.43 Statins are not known to alter tocopherol absorption or transport from the intestine to the liver, which is carried out via chylomicrons and remnants. In fact, it is likely that increased tocopherol delivery to hepatic and other LDL receptor–containing tissue is enhanced by statins, which upregulate receptor activity and facilitate LDL delivery to these cells.

The 2 most common concerns with statins in adults, namely hepatic transaminase elevations and CK increases with myalgia, were not apparent in this study. At no point were there significant between-group differences in these enzyme measurements. There was a trend toward increased ALT over the 48 weeks in both groups, which was slightly accentuated in those taking lovastatin. However, this trend was not significantly different between groups. Increases in ALT during the duration of this trial are not unexpected in adolescent boys because cross-sectional studies reveal a rise in levels in men beginning in adolescence and peaking at about age 35 to 44 years.44,45 Although the exact reason for the rise is not clear, it may be related to changing hormone levels, obesity, or alcohol use. Aspartate transaminase levels remained stable, as would be expected.44 Although many of the boys participated in strenuous exercise and contact sports, no myopathy or sustained CK elevation was noted, and the only withdrawal from the study for myalgia was later found to have been receiving placebo.

The amount of LDL-C reduction achieved is modest in view of the extremely elevated initial levels in these subjects. However, there is evidence in adults that even a 25% decrease in LDL-C will reduce CAD progression in adult FH46 and clinical events in subjects without FH and with13 or without CAD.12,47 Furthermore, additional LDL-C reduction may be obtained in these subjects with either larger dosages of lovastatin,11 more efficacious statins,48,49 or combination therapy with low-dose resins.50 In a small uncontrolled study14 of 4 adolescents with severe HeFH, reductions in LDL-C of 44% were observed with large dosages of statins and resins and moderate dosages of nicotinic acid. However, this is a demanding regimen, and whether more aggressive LDL-C reduction achieved by such combination therapy will have a significant clinical benefit or is cost-effective is uncertain in adults, let alone adolescents.

Although this study is the largest and longest placebo-controlled study in this age group and raised no safety or growth and development concerns, it is still of limited size, and the direct clinical benefit and adverse effects of much longer-term therapy in larger populations is difficult to predict. It also provides no data on adolescent girls. However, in the adolescent male population with severe HeFH similar to that evaluated in this study, there is a substantial risk of CAD within the next 2 decades. The potential benefits of lowering LDL-C levels with statins seems to outweigh the theoretical risks.

Muller C. Angina pectoris in hereditary xanthomatosis.  Arch Intern Med.1939;64:675-700.
Brown MS, Goldstein JL. A receptor mediated pathway for cholesterol homeostasis.  Science.1986;232:34-47.
Slack J. Risks of ischaemic heart disease in familial hyperlipoproteinemic states.  Lancet.1969;2:1380-1382.
Stone NJ, Levy RI, Fredrickson DS, Verter J. Coronary artery disease in 116 kindred with familial type II hyperlipoproteinemia.  Circulation.1974;49:476-488.
Sugrue DD, Thompson GR, Oakley CM, Trayner IM, Steiner RE. Contrasting patterns of coronary atherosclerosis in normocholesterolaemic smokers and patients with familial hypercholesterolaemia.  BMJ.1981;283:1358-1360.
Stein EA, Shapero J, McNerney C. Changes in plasma lipid and lipoprotein fractions after alteration in dietary cholesterol polyunsaturated, saturated, and total fat in free living normal and hypercholesterolemic children.  Am J Clin Nutr.1982;35:1375-1390.
Lauer RM, Obarzanek E, Kwiterovich Jr PO.  et al.  Efficacy and safety of lowering dietary intake of fat and cholesterol in children with elevated low-density lipoprotein cholesterol.  JAMA.1995;273:1429-1435.
 National Cholesterol Education Program: Report of the Expert Panel on Blood Cholesterol Levels in Children and AdolescentsBethesda, Md: National Heart, Lung, and Blood Institute; 1991. NIH publication 91-2732.
West RJ, Lloyd JK, Leonard JV. Long-term follow-up of children with familial hypercholesterolemia tested with cholestyramine.  Lancet.1980;2:873-875.
Groot PH, Dijkuis-Stoffelsma ER, Grose WFA, Anbagtsheer JJ, Fernandes J. The effects of colestipol hydrochloride on serum lipoprotein, lipid and lipoprotein B and A-I concentrations in children heterozygous for familial hypercholesterolemia.  Acta Paediatr Scand.1983;72:81-85.
Havel RJ, Hunninghake DB, Illingworth DR.  et al.  Lovastatin (mevinolin) in the treatment of heterozygous familial hypercholesterolemia: a multi-center study.  Ann Intern Med.1987;107:609-615.
Shepherd J, Cobbe SM, Ford I.  et al.  Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia.  N Engl J Med.1995;333:1301-1307.
Scandinavian Simvastatin Survival Study Group.  Randomized trial of cholesterol-lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study.  Lancet.1994;344:1383-1389.
Stein EA. Treatment of familial hypercholesterolemia with drugs in children.  Arteriosclerosis.1989;9(suppl 1):145-151.
Ducobu J, Brasseur D, Chaudron JM.  et al.  Simvastatin use in children.  Lancet.1992;339:1488-1491.
Knipscheer HC, Boelen CCA, Kastelein JJP.  et al.  Short-term efficacy and safety of pravastatin in 72 children with familial hypercholesterolemia.  Pediatr Res.1996;39(suppl 5):867-871.
Lambert M, Lupien PJ, Gagne C.  et al. for the Canadian Lovastatin in Children Study Group.  Treatment of familial hypercholesterolemia in children and adolescents: effects of lovastatin.  Pediatrics.1996;97:619-628.
Weidman W, Kwiterovich Jr PO, Jesse MJ, Nugent E. AHA committee report: diet in the healthy child.  Circulation.1983;67:1411A-1414A.
Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys.  Arch Dis Child.1970;45:13-23.
Steiner PM, Freidel J, Brenner WF, Stein EA. Standardization of micromethods for plasma cholesterol, triglyceride, and HDL-cholesterol with the lipid clinics' methodology [abstract].  J Clin Chem.1981;19:850.
Myers GL, Cooper GR, Winn CL, Smith SJ. The Centers for Disease Control–National Heart, Lung, and Blood Institute Lipid Standardization Program: an approach to accurate and precise lipid measurements.  Clin Lab Med.1989;9:105-135.
Warnick GR, Albers JJ. A comprehensive evaluation of the heparin manganese precipitation procedure for estimating high-density lipoprotein cholesterol.  J Lipid Res.1978;19:65-76.
Stein EA, Kreisberg R, Miller V.  et al.  Effect of simvastatin and cholestyramine in familial and nonfamilial hypercholesterolemia.  Arch Intern Med.1990;150:341-345.
Stein EA, DiPersio L, Pesce AJ.  et al.  Enzyme-linked immunoabsorbent assay of apolipoprotein A-II in plasma using a monoclonal antibody.  Clin Chem.1986;32:967-971.
Stein EA, Kumbla L, Miller J, Srivastiva L, Kashyap ML. Development and evaluation of a competitive ELISA for Lp(a).  Clin Chem.1992;38:1067.
Kaplan LA, Miller JA, Stein EA. Simultaneous measurement of serum retinol, tocopherols, carotenes and carotenoids by high pressure liquid chromatography.  J Clin Lab Anal.1987;1:147-152.
Hollander M, Wolfe DA. Nonparametric Statistical MethodsNew York, NY: John Wiley & Sons Inc; 1973.
Cochran WG. Some methods for strengthening the common χ2 tests.  Biometrics.1954;10:417-451.
Mehta CR, Patel NR. A network algorithm for performing Fisher's exact test in r × c contingency tables.  J Am Stat Assoc.1983;78:427-434.
Lipid Research Clinics Program Epidemiology Committee.  Plasma lipid distributions in selected North American populations: the Lipid Research Clinics Program Prevalence Study.  Circulation.1979;60:427-439.
Donahue RP, Orchard TJ, Stein EA, Kuller LH. Apolipoproteins A-I, A-II, and B in young adults: associations with CHD risk factors.  J Chronic Dis.1986;39:823-830.
Tonstad S, Knudtzon J, Siversten M, Refsum H, Ose L. Efficacy and safety of cholestyramine therapy in peripubertal and prepubertal children with familial hypercholesterolemia.  J Pediatr.1996;129:42-49.
Colletti RB, Neufeld EJ, Roff NK, McAuliffe TL, Baker AL, Newburger JW. Niacin treatment of hypercholesterolemia in children.  Pediatrics.1993;92:78-82.
Steinmetz J, Morin C, Panek E, Siest G, Drouin P. Biological variations in hyperlipidemic children and adolescents treated with fenofibrate.  Clin Chem Acta.1981;112:43-53.
Wheeler KAH, West RJ, Lloyd JK, Barley J. Double-blind trial of bezafibrate in familial hypercholesterolemia.  Arch Dis Child.1985;60:34-37.
Schaefer EJ. Letter to the editor.  N Engl J Med.1988;319:1222.
Black DM, Lamkin G, Olivera EH, Laskarzewski PM, Stein EA. Sleep disturbance and HMG CoA reductase inhibitors [letter].  JAMA.1990;264:1105.
Kostis JB, Rosen RC, Wilson AC. Central nervous system effects of HMG CoA reductase inhibitors: lovastatin and pravastatin on sleep and cognitive performance in patients with hypercholesterolemia.  J Clin Pharmacol.1994;34:989-996.
Muldoon MF, Ryan CM, Flory JD, Mathews KA, Manuck SB. Effects of cholesterol reduction on cognitive performance [abstract].  Circulation.1997;96:1-66. Abstract 360.
Gengo F, Cwudzinski D, Kinkel P, Block G, Stauffer L, Lines C. Effects of treatment with lovastatin and pravastatin on daytime cognitive performance.  Clin Cardiol.1995;18:209-214.
Harrison RW, Ashton CH. Do cholesterol-lowering agents affect brain activity? a comparison of simvastatin, pravastatin, and placebo in healthy volunteers.  Br J Clin Pharmacol.1994;37:231-236.
Cutler N, Sramek J, Veroff A, Block G, Stauffer L, Lines C. Effects of treatment with simvastatin and pravastatin on cognitive function in patients with hypercholesterolaemia.  Br J Clin Pharmacol.1995;39:333-336.
McCormick DB, Greene HL. Vitamins. In: Burtis CA, Ashwood ER, eds. Tietz Textbook of Clinical Chemistry. Philadelphia, Pa: WB Saunders Co; 1994:1275-1316.
Whitehead TP, Robinson D, Hale AC, Bailey AR. Clinical Chemistry and Hematology: Adult Reference Values: BUPA Medical Research and Development. London, England: Battle Bridge House; 1994.
Kincaid HL. Clinical enzymology in pediatrics. In: Hicks JM, Boeckx RL, eds. Pediatrics Clinical Chemistry. Philadelphia, Pa: WB Saunders Co; 1984:349-402.
Kane JP, Malloy J, Ports TA, Phillips NR, Diehl CJ, Havel RJ. Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens.  JAMA.1990;264:3007-3012.
Downs JR, Clearfield M, Weis S.  et al.  Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS.  JAMA.1998;279:1615-1622.
Stein E, Davidson M, Dobs A.  et al.  Efficacy and safety of simvastatin 80 mg/day in hypercholesterolemic patients.  Am J Cardiol.1998;82:311-316.
Jones P, Kafonek S, Laurora I, Hunninghake D. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study).  Am J Cardiol.1998;81:582-587.
Schrott HG, Stein EA, DuJovne CA.  et al.  Enhanced low-density lipoprotein cholesterol reduction and cost effectiveness by low-dose colestipol plus lovastatin combination therapy.  Am J Cardiol.1995;75:34-39.

Figures

Figure. Profile of Patient Allocation and Participation
Graphic Jump Location
FDA indicates US Food and Drug Administration.

Tables

Table Graphic Jump LocationTable 1. Demographic Characteristics and Lipid and Apolipoprotein Values of Patients at Randomization*
Table Graphic Jump LocationTable 2. Changes in Lipid and Apolipoprotein Levels During Treatment*
Table Graphic Jump LocationTable 3. Growth and Development During Treatment*
Table Graphic Jump LocationTable 4. Baseline Endocrine Function and Effects of Treatment After 48 Weeks*
Table Graphic Jump LocationTable 5. Baseline Serum Nutritional Parameters and Effects of Treatment After 48 Weeks*
Table Graphic Jump LocationTable 6. Hepatic Transaminase and Creatine Kinase Levels During Treatment*
Table Graphic Jump LocationTable 7. New or Worsening Adverse Experiences*

References

Muller C. Angina pectoris in hereditary xanthomatosis.  Arch Intern Med.1939;64:675-700.
Brown MS, Goldstein JL. A receptor mediated pathway for cholesterol homeostasis.  Science.1986;232:34-47.
Slack J. Risks of ischaemic heart disease in familial hyperlipoproteinemic states.  Lancet.1969;2:1380-1382.
Stone NJ, Levy RI, Fredrickson DS, Verter J. Coronary artery disease in 116 kindred with familial type II hyperlipoproteinemia.  Circulation.1974;49:476-488.
Sugrue DD, Thompson GR, Oakley CM, Trayner IM, Steiner RE. Contrasting patterns of coronary atherosclerosis in normocholesterolaemic smokers and patients with familial hypercholesterolaemia.  BMJ.1981;283:1358-1360.
Stein EA, Shapero J, McNerney C. Changes in plasma lipid and lipoprotein fractions after alteration in dietary cholesterol polyunsaturated, saturated, and total fat in free living normal and hypercholesterolemic children.  Am J Clin Nutr.1982;35:1375-1390.
Lauer RM, Obarzanek E, Kwiterovich Jr PO.  et al.  Efficacy and safety of lowering dietary intake of fat and cholesterol in children with elevated low-density lipoprotein cholesterol.  JAMA.1995;273:1429-1435.
 National Cholesterol Education Program: Report of the Expert Panel on Blood Cholesterol Levels in Children and AdolescentsBethesda, Md: National Heart, Lung, and Blood Institute; 1991. NIH publication 91-2732.
West RJ, Lloyd JK, Leonard JV. Long-term follow-up of children with familial hypercholesterolemia tested with cholestyramine.  Lancet.1980;2:873-875.
Groot PH, Dijkuis-Stoffelsma ER, Grose WFA, Anbagtsheer JJ, Fernandes J. The effects of colestipol hydrochloride on serum lipoprotein, lipid and lipoprotein B and A-I concentrations in children heterozygous for familial hypercholesterolemia.  Acta Paediatr Scand.1983;72:81-85.
Havel RJ, Hunninghake DB, Illingworth DR.  et al.  Lovastatin (mevinolin) in the treatment of heterozygous familial hypercholesterolemia: a multi-center study.  Ann Intern Med.1987;107:609-615.
Shepherd J, Cobbe SM, Ford I.  et al.  Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia.  N Engl J Med.1995;333:1301-1307.
Scandinavian Simvastatin Survival Study Group.  Randomized trial of cholesterol-lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study.  Lancet.1994;344:1383-1389.
Stein EA. Treatment of familial hypercholesterolemia with drugs in children.  Arteriosclerosis.1989;9(suppl 1):145-151.
Ducobu J, Brasseur D, Chaudron JM.  et al.  Simvastatin use in children.  Lancet.1992;339:1488-1491.
Knipscheer HC, Boelen CCA, Kastelein JJP.  et al.  Short-term efficacy and safety of pravastatin in 72 children with familial hypercholesterolemia.  Pediatr Res.1996;39(suppl 5):867-871.
Lambert M, Lupien PJ, Gagne C.  et al. for the Canadian Lovastatin in Children Study Group.  Treatment of familial hypercholesterolemia in children and adolescents: effects of lovastatin.  Pediatrics.1996;97:619-628.
Weidman W, Kwiterovich Jr PO, Jesse MJ, Nugent E. AHA committee report: diet in the healthy child.  Circulation.1983;67:1411A-1414A.
Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys.  Arch Dis Child.1970;45:13-23.
Steiner PM, Freidel J, Brenner WF, Stein EA. Standardization of micromethods for plasma cholesterol, triglyceride, and HDL-cholesterol with the lipid clinics' methodology [abstract].  J Clin Chem.1981;19:850.
Myers GL, Cooper GR, Winn CL, Smith SJ. The Centers for Disease Control–National Heart, Lung, and Blood Institute Lipid Standardization Program: an approach to accurate and precise lipid measurements.  Clin Lab Med.1989;9:105-135.
Warnick GR, Albers JJ. A comprehensive evaluation of the heparin manganese precipitation procedure for estimating high-density lipoprotein cholesterol.  J Lipid Res.1978;19:65-76.
Stein EA, Kreisberg R, Miller V.  et al.  Effect of simvastatin and cholestyramine in familial and nonfamilial hypercholesterolemia.  Arch Intern Med.1990;150:341-345.
Stein EA, DiPersio L, Pesce AJ.  et al.  Enzyme-linked immunoabsorbent assay of apolipoprotein A-II in plasma using a monoclonal antibody.  Clin Chem.1986;32:967-971.
Stein EA, Kumbla L, Miller J, Srivastiva L, Kashyap ML. Development and evaluation of a competitive ELISA for Lp(a).  Clin Chem.1992;38:1067.
Kaplan LA, Miller JA, Stein EA. Simultaneous measurement of serum retinol, tocopherols, carotenes and carotenoids by high pressure liquid chromatography.  J Clin Lab Anal.1987;1:147-152.
Hollander M, Wolfe DA. Nonparametric Statistical MethodsNew York, NY: John Wiley & Sons Inc; 1973.
Cochran WG. Some methods for strengthening the common χ2 tests.  Biometrics.1954;10:417-451.
Mehta CR, Patel NR. A network algorithm for performing Fisher's exact test in r × c contingency tables.  J Am Stat Assoc.1983;78:427-434.
Lipid Research Clinics Program Epidemiology Committee.  Plasma lipid distributions in selected North American populations: the Lipid Research Clinics Program Prevalence Study.  Circulation.1979;60:427-439.
Donahue RP, Orchard TJ, Stein EA, Kuller LH. Apolipoproteins A-I, A-II, and B in young adults: associations with CHD risk factors.  J Chronic Dis.1986;39:823-830.
Tonstad S, Knudtzon J, Siversten M, Refsum H, Ose L. Efficacy and safety of cholestyramine therapy in peripubertal and prepubertal children with familial hypercholesterolemia.  J Pediatr.1996;129:42-49.
Colletti RB, Neufeld EJ, Roff NK, McAuliffe TL, Baker AL, Newburger JW. Niacin treatment of hypercholesterolemia in children.  Pediatrics.1993;92:78-82.
Steinmetz J, Morin C, Panek E, Siest G, Drouin P. Biological variations in hyperlipidemic children and adolescents treated with fenofibrate.  Clin Chem Acta.1981;112:43-53.
Wheeler KAH, West RJ, Lloyd JK, Barley J. Double-blind trial of bezafibrate in familial hypercholesterolemia.  Arch Dis Child.1985;60:34-37.
Schaefer EJ. Letter to the editor.  N Engl J Med.1988;319:1222.
Black DM, Lamkin G, Olivera EH, Laskarzewski PM, Stein EA. Sleep disturbance and HMG CoA reductase inhibitors [letter].  JAMA.1990;264:1105.
Kostis JB, Rosen RC, Wilson AC. Central nervous system effects of HMG CoA reductase inhibitors: lovastatin and pravastatin on sleep and cognitive performance in patients with hypercholesterolemia.  J Clin Pharmacol.1994;34:989-996.
Muldoon MF, Ryan CM, Flory JD, Mathews KA, Manuck SB. Effects of cholesterol reduction on cognitive performance [abstract].  Circulation.1997;96:1-66. Abstract 360.
Gengo F, Cwudzinski D, Kinkel P, Block G, Stauffer L, Lines C. Effects of treatment with lovastatin and pravastatin on daytime cognitive performance.  Clin Cardiol.1995;18:209-214.
Harrison RW, Ashton CH. Do cholesterol-lowering agents affect brain activity? a comparison of simvastatin, pravastatin, and placebo in healthy volunteers.  Br J Clin Pharmacol.1994;37:231-236.
Cutler N, Sramek J, Veroff A, Block G, Stauffer L, Lines C. Effects of treatment with simvastatin and pravastatin on cognitive function in patients with hypercholesterolaemia.  Br J Clin Pharmacol.1995;39:333-336.
McCormick DB, Greene HL. Vitamins. In: Burtis CA, Ashwood ER, eds. Tietz Textbook of Clinical Chemistry. Philadelphia, Pa: WB Saunders Co; 1994:1275-1316.
Whitehead TP, Robinson D, Hale AC, Bailey AR. Clinical Chemistry and Hematology: Adult Reference Values: BUPA Medical Research and Development. London, England: Battle Bridge House; 1994.
Kincaid HL. Clinical enzymology in pediatrics. In: Hicks JM, Boeckx RL, eds. Pediatrics Clinical Chemistry. Philadelphia, Pa: WB Saunders Co; 1984:349-402.
Kane JP, Malloy J, Ports TA, Phillips NR, Diehl CJ, Havel RJ. Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens.  JAMA.1990;264:3007-3012.
Downs JR, Clearfield M, Weis S.  et al.  Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS.  JAMA.1998;279:1615-1622.
Stein E, Davidson M, Dobs A.  et al.  Efficacy and safety of simvastatin 80 mg/day in hypercholesterolemic patients.  Am J Cardiol.1998;82:311-316.
Jones P, Kafonek S, Laurora I, Hunninghake D. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study).  Am J Cardiol.1998;81:582-587.
Schrott HG, Stein EA, DuJovne CA.  et al.  Enhanced low-density lipoprotein cholesterol reduction and cost effectiveness by low-dose colestipol plus lovastatin combination therapy.  Am J Cardiol.1995;75:34-39.

Letters

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles