Efficacy and Safety of Lovastatin Therapy in Adolescent Girls With Heterozygous Familial Hypercholesterolemia
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《小儿科》
The Johns Hopkins Medical Institutions, Baltimore, Maryland
Cardiovascular Genetics, Salt Lake City, Utah
Metabolic and Atherosclerosis Research Center, Cincinnati, Ohio
Merck Research Laboratories, Rahway, New Jersey
ABSTRACT
Objective. The present study was designed to evaluate the lipid-altering efficacy, safety, and tolerability of lovastatin treatment in adolescent girls with heterozygous familial hypercholesterolemia.
Methods. A total of 54 postmenarchal girls, aged 10 to 17 years, were enrolled in a 24-week, double-blind, randomized, placebo-controlled study. After a 4-week diet/placebo run-in period, patients were randomized to 1 of 2 groups: (1) treatment with diet plus lovastatin 20 mg/day for 4 weeks, followed by diet plus lovastatin 40 mg/day for 20 weeks, or (2) diet plus placebo for 24 weeks.
Results. Baseline values of lipids, lipoproteins, and apolipoproteins (apo) were comparable between treatment groups. Lovastatin treatment was efficacious at reducing low-density lipoprotein cholesterol by 23% to 27%, total cholesterol by 17% to 22%, and apo B by 20% to 23% at weeks 4 and 24, respectively. Between-treatment group differences were not statistically significant for triglycerides, very-low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or apo A-I. Lovastatin was generally safe and well tolerated. There were no clinically significant alterations in vital signs (blood pressure and pulse rate), anthropomorphic measurements (height, weight, and BMI), hormone levels (luteinizing hormone, follicle-stimulating hormone, dehydroepiandrosterone sulfate, estradiol, and cortisol), menstrual cycle length, or tests of liver and muscle function.
Conclusions. Lovastatin offers an efficacious and well-tolerated treatment option for improving lipid profiles in adolescent girls with familial hypercholesterolemia.
Key Words: adolescents cholesterol lipids
Abbreviations: CAD, coronary artery disease TC, total cholesterol LDL, low-density lipoprotein HDL, high-density lipoprotein FH, familial hypercholesterolemia TG, triglycerides VLDL, very-low-density lipoprotein apo, apolipoprotein ALT, alanine aminotransferase AST, aspartate aminotransferase CK, creatine kinase DHEAS, dehydroepiandrosterone sulfate FSH, follicle-stimulating hormone LH, luteinizing hormone ULN, upper limit of normal ANOVA, analysis of variance AE, adverse event
Coronary artery disease (CAD) is a leading cause of morbidity and mortality among women in the United States. CAD produces more deaths in women than cancer of the breast, uterus, and ovary combined. Recently, there has been an emphasis to raise the awareness of CAD and its risk factors in women. The lesions of atherosclerosis that are found in adult men and women begin to develop in childhood.1–6 The development of early lesions of atherosclerosis in adolescents and young adults is related directly to elevated plasma concentrations of total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, and decreased levels of high-density lipoprotein (HDL) cholesterol during childhood.7
Familial hypercholesterolemia (FH) is an autosomal dominant disorder that is caused by mutations in the gene encoding the LDL receptor. The prevalence of FH heterozygotes in the population is estimated to be 1 in 500 individuals. FH is completely expressed at birth in both girls and boys.8 By the age of 1 year, individuals with FH demonstrate marked elevations in TC and LDL cholesterol averaging 300 mg/dL and 240 mg/dL, respectively.8,9 During adolescence, both FH heterozygotes and normal individuals manifest a significant decrease of 10% to 15% in plasma concentrations of LDL cholesterol.9,10 Between 1 and 19 years of age, adolescents with FH usually do not express clinical signs or symptoms of CAD, although 1 in 10 individuals will present with tendon xanthomas and Achilles tendonitis. Individuals with FH develop premature CAD in adulthood, sometimes in their fourth decade but often by the time they reach 40 and 50 years of age in men and a decade later in women. Recent studies in FH heterozygous children using carotid ultrasound have demonstrated that by their early teens, there is significant carotid artery thickening and that the rate of progression is substantially greater than that of children without FH.11,12 Therefore, it is important to lower LDL cholesterol aggressively in this population to reduce the rate of atherosclerosis in anticipation that this will prevent or delay onset of CAD.
The current recommendation of the National Cholesterol Education Program Expert Panel on Blood Cholesterol Levels in Children and Adolescents is to use pharmacologic therapy in children who are older than 10 years and have after dietary intervention (1) an LDL cholesterol of >160 mg/dL with a family history of premature CAD or (2) an LDL cholesterol of >190 mg/dL with no family history.13,14 The panel recommends using bile acid sequestrants to manage LDL cholesterol concentrations in such patients; however, these agents provide only modest LDL cholesterol reductions, and they suffer from tolerability issues. For example, Tonstad et al15 studied the effect of 8 g of cholestyramine in boys and girls aged 6 to 11 years who have FH and found only a 16.9% change in LDL cholesterol concentrations. Furthermore, in a study by Liacouras et al,16 52 of 62 children discontinued treatment after an average of 21.9 months because of gritty taste and symptoms of constipation and bloating.
Hydroxymethylglutaryl coenzyme A reductase inhibitors are widely used to manage TC and LDL cholesterol concentrations and reduce the risk for cardiovascular events in adult patients with hypercholesterolemia.17,18 Lovastatin is a potent inhibitor of hydroxymethylglutaryl coenzyme A reductase that catalyzes the conversion of hydroxymethyl-glutarate to mevalonate, an early and rate-limiting step in the synthesis of cholesterol. Lovastatin has an overall favorable safety profile in adults as demonstrated by several large clinical studies.19–22 Furthermore, lovastatin has been shown to prevent CAD in healthy adults with moderately elevated LDL cholesterol concentrations.17 Previous studies demonstrated the efficacy and safety profile of statins in adolescent children.12,23–29 However, none of these studies exclusively examined the effects of statins in adolescent girls. Because lovastatin is available generically, it is important to evaluate its efficacy and safety profile in adolescent girls with FH to provide a less expensive therapeutic alternative.
METHODS
Study Design
July 1999 through August 2000, 54 female patients with FH were enrolled in this multicenter (12 sites), randomized, parallel-group, and placebo-controlled study. Each institutional review board approved the study, and consent was obtained from patients and their parents. All lipid-altering drugs were discontinued for 6 weeks (statins, bile acid sequestrants, and nicotinic acid) or 8 weeks (fibrates) before patient randomization. Patients were instructed to follow an American Heart Association Step I or similar diet throughout the trial. After a 4-week placebo/diet run-in period, eligible patients were randomized using a computer-generated allocation schedule to receive either lovastatin 20 mg/day for 4 weeks followed by lovastatin 40 mg/day for 20 weeks or placebo for 24 weeks. Patients were randomized in a 2:1 ratio to ensure adequate power for the primary comparison (percentage change in LDL cholesterol after 24 weeks of lovastatin vs placebo). Patients were assigned a randomized allocation number by the clinic staff on the basis of the distribution of allocation numbers to each clinic. For the randomized treatment period, all drug was packaged by allocation number to maintain patient and investigator blinding. Lovastatin 20 and 40 mg were chosen for evaluation in this study because these doses previously were shown to be safe and effective in adolescent boys with FH.24 Patient compliance to study medication was evaluated by pill count.
Eligibility Criteria
Eligible patients included girls who were postmenarchal for at least 1 year (defined as at least 1 year after first menstrual period and having at least 3 menstrual periods), were aged 10 to 17 years, had FH, and had a BMI (kg/m2) between the 10th and 95th percentiles for age. A patient was judged to have FH if she met the following criteria: 1 parent with FH, LDL cholesterol between 160 and 400 mg/dL at visit 2 (week –1), and triglycerides (TG) <350 mg/dL. Three patients (1 in lovastatin and 2 in placebo group) who had reached their 18th birthday <6 months before randomization were allowed to enter the study. Patients were allowed to participate when they had a negative pregnancy test at the baseline screening visit and were perceived by the study investigator to be highly unlikely to conceive. Exclusionary concomitant conditions included homozygous FH, dyslipidemias (types I, III, IV, and V), diabetes, hypothyroidism, liver disease, known impairment of renal function, or nephrotic syndrome. Individuals who were taking immunosuppressant drugs, corticosteroids, or drugs that are potent inhibitors of cytochrome P-450 3A4 were ineligible to participate in this study.
Clinical Monitoring/Laboratory Testing
Clinic visits were scheduled for weeks –4 and –1 (screening/placebo run-in); week 1 (day 1; randomization); and weeks 4, 8, 12, 16, 20, and 24 (lipid profile and safety assessment). Fasting (at least 12 hours from the last meal) blood samples were obtained at each clinic visit for quantifying lipid values. The central laboratory (Medical Research Laboratory, Highland Heights, KY) performed all laboratory analyses.24 LDL cholesterol concentrations were calculated by the Friedewald equation.30 Concentrations of TC, TG, and HDL cholesterol were measured enzymatically with the Hitachi 747 analyzer (Roche Diagnostics Corp., Indianapolis, IN). HDL cholesterol was measured after precipitation of LDL cholesterol and very-low-density lipoprotein (VLDL) cholesterol by heparin-manganese chloride.31 The apolipoproteins (apo B, apo A-I) were measured by immunonephelometry (Behring, Marburg, Germany).
Measurements of liver function tests (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), creatinine, glucose, creatine kinase (CK), and urine and serum -human chorionic gonadotrophin were performed at each study visit. Baseline lipid chemistries were calculated on the basis of the average value obtained at weeks –1 and 1. Hematology and urine analyses were performed at weeks –4, 1, 12, and 24. Physical examinations were performed at week –1 and 24. Plasma levels of estradiol, dehydroepiandrosterone sulfate (DHEAS), morning cortisol, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were measured at weeks 1 and 24. Monitoring of menstrual cycle length through the review of menstrual diaries occurred during weeks –4 to 24.
Safety and tolerability were evaluated throughout the study by reviewing patients’ reports, investigators’ observations, and results of specific tests and measurements. Prespecified reasons for discontinuation from the study included persistent elevations in ALT and/or AST at least 3 times the upper limit of normal (ULN), CK levels at least 10 times the ULN with or without associated muscle symptoms, or CK elevations >5 to 10 times ULN with associated muscle symptoms. Patients also were discontinued from the study when they required >2 weeks’ treatment with systemic corticosteroids or immunosuppressants, antifungals, erythromycin, or similar drugs or when they had a positive pregnancy test at any point during the study.
Efficacy Assessments
The primary objective was to compare the LDL cholesterol-lowering efficacy of lovastatin and placebo after 24 weeks of treatment. Secondary efficacy endpoints included percentage change from baseline in plasma concentrations of TC, TG, HDL cholesterol, VLDL cholesterol, apo B, and apo A-I at week 24. An additional secondary efficacy parameter was to compare the LDL cholesterol-lowering efficacy of lovastatin 20 mg/day and placebo after 4 weeks of treatment.
Statistics
The primary efficacy analysis was based on the intention-to-treat population (ie, the analysis included all randomized patients who had a baseline measurement and at least 1 postbaseline measurement). Data were carried forward to the next scheduled time point to impute missing values. Sample size, mean, median, SD, range, and proportion were calculated for all baseline characteristics, including age and race. With a planned sample size of 60 patients (40 lovastatin and 20 placebo), a 13.5% difference in LDL cholesterol percentage change from baseline between the 2 treatment groups could be detected with 90% power (2-sided; = .050). All P values were rounded to 3 decimal places, and P .050 was considered statistically significant. Borderline significance was defined as .050 < P .100.
The primary hypothesis was that lovastatin treatment would result in a significantly greater reduction in LDL cholesterol concentrations from baseline to week 24 compared with placebo. The primary efficacy analysis was performed using an analysis of variance (ANOVA) model for a multicenter, forced-titration, parallel-design study with terms for treatment (yes, no), center, and treatment-by-center interaction. The interaction term was tested and removed from the model when it was nonsignificant (P > .05) or quantitative in nature. A paired t test or Wilcoxon signed rank test was used to evaluate percentage change from baseline within each group. A nonparametric ANOVA was used to corroborate the parametric results.
Secondary efficacy endpoints (TC, TG, HDL cholesterol, VLDL cholesterol, apo B, and apo A-I) were evaluated using the same ANOVA model. Pairwise comparisons between treatment groups were performed using the least-squares means procedure. For TG and VLDL cholesterol, a nonparametric evaluation based on an ANOVA model using Tukey’s normalized ranks was used because these variables are typically not normally distributed. As prespecified in the data analysis plan for this study, the treatment effects for all secondary efficacy analyses were evaluated at weeks 4 (secondary time point) and 24 (primary time point).
Safety and tolerability were assessed by clinical review of all safety factors, including adverse events (AEs), laboratory values, body measurements, and vital signs. The Fisher exact test was used to compare between-treatment incidence of prespecified AEs and the proportion of patients whose levels of ALT, AST, and CK exceeded predefined limits of change at weeks 4 and 24 (primary time point). An ANOVA model, as described above, was used to assess between-treatment differences for changes from baseline in AST, ALT, and CK. Between-group differences in hormone levels (LH, FSH, DHEAS, estradiol, and morning cortisol), menstrual cycle length, weight, height, and BMI were analyzed using the ANOVA model described above. Patients were excluded from the estradiol and menstrual cycle length analyses when they were taking an oral contraceptive.
RESULTS
Patient Accounting and Demographics
Of 81 patients screened, 54 were randomized to treatment with lovastatin (n = 35) or placebo (n = 19). The majority of the 27 excluded patients (17 [63%]) did not meet eligibility criteria as defined by the protocol. Of patients who were randomized to study treatment, 51 (94%) completed the study and 3 (6%) patients discontinued treatment because of consent withdrawn (n = 2 lovastatin) and lost to follow-up (n = 1 placebo). No patients had their treatments prematurely unblinded during this study. The treatment groups were generally well balanced with respect to patient demographics and baseline characteristics (Table 1). The intention-to-treat population consisted of 54 female FH patients, aged 10 to 18 years, with mean baseline LDL cholesterol plasma concentrations ranging from 136 to 364 mg/dL across the treatment groups. Baseline LDL cholesterol values (presented in Table 1 and used to calculate percentage change from baseline) were defined as the average LDL cholesterol value obtained from visit 2 (screening period; week -1) and visit 3 (predrug; week 1). The lower limit of the range falls below 160 mg/dL because of variability in LDL cholesterol levels between the 2 visits (prescreening and predrug measurements).
Lipids, Lipoproteins, and Apolipoproteins
Administration of lovastatin 20 mg/day for 4 weeks led to a mean percentage reduction in LDL cholesterol concentrations from baseline of –23% compared with an increase of 3% with placebo (Table 2). After 24 weeks of treatment, lovastatin produced reductions in LDL cholesterol from baseline of –27% relative to 5% with placebo. The between-treatment group differences for LDL cholesterol ranged from –26% to –32% at weeks 4 and 24, respectively (P < .001 for 4 and 24 weeks).
In addition to lowering LDL cholesterol, treatment with lovastatin produced significant reductions in TC and apo B concentrations relative to placebo at weeks 4 and 24 (P < .001 for both parameters at 4 and 24 weeks; Table 2). The mean percentage change from baseline in TC at week 4 was –17% and 2% in the lovastatin and placebo groups, respectively; at week 24, the mean percentage change was –22% with lovastatin relative to 5% with placebo. For apo B, the mean percentage change from baseline at week 4 was –20% and 6% in the lovastatin and placebo groups, respectively; at week 24, the mean percentage change was –23% with lovastatin compared with 7% with placebo. At study end, lovastatin produced borderline significant reductions in TG concentrations of –23% compared with –3% for the placebo group (P = .067). Plasma concentrations of apo A-I increased in the lovastatin and placebo groups at both time points; however, the increase was actually greater in the placebo group, leading to a borderline significant between-group difference at week 24 (P = .077). There were no significant differences in HDL cholesterol or VLDL cholesterol between the treatment groups at weeks 4 or 24.
Vital Signs/Growth
There were no clinically significant alterations in vital signs (pulse rate and systolic and diastolic blood pressures) or anthropomorphic measurements (height, weight, and BMI) between the treatment groups (Table 3). Systolic blood pressure did not change in the lovastatin group but decreased in the placebo group after 24 weeks of therapy, leading to a significant between-treatment group difference (P < .050).
Hormonal Assessment
There were no significant alterations in plasma concentrations of FSH, cortisol, estradiol, and DHEAS between the lovastatin and placebo groups (Table 3). Treatment with lovastatin for 24 weeks did not affect plasma LH concentrations; however, the median LH value at 24 weeks was slightly decreased in the placebo group. The difference between the lovastatin and placebo groups was significant (P < .050) but not clinically meaningful. There were no significant between-treatment group differences in mean change from baseline in menstrual cycle length (data not shown). A total of 2 patients were excluded from the menstrual cycle length analysis; 1 placebo patient had amenorrhea, and 1 lovastatin patient was taking oral contraceptives.
Safety/Serum Chemistries
There were no significant between-treatment group differences in median change from baseline in ALT, AST, or CK concentrations at weeks 4 and 24 (Table 4).
AEs
The safety results and most commonly reported AEs for the 2 treatment groups are shown in Table 5. Generally, the observed AE profiles were similar across the treatment groups. Clinical AEs were reported for 66% (23 of 35) of patients who received lovastatin and 68% (13 of 19) of patients who received placebo. Most AEs were considered by the study investigator to be mild to moderate in intensity and unlikely related to study medication. The most common AEs were upper respiratory tract infection, pharyngitis, and headache.
There were no clinically meaningful differences between the treatment groups in the incidence of treatment-related adverse events. Three patients in the lovastatin group (3 of 35 [8.6%]) and 1 patient in the placebo group (1 of 19 [5%]) experienced AEs that were considered by the study investigator to be possibly, probably, or definitely related to study medication. The individual treatment-related AEs that were reported by patients in the lovastatin group included abdominal pain (2 of 35 [6%]), diarrhea (1 of 35 [3%]), nausea (1 of 35 [3%]), and headache (1 of 35 [3%]). One patient in the placebo group experienced a clinical AE of amenorrhea, which was considered by the investigator to be possibly related to treatment. In all cases, treatment-related AEs resolved spontaneously while patients continued on study medication. There was only 1 report of a laboratory AE that occurred in a patient who received lovastatin 40 mg/day. This patient experienced decreases in hematocrit and hemoglobin values on day 162 (visit 9) that were considered probably not related to study treatment. This finding was unlikely to be of any significance, given that at visit 6 (study week 12) these values were actually higher than they had been at baseline.
No patients discontinued treatment as a result of an AE (either clinical or laboratory in nature) at any point during this study. There were no deaths, serious AEs (death, life-threatening event, significant disability/incapacity, hospitalization, or any other event deemed by the investigator to be serious), or other significant AEs. No cases of myopathy or rhabdomyolysis were reported in either treatment group. There were no instances of clinically important CK elevations 5 to 10 or >10 times ULN, and no patients experienced single or consecutive elevations in liver transaminases (ALT or AST) at least 3 times ULN.
DISCUSSION
Adult women with FH clinically manifest CAD 10 years later than afflicted men. Nevertheless, the early onset of atherosclerosis in diseased women, sometimes as early as the fourth decade, highlights the need for early and aggressive treatment. Adult women with FH and clinical evidence of CAD may be more responsive to LDL cholesterol–lowering therapy than similarly affected men as assessed by regression of coronary plaques and the incidence of tendon xanthomas.32 Recently published data from a large, well-controlled, double-blind study in heterozygous children with FH using carotid intima-media thickness as a surrogate marker for atherosclerosis established that even a moderate decrease in LDL cholesterol of 24% with pravastatin induced regression of carotid intimal thickening.12 Currently, the recommended guidelines for pharmacologic treatment of children who are 10 years or older and have persistent elevations of LDL cholesterol is (1) LDL cholesterol >160 mg/dL with a family history of premature CAD or (2) an LDL cholesterol >190 mg/dL with no family history, after intervention with a diet restricted in total and saturated fat and cholesterol for 6 months.13,14 Because early intervention with statins is likely to be effective at reducing future coronary risk in young female patients with this dominantly inherited disease, aggressive intervention with a minimal goal of a LDL cholesterol <130 mg/dL and an optimal goal of <110 mg/dL13,14 is warranted.
This study examined the lipid-altering efficacy and safety profile of lovastatin 20 to 40 mg/day in adolescent girls with FH. The number of patients who participated in this study (n = 54) was necessarily small because of the rarity of FH and that it is often not diagnosed until later in life. Nevertheless, the ability of lovastatin to improve LDL cholesterol concentrations was demonstrated in this study. The mean LDL cholesterol reductions observed after treatment with lovastatin 20 mg/day and 40 mg/day ranged from –23% (week 4) to –27% (week 24). The magnitude of the LDL cholesterol reductions seen in this study was similar to that reported in previous studies that examined the effects of lovastatin 40 mg/day in adult patients of both genders with or without FH19,22,33 and in adult women without FH.21,34
In addition to its beneficial effects on LDL cholesterol, lovastatin produced significant reductions in TC and apo B compared with placebo at weeks 4 and 24. The between-group differences were greatest after treatment with lovastatin 40 mg/day. Changes in HDL cholesterol, VLDL cholesterol, and apo A-I produced by the administration of lovastatin 20 to 40 mg/day were not statistically significant. The finding that lovastatin produced borderline statistically significant changes in TG is likely related to the small sample size and high variability associated with this parameter.
Numerous studies have documented the overall favorable safety profile of statin therapy in adult women35–37; however, few have examined the effects of these drugs in adolescent girls.23 The recent study by Wiegman et al12 included 114 female children, 68 of whom were postmenarchal. In the 2-year, study the investigators reported no AEs on growth or sexual development parameters for children who were treated with pravastatin compared with those who were on placebo; however, no specific data were provided for the subset of postmenarchal girls. Because cholesterol is a precursor of the adrenal (DHEAS and cortisol) and gonadal (estradiol) hormones, statin treatment may result in decreased production of these hormones by inhibiting the rate-limiting enzyme involved in cholesterol production. Additional safety concerns in a younger female population include potential effects on pituitary hormones (LH and FSH), menstrual cycle length, and physical development (height, weight, and BMI).
There was a statistically significant (but not clinically meaningful) between-group difference in LH measurements (P = .04). The significant difference between the lovastatin and placebo groups is probably spurious as a result of the large number of laboratory safety variables analyzed without adjustment for multiplicity. Adjustments for multiplicity are not typically performed on safety variables because it reduces the test’s ability to detect significant changes. Of note, the reduction in plasma cholesterol produced by lovastatin was not accompanied by an observed decrease in LH. Furthermore, there were no detectable effects on plasma FSH, estradiol, or menstrual cycle length, supporting our conclusion that the between-group difference in LH levels was not clinically significant. The single patient who experienced a possibly drug-related endocrine AE (amenorrhea) in this study was receiving placebo treatment. Of interest, de Jongh et al23 did not report differences in LH, FSH, estradiol, or menstrual cycle length with simvastatin treatment in female adolescents. However, these investigators found that simvastatin significantly decreased DHEAS levels in both girls and boys. No differences in DHEAS levels were observed in the present study.
The 2 most common concerns with the use of statin therapy, namely critical elevations in liver (ALT and/or AST >3 times ULN) and muscle enzymes (5–10 or >10 times ULN), were not observed during this study. Furthermore, no patients developed hepatitis, myopathy, or rhabdomyolysis. However, because of the small number of patients in the study, no conclusions can be drawn concerning the differences in any AEs between groups. A larger study randomizing several hundred patients to lovastatin would be necessary to estimate accurately the incidence of AEs, but such a study is not feasible given the rarity of FH in the general population.
Although we and others did not find increases in ALT and AST with lovastatin therapy, increases in liver function tests up to 3 times ULN have been reported in several adolescents who were treated with higher doses of simvastatin (40 mg/day)23 and atorvastatin (20 mg/day).29 In addition, instances of asymptomatic increases in CK levels, although unusual, have been reported in female and male adolescents who received statin therapy.23–25 Thus, physicians should carefully monitor adolescent patients for elevations in hepatic transaminases and CK concentrations, particularly when using higher doses of lovastatin.
In summary, lovastatin at doses up to 40 mg significantly reduced LDL cholesterol, TC, and apo B concentrations and was well tolerated in adolescent girls with FH. Although the treatment of adolescent patients with FH is indicated, especially in those with a family history of premature CAD, additional studies are needed to document the long-term safety of lovastatin therapy and to determine its potential effects on the prevention of atherosclerosis and coronary events. In that regard, a recent report showed a trend toward regression of carotid intima-media thickness in FH heterozygous children who were treated with pravastatin and a trend toward progression in the placebo group.12 It is important to note that statins are contraindicated during pregnancy because of the potential risk to a developing fetus. Hence, lovastatin should be administered to adolescent girls only when they are highly unlikely to conceive.
ACKNOWLEDGMENTS
This study was supported by a grant from Merck & Co, Inc.
The Mevacor Girls Study Group (Protocol 083) consisted of the following investigators: C.A. Dujovne, MD, Overland Park, KS; C.A. Friedrich, MD, and D.J. Rader, MD, Philadelphia, PA; P. Hopkins, MD, Salt Lake City, UT; W. Insull, MD, Houston, TX; M.S. Jacobson, MD, New Hyde Park, NY; R. Knopp, MD, Seattle, WA; P.O. Kwiterovich, Jr., MD, Baltimore, MD; R. Lees, MD, Cambridge, MA; C.A. Liacouras, MD, Philadelphia, PA; M. McGowan, MD, Manchester, NH; T. Orchard, MD, Pittsburgh, PA; and E.A. Stein, MD, Cincinnati, OH.
We thank the children and parents who participated in this study. Thanks also are extended to Dr Arvind Shah, Merck & Co, Inc, for assistance with preparing the manuscript for submission.
FOOTNOTES
Accepted Dec 9, 2004.
Conflict of interest: P. Hopkins is a member of Merck Laboratories Speakers Bureau; M. Cho, A. Tate, and A. O. Johnson-Levonas are employees of Merck Company Inc.
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Shear CL, Franklin FA, Stinnett S, et al. Expanded Clinical Evaluation of Lovastatin (EXCEL) study results. Effect of patient characteristics on lovastatin-induced changes in plasma concentrations of lipids and lipoproteins. Circulation. 1992;85 :1293 –1303
Bairey Merz CN, Olson MB, Johnson BD, et al. Cholesterol-lowering medication, cholesterol level, and reproductive hormones in women: the Women’s Ischemia Syndrome Evaluation (WISE). Am J Med. 2002;113 :723 –727
Plotkin D, Miller S, Nakajima S, et al. Lowering low density lipoprotein cholesterol with simvastatin, a hydroxy-3-methylglutaryl-coenzyme a reductase inhibitor, does not affect luteal function in premenopausal women. J Clin Endocrinol Metab. 2002;87 :3155 –3161
Ushiroyama T, Ikeda A, Ueki M, Sugimoto O. Efficacy and short-term effects of pravastatin, a potent inhibitor of HMG-Co A reductase, on hypercholesterolemia in climacteric women. J Med. 1994;25 :319 –331(Sarah B. Clauss, MD, Kath)
Cardiovascular Genetics, Salt Lake City, Utah
Metabolic and Atherosclerosis Research Center, Cincinnati, Ohio
Merck Research Laboratories, Rahway, New Jersey
ABSTRACT
Objective. The present study was designed to evaluate the lipid-altering efficacy, safety, and tolerability of lovastatin treatment in adolescent girls with heterozygous familial hypercholesterolemia.
Methods. A total of 54 postmenarchal girls, aged 10 to 17 years, were enrolled in a 24-week, double-blind, randomized, placebo-controlled study. After a 4-week diet/placebo run-in period, patients were randomized to 1 of 2 groups: (1) treatment with diet plus lovastatin 20 mg/day for 4 weeks, followed by diet plus lovastatin 40 mg/day for 20 weeks, or (2) diet plus placebo for 24 weeks.
Results. Baseline values of lipids, lipoproteins, and apolipoproteins (apo) were comparable between treatment groups. Lovastatin treatment was efficacious at reducing low-density lipoprotein cholesterol by 23% to 27%, total cholesterol by 17% to 22%, and apo B by 20% to 23% at weeks 4 and 24, respectively. Between-treatment group differences were not statistically significant for triglycerides, very-low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or apo A-I. Lovastatin was generally safe and well tolerated. There were no clinically significant alterations in vital signs (blood pressure and pulse rate), anthropomorphic measurements (height, weight, and BMI), hormone levels (luteinizing hormone, follicle-stimulating hormone, dehydroepiandrosterone sulfate, estradiol, and cortisol), menstrual cycle length, or tests of liver and muscle function.
Conclusions. Lovastatin offers an efficacious and well-tolerated treatment option for improving lipid profiles in adolescent girls with familial hypercholesterolemia.
Key Words: adolescents cholesterol lipids
Abbreviations: CAD, coronary artery disease TC, total cholesterol LDL, low-density lipoprotein HDL, high-density lipoprotein FH, familial hypercholesterolemia TG, triglycerides VLDL, very-low-density lipoprotein apo, apolipoprotein ALT, alanine aminotransferase AST, aspartate aminotransferase CK, creatine kinase DHEAS, dehydroepiandrosterone sulfate FSH, follicle-stimulating hormone LH, luteinizing hormone ULN, upper limit of normal ANOVA, analysis of variance AE, adverse event
Coronary artery disease (CAD) is a leading cause of morbidity and mortality among women in the United States. CAD produces more deaths in women than cancer of the breast, uterus, and ovary combined. Recently, there has been an emphasis to raise the awareness of CAD and its risk factors in women. The lesions of atherosclerosis that are found in adult men and women begin to develop in childhood.1–6 The development of early lesions of atherosclerosis in adolescents and young adults is related directly to elevated plasma concentrations of total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, and decreased levels of high-density lipoprotein (HDL) cholesterol during childhood.7
Familial hypercholesterolemia (FH) is an autosomal dominant disorder that is caused by mutations in the gene encoding the LDL receptor. The prevalence of FH heterozygotes in the population is estimated to be 1 in 500 individuals. FH is completely expressed at birth in both girls and boys.8 By the age of 1 year, individuals with FH demonstrate marked elevations in TC and LDL cholesterol averaging 300 mg/dL and 240 mg/dL, respectively.8,9 During adolescence, both FH heterozygotes and normal individuals manifest a significant decrease of 10% to 15% in plasma concentrations of LDL cholesterol.9,10 Between 1 and 19 years of age, adolescents with FH usually do not express clinical signs or symptoms of CAD, although 1 in 10 individuals will present with tendon xanthomas and Achilles tendonitis. Individuals with FH develop premature CAD in adulthood, sometimes in their fourth decade but often by the time they reach 40 and 50 years of age in men and a decade later in women. Recent studies in FH heterozygous children using carotid ultrasound have demonstrated that by their early teens, there is significant carotid artery thickening and that the rate of progression is substantially greater than that of children without FH.11,12 Therefore, it is important to lower LDL cholesterol aggressively in this population to reduce the rate of atherosclerosis in anticipation that this will prevent or delay onset of CAD.
The current recommendation of the National Cholesterol Education Program Expert Panel on Blood Cholesterol Levels in Children and Adolescents is to use pharmacologic therapy in children who are older than 10 years and have after dietary intervention (1) an LDL cholesterol of >160 mg/dL with a family history of premature CAD or (2) an LDL cholesterol of >190 mg/dL with no family history.13,14 The panel recommends using bile acid sequestrants to manage LDL cholesterol concentrations in such patients; however, these agents provide only modest LDL cholesterol reductions, and they suffer from tolerability issues. For example, Tonstad et al15 studied the effect of 8 g of cholestyramine in boys and girls aged 6 to 11 years who have FH and found only a 16.9% change in LDL cholesterol concentrations. Furthermore, in a study by Liacouras et al,16 52 of 62 children discontinued treatment after an average of 21.9 months because of gritty taste and symptoms of constipation and bloating.
Hydroxymethylglutaryl coenzyme A reductase inhibitors are widely used to manage TC and LDL cholesterol concentrations and reduce the risk for cardiovascular events in adult patients with hypercholesterolemia.17,18 Lovastatin is a potent inhibitor of hydroxymethylglutaryl coenzyme A reductase that catalyzes the conversion of hydroxymethyl-glutarate to mevalonate, an early and rate-limiting step in the synthesis of cholesterol. Lovastatin has an overall favorable safety profile in adults as demonstrated by several large clinical studies.19–22 Furthermore, lovastatin has been shown to prevent CAD in healthy adults with moderately elevated LDL cholesterol concentrations.17 Previous studies demonstrated the efficacy and safety profile of statins in adolescent children.12,23–29 However, none of these studies exclusively examined the effects of statins in adolescent girls. Because lovastatin is available generically, it is important to evaluate its efficacy and safety profile in adolescent girls with FH to provide a less expensive therapeutic alternative.
METHODS
Study Design
July 1999 through August 2000, 54 female patients with FH were enrolled in this multicenter (12 sites), randomized, parallel-group, and placebo-controlled study. Each institutional review board approved the study, and consent was obtained from patients and their parents. All lipid-altering drugs were discontinued for 6 weeks (statins, bile acid sequestrants, and nicotinic acid) or 8 weeks (fibrates) before patient randomization. Patients were instructed to follow an American Heart Association Step I or similar diet throughout the trial. After a 4-week placebo/diet run-in period, eligible patients were randomized using a computer-generated allocation schedule to receive either lovastatin 20 mg/day for 4 weeks followed by lovastatin 40 mg/day for 20 weeks or placebo for 24 weeks. Patients were randomized in a 2:1 ratio to ensure adequate power for the primary comparison (percentage change in LDL cholesterol after 24 weeks of lovastatin vs placebo). Patients were assigned a randomized allocation number by the clinic staff on the basis of the distribution of allocation numbers to each clinic. For the randomized treatment period, all drug was packaged by allocation number to maintain patient and investigator blinding. Lovastatin 20 and 40 mg were chosen for evaluation in this study because these doses previously were shown to be safe and effective in adolescent boys with FH.24 Patient compliance to study medication was evaluated by pill count.
Eligibility Criteria
Eligible patients included girls who were postmenarchal for at least 1 year (defined as at least 1 year after first menstrual period and having at least 3 menstrual periods), were aged 10 to 17 years, had FH, and had a BMI (kg/m2) between the 10th and 95th percentiles for age. A patient was judged to have FH if she met the following criteria: 1 parent with FH, LDL cholesterol between 160 and 400 mg/dL at visit 2 (week –1), and triglycerides (TG) <350 mg/dL. Three patients (1 in lovastatin and 2 in placebo group) who had reached their 18th birthday <6 months before randomization were allowed to enter the study. Patients were allowed to participate when they had a negative pregnancy test at the baseline screening visit and were perceived by the study investigator to be highly unlikely to conceive. Exclusionary concomitant conditions included homozygous FH, dyslipidemias (types I, III, IV, and V), diabetes, hypothyroidism, liver disease, known impairment of renal function, or nephrotic syndrome. Individuals who were taking immunosuppressant drugs, corticosteroids, or drugs that are potent inhibitors of cytochrome P-450 3A4 were ineligible to participate in this study.
Clinical Monitoring/Laboratory Testing
Clinic visits were scheduled for weeks –4 and –1 (screening/placebo run-in); week 1 (day 1; randomization); and weeks 4, 8, 12, 16, 20, and 24 (lipid profile and safety assessment). Fasting (at least 12 hours from the last meal) blood samples were obtained at each clinic visit for quantifying lipid values. The central laboratory (Medical Research Laboratory, Highland Heights, KY) performed all laboratory analyses.24 LDL cholesterol concentrations were calculated by the Friedewald equation.30 Concentrations of TC, TG, and HDL cholesterol were measured enzymatically with the Hitachi 747 analyzer (Roche Diagnostics Corp., Indianapolis, IN). HDL cholesterol was measured after precipitation of LDL cholesterol and very-low-density lipoprotein (VLDL) cholesterol by heparin-manganese chloride.31 The apolipoproteins (apo B, apo A-I) were measured by immunonephelometry (Behring, Marburg, Germany).
Measurements of liver function tests (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), creatinine, glucose, creatine kinase (CK), and urine and serum -human chorionic gonadotrophin were performed at each study visit. Baseline lipid chemistries were calculated on the basis of the average value obtained at weeks –1 and 1. Hematology and urine analyses were performed at weeks –4, 1, 12, and 24. Physical examinations were performed at week –1 and 24. Plasma levels of estradiol, dehydroepiandrosterone sulfate (DHEAS), morning cortisol, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were measured at weeks 1 and 24. Monitoring of menstrual cycle length through the review of menstrual diaries occurred during weeks –4 to 24.
Safety and tolerability were evaluated throughout the study by reviewing patients’ reports, investigators’ observations, and results of specific tests and measurements. Prespecified reasons for discontinuation from the study included persistent elevations in ALT and/or AST at least 3 times the upper limit of normal (ULN), CK levels at least 10 times the ULN with or without associated muscle symptoms, or CK elevations >5 to 10 times ULN with associated muscle symptoms. Patients also were discontinued from the study when they required >2 weeks’ treatment with systemic corticosteroids or immunosuppressants, antifungals, erythromycin, or similar drugs or when they had a positive pregnancy test at any point during the study.
Efficacy Assessments
The primary objective was to compare the LDL cholesterol-lowering efficacy of lovastatin and placebo after 24 weeks of treatment. Secondary efficacy endpoints included percentage change from baseline in plasma concentrations of TC, TG, HDL cholesterol, VLDL cholesterol, apo B, and apo A-I at week 24. An additional secondary efficacy parameter was to compare the LDL cholesterol-lowering efficacy of lovastatin 20 mg/day and placebo after 4 weeks of treatment.
Statistics
The primary efficacy analysis was based on the intention-to-treat population (ie, the analysis included all randomized patients who had a baseline measurement and at least 1 postbaseline measurement). Data were carried forward to the next scheduled time point to impute missing values. Sample size, mean, median, SD, range, and proportion were calculated for all baseline characteristics, including age and race. With a planned sample size of 60 patients (40 lovastatin and 20 placebo), a 13.5% difference in LDL cholesterol percentage change from baseline between the 2 treatment groups could be detected with 90% power (2-sided; = .050). All P values were rounded to 3 decimal places, and P .050 was considered statistically significant. Borderline significance was defined as .050 < P .100.
The primary hypothesis was that lovastatin treatment would result in a significantly greater reduction in LDL cholesterol concentrations from baseline to week 24 compared with placebo. The primary efficacy analysis was performed using an analysis of variance (ANOVA) model for a multicenter, forced-titration, parallel-design study with terms for treatment (yes, no), center, and treatment-by-center interaction. The interaction term was tested and removed from the model when it was nonsignificant (P > .05) or quantitative in nature. A paired t test or Wilcoxon signed rank test was used to evaluate percentage change from baseline within each group. A nonparametric ANOVA was used to corroborate the parametric results.
Secondary efficacy endpoints (TC, TG, HDL cholesterol, VLDL cholesterol, apo B, and apo A-I) were evaluated using the same ANOVA model. Pairwise comparisons between treatment groups were performed using the least-squares means procedure. For TG and VLDL cholesterol, a nonparametric evaluation based on an ANOVA model using Tukey’s normalized ranks was used because these variables are typically not normally distributed. As prespecified in the data analysis plan for this study, the treatment effects for all secondary efficacy analyses were evaluated at weeks 4 (secondary time point) and 24 (primary time point).
Safety and tolerability were assessed by clinical review of all safety factors, including adverse events (AEs), laboratory values, body measurements, and vital signs. The Fisher exact test was used to compare between-treatment incidence of prespecified AEs and the proportion of patients whose levels of ALT, AST, and CK exceeded predefined limits of change at weeks 4 and 24 (primary time point). An ANOVA model, as described above, was used to assess between-treatment differences for changes from baseline in AST, ALT, and CK. Between-group differences in hormone levels (LH, FSH, DHEAS, estradiol, and morning cortisol), menstrual cycle length, weight, height, and BMI were analyzed using the ANOVA model described above. Patients were excluded from the estradiol and menstrual cycle length analyses when they were taking an oral contraceptive.
RESULTS
Patient Accounting and Demographics
Of 81 patients screened, 54 were randomized to treatment with lovastatin (n = 35) or placebo (n = 19). The majority of the 27 excluded patients (17 [63%]) did not meet eligibility criteria as defined by the protocol. Of patients who were randomized to study treatment, 51 (94%) completed the study and 3 (6%) patients discontinued treatment because of consent withdrawn (n = 2 lovastatin) and lost to follow-up (n = 1 placebo). No patients had their treatments prematurely unblinded during this study. The treatment groups were generally well balanced with respect to patient demographics and baseline characteristics (Table 1). The intention-to-treat population consisted of 54 female FH patients, aged 10 to 18 years, with mean baseline LDL cholesterol plasma concentrations ranging from 136 to 364 mg/dL across the treatment groups. Baseline LDL cholesterol values (presented in Table 1 and used to calculate percentage change from baseline) were defined as the average LDL cholesterol value obtained from visit 2 (screening period; week -1) and visit 3 (predrug; week 1). The lower limit of the range falls below 160 mg/dL because of variability in LDL cholesterol levels between the 2 visits (prescreening and predrug measurements).
Lipids, Lipoproteins, and Apolipoproteins
Administration of lovastatin 20 mg/day for 4 weeks led to a mean percentage reduction in LDL cholesterol concentrations from baseline of –23% compared with an increase of 3% with placebo (Table 2). After 24 weeks of treatment, lovastatin produced reductions in LDL cholesterol from baseline of –27% relative to 5% with placebo. The between-treatment group differences for LDL cholesterol ranged from –26% to –32% at weeks 4 and 24, respectively (P < .001 for 4 and 24 weeks).
In addition to lowering LDL cholesterol, treatment with lovastatin produced significant reductions in TC and apo B concentrations relative to placebo at weeks 4 and 24 (P < .001 for both parameters at 4 and 24 weeks; Table 2). The mean percentage change from baseline in TC at week 4 was –17% and 2% in the lovastatin and placebo groups, respectively; at week 24, the mean percentage change was –22% with lovastatin relative to 5% with placebo. For apo B, the mean percentage change from baseline at week 4 was –20% and 6% in the lovastatin and placebo groups, respectively; at week 24, the mean percentage change was –23% with lovastatin compared with 7% with placebo. At study end, lovastatin produced borderline significant reductions in TG concentrations of –23% compared with –3% for the placebo group (P = .067). Plasma concentrations of apo A-I increased in the lovastatin and placebo groups at both time points; however, the increase was actually greater in the placebo group, leading to a borderline significant between-group difference at week 24 (P = .077). There were no significant differences in HDL cholesterol or VLDL cholesterol between the treatment groups at weeks 4 or 24.
Vital Signs/Growth
There were no clinically significant alterations in vital signs (pulse rate and systolic and diastolic blood pressures) or anthropomorphic measurements (height, weight, and BMI) between the treatment groups (Table 3). Systolic blood pressure did not change in the lovastatin group but decreased in the placebo group after 24 weeks of therapy, leading to a significant between-treatment group difference (P < .050).
Hormonal Assessment
There were no significant alterations in plasma concentrations of FSH, cortisol, estradiol, and DHEAS between the lovastatin and placebo groups (Table 3). Treatment with lovastatin for 24 weeks did not affect plasma LH concentrations; however, the median LH value at 24 weeks was slightly decreased in the placebo group. The difference between the lovastatin and placebo groups was significant (P < .050) but not clinically meaningful. There were no significant between-treatment group differences in mean change from baseline in menstrual cycle length (data not shown). A total of 2 patients were excluded from the menstrual cycle length analysis; 1 placebo patient had amenorrhea, and 1 lovastatin patient was taking oral contraceptives.
Safety/Serum Chemistries
There were no significant between-treatment group differences in median change from baseline in ALT, AST, or CK concentrations at weeks 4 and 24 (Table 4).
AEs
The safety results and most commonly reported AEs for the 2 treatment groups are shown in Table 5. Generally, the observed AE profiles were similar across the treatment groups. Clinical AEs were reported for 66% (23 of 35) of patients who received lovastatin and 68% (13 of 19) of patients who received placebo. Most AEs were considered by the study investigator to be mild to moderate in intensity and unlikely related to study medication. The most common AEs were upper respiratory tract infection, pharyngitis, and headache.
There were no clinically meaningful differences between the treatment groups in the incidence of treatment-related adverse events. Three patients in the lovastatin group (3 of 35 [8.6%]) and 1 patient in the placebo group (1 of 19 [5%]) experienced AEs that were considered by the study investigator to be possibly, probably, or definitely related to study medication. The individual treatment-related AEs that were reported by patients in the lovastatin group included abdominal pain (2 of 35 [6%]), diarrhea (1 of 35 [3%]), nausea (1 of 35 [3%]), and headache (1 of 35 [3%]). One patient in the placebo group experienced a clinical AE of amenorrhea, which was considered by the investigator to be possibly related to treatment. In all cases, treatment-related AEs resolved spontaneously while patients continued on study medication. There was only 1 report of a laboratory AE that occurred in a patient who received lovastatin 40 mg/day. This patient experienced decreases in hematocrit and hemoglobin values on day 162 (visit 9) that were considered probably not related to study treatment. This finding was unlikely to be of any significance, given that at visit 6 (study week 12) these values were actually higher than they had been at baseline.
No patients discontinued treatment as a result of an AE (either clinical or laboratory in nature) at any point during this study. There were no deaths, serious AEs (death, life-threatening event, significant disability/incapacity, hospitalization, or any other event deemed by the investigator to be serious), or other significant AEs. No cases of myopathy or rhabdomyolysis were reported in either treatment group. There were no instances of clinically important CK elevations 5 to 10 or >10 times ULN, and no patients experienced single or consecutive elevations in liver transaminases (ALT or AST) at least 3 times ULN.
DISCUSSION
Adult women with FH clinically manifest CAD 10 years later than afflicted men. Nevertheless, the early onset of atherosclerosis in diseased women, sometimes as early as the fourth decade, highlights the need for early and aggressive treatment. Adult women with FH and clinical evidence of CAD may be more responsive to LDL cholesterol–lowering therapy than similarly affected men as assessed by regression of coronary plaques and the incidence of tendon xanthomas.32 Recently published data from a large, well-controlled, double-blind study in heterozygous children with FH using carotid intima-media thickness as a surrogate marker for atherosclerosis established that even a moderate decrease in LDL cholesterol of 24% with pravastatin induced regression of carotid intimal thickening.12 Currently, the recommended guidelines for pharmacologic treatment of children who are 10 years or older and have persistent elevations of LDL cholesterol is (1) LDL cholesterol >160 mg/dL with a family history of premature CAD or (2) an LDL cholesterol >190 mg/dL with no family history, after intervention with a diet restricted in total and saturated fat and cholesterol for 6 months.13,14 Because early intervention with statins is likely to be effective at reducing future coronary risk in young female patients with this dominantly inherited disease, aggressive intervention with a minimal goal of a LDL cholesterol <130 mg/dL and an optimal goal of <110 mg/dL13,14 is warranted.
This study examined the lipid-altering efficacy and safety profile of lovastatin 20 to 40 mg/day in adolescent girls with FH. The number of patients who participated in this study (n = 54) was necessarily small because of the rarity of FH and that it is often not diagnosed until later in life. Nevertheless, the ability of lovastatin to improve LDL cholesterol concentrations was demonstrated in this study. The mean LDL cholesterol reductions observed after treatment with lovastatin 20 mg/day and 40 mg/day ranged from –23% (week 4) to –27% (week 24). The magnitude of the LDL cholesterol reductions seen in this study was similar to that reported in previous studies that examined the effects of lovastatin 40 mg/day in adult patients of both genders with or without FH19,22,33 and in adult women without FH.21,34
In addition to its beneficial effects on LDL cholesterol, lovastatin produced significant reductions in TC and apo B compared with placebo at weeks 4 and 24. The between-group differences were greatest after treatment with lovastatin 40 mg/day. Changes in HDL cholesterol, VLDL cholesterol, and apo A-I produced by the administration of lovastatin 20 to 40 mg/day were not statistically significant. The finding that lovastatin produced borderline statistically significant changes in TG is likely related to the small sample size and high variability associated with this parameter.
Numerous studies have documented the overall favorable safety profile of statin therapy in adult women35–37; however, few have examined the effects of these drugs in adolescent girls.23 The recent study by Wiegman et al12 included 114 female children, 68 of whom were postmenarchal. In the 2-year, study the investigators reported no AEs on growth or sexual development parameters for children who were treated with pravastatin compared with those who were on placebo; however, no specific data were provided for the subset of postmenarchal girls. Because cholesterol is a precursor of the adrenal (DHEAS and cortisol) and gonadal (estradiol) hormones, statin treatment may result in decreased production of these hormones by inhibiting the rate-limiting enzyme involved in cholesterol production. Additional safety concerns in a younger female population include potential effects on pituitary hormones (LH and FSH), menstrual cycle length, and physical development (height, weight, and BMI).
There was a statistically significant (but not clinically meaningful) between-group difference in LH measurements (P = .04). The significant difference between the lovastatin and placebo groups is probably spurious as a result of the large number of laboratory safety variables analyzed without adjustment for multiplicity. Adjustments for multiplicity are not typically performed on safety variables because it reduces the test’s ability to detect significant changes. Of note, the reduction in plasma cholesterol produced by lovastatin was not accompanied by an observed decrease in LH. Furthermore, there were no detectable effects on plasma FSH, estradiol, or menstrual cycle length, supporting our conclusion that the between-group difference in LH levels was not clinically significant. The single patient who experienced a possibly drug-related endocrine AE (amenorrhea) in this study was receiving placebo treatment. Of interest, de Jongh et al23 did not report differences in LH, FSH, estradiol, or menstrual cycle length with simvastatin treatment in female adolescents. However, these investigators found that simvastatin significantly decreased DHEAS levels in both girls and boys. No differences in DHEAS levels were observed in the present study.
The 2 most common concerns with the use of statin therapy, namely critical elevations in liver (ALT and/or AST >3 times ULN) and muscle enzymes (5–10 or >10 times ULN), were not observed during this study. Furthermore, no patients developed hepatitis, myopathy, or rhabdomyolysis. However, because of the small number of patients in the study, no conclusions can be drawn concerning the differences in any AEs between groups. A larger study randomizing several hundred patients to lovastatin would be necessary to estimate accurately the incidence of AEs, but such a study is not feasible given the rarity of FH in the general population.
Although we and others did not find increases in ALT and AST with lovastatin therapy, increases in liver function tests up to 3 times ULN have been reported in several adolescents who were treated with higher doses of simvastatin (40 mg/day)23 and atorvastatin (20 mg/day).29 In addition, instances of asymptomatic increases in CK levels, although unusual, have been reported in female and male adolescents who received statin therapy.23–25 Thus, physicians should carefully monitor adolescent patients for elevations in hepatic transaminases and CK concentrations, particularly when using higher doses of lovastatin.
In summary, lovastatin at doses up to 40 mg significantly reduced LDL cholesterol, TC, and apo B concentrations and was well tolerated in adolescent girls with FH. Although the treatment of adolescent patients with FH is indicated, especially in those with a family history of premature CAD, additional studies are needed to document the long-term safety of lovastatin therapy and to determine its potential effects on the prevention of atherosclerosis and coronary events. In that regard, a recent report showed a trend toward regression of carotid intima-media thickness in FH heterozygous children who were treated with pravastatin and a trend toward progression in the placebo group.12 It is important to note that statins are contraindicated during pregnancy because of the potential risk to a developing fetus. Hence, lovastatin should be administered to adolescent girls only when they are highly unlikely to conceive.
ACKNOWLEDGMENTS
This study was supported by a grant from Merck & Co, Inc.
The Mevacor Girls Study Group (Protocol 083) consisted of the following investigators: C.A. Dujovne, MD, Overland Park, KS; C.A. Friedrich, MD, and D.J. Rader, MD, Philadelphia, PA; P. Hopkins, MD, Salt Lake City, UT; W. Insull, MD, Houston, TX; M.S. Jacobson, MD, New Hyde Park, NY; R. Knopp, MD, Seattle, WA; P.O. Kwiterovich, Jr., MD, Baltimore, MD; R. Lees, MD, Cambridge, MA; C.A. Liacouras, MD, Philadelphia, PA; M. McGowan, MD, Manchester, NH; T. Orchard, MD, Pittsburgh, PA; and E.A. Stein, MD, Cincinnati, OH.
We thank the children and parents who participated in this study. Thanks also are extended to Dr Arvind Shah, Merck & Co, Inc, for assistance with preparing the manuscript for submission.
FOOTNOTES
Accepted Dec 9, 2004.
Conflict of interest: P. Hopkins is a member of Merck Laboratories Speakers Bureau; M. Cho, A. Tate, and A. O. Johnson-Levonas are employees of Merck Company Inc.
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