© 1995 American Heart Association, Inc.
Articles |
A Prospective, Randomized Trial of Phenytoin in Nonepileptic Subjects With Reduced HDL Cholesterol
From the University of Maryland Medical System, Baltimore (M.M., R.G.B.), and the University of Alabama at Birmingham (L.O., J.P.S., D.W.G.).
Correspondence to David W. Garber, PhD, University of Alabama at Birmingham, DREB Room 630, Birmingham, AL 35294-0012.
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Abstract |
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Abstract Observational studies have demonstrated a positive association between phenytoin use and HDL cholesterol (HDL-C). Our goal was to determine whether phenytoin raises HDL-C in nonepileptic subjects at risk for coronary artery disease. We performed a double-blind, placebo-controlled, parallel-group study in 41 subjects with reduced levels of HDL-C. Subjects were placed on an American Heart Association Step I diet and were randomized to receive either phenytoin or placebo for 3 months. Serum levels of phenytoin were monitored and adjusted to between 7.5 and 15 µg/mL. Fasting levels of lipids and lipoproteins were determined twice at baseline (weeks -2 and -1) and during the treatment phase of the study (weeks 11 and 12). Compared with dietary baseline, phenytoin-treated subjects experienced significant paired percent increases in total HDL-C (12.4%; P<.01), an effect confined to the HDL2 subfraction (137%; P<.01). The paired percent increases in HDL-C and HDL2 levels remained significant after adjustment for placebo (P<.05, P<.025, respectively). There were no significant differences in the paired percent changes from dietary baseline in total cholesterol, triglyceride, or LDL cholesterol levels between placebo and phenytoin-treated groups. The significant paired percent increases in total HDL-C and HDL2 from dietary baseline suggest a potential role for phenytoin in subjects with reduced levels of HDL-C.
Key Words: cholesterol • phenytoin • humans • HDL
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Introduction |
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Epidemiological studies have convincingly demonstrated an inverse association between HDL-C and CAD.1 These observations were extended in a randomized, controlled, intervention trial that demonstrated that a 1% increase in HDL-C corresponded to a 3% reduction in CAD event rate.2 Unfortunately, conservative measures (eg, smoking cessation, aerobic exercise) may only raise HDL-C modestly,3 4 and the pharmaceutical armamentarium is limited.5 6 The antiseizure medication phenytoin has spawned interest because the associated HDL-C–raising effect7 8 has been invoked as a contributor to the low cardiovascular mortality observed in epileptic patients.9 However, limited information is available regarding the efficacy of phenytoin in nonepileptic subjects with reduced HDL-C. A prospective study was therefore designed to evaluate this effect in association with CAD or cardiovascular risk factors.
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Methods |
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Study Population and Entry Criteria
Men and women (either surgically sterile or 2-year postmenopausal) between the ages of 21 and 70 years were eligible. The following mean fasting lipid and lipoprotein levels were used as entry criteria: HDL-C
1.03 mmol/L (40 mg/dL), TG 4.5 mmol/L (400 mg/dL),
and LDL-C 4.9 mmol/L (190 mg/dL) without CAD or risk factors for CAD
or LDL-C 4.1 mmol/L (160 mg/dL) with preexisting CAD or with at
least one risk factor for CAD.10 Subjects with unstable
angina, insulin-dependent diabetes mellitus, uncontrolled
hypertension (systolic pressure 
160 mm Hg and/or
diastolic pressure 100 mm Hg on two successive visits),
thyroid disease, hepatic disease (serum transaminases or total
bilirubin greater than the upper limit of the laboratory reference
range), renal disease (serum creatinine 2 mg/dL),
obesity, hypersensitivity to phenytoin or other hydantoins were
excluded. Subjects were also excluded if they were concurrently
receiving lipid-regulating medications, immunosuppressive agents,
oral contraceptives, hormone replacement therapy, ß-blockers,
thiazide diuretics, isotretinoin, or antiseizure medications.
The study was approved by the Institutional Review Boards at the
University of Maryland Hospital and the University of Alabama at
Birmingham.
Study Design
The experimental design is displayed in Table 1
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The study phases included screening, baseline (eg, dietary
equilibration), and blinded therapy. Fasting blood was sampled during
screening for eligibility consideration and twice subsequently during
the 2-week baseline phase. All participants were provided nutritional
instruction in accordance with the American Heart Association Step I
diet.10 If qualifying lipids were obtained (based on the
mean values of weeks -2 and -1), subjects were randomized
to receive either study medication or phenytoin. Randomization
schedules were provided by the study sponsor and were made available
only to an unblinded observer at each study site. To preserve blinding,
all subjects received 5 capsules daily during the baseline and
double-blind study periods (see below).
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Study Medication
Medication for the baseline period consisted of placebo capsules
identical in appearance to the phenytoin capsules. After randomization,
all subjects were asked to take 1 capsule in the morning and 4 capsules
in the evening, irrespective of whether placebo or medication was
assigned. Medication supplied for blinded therapy consisted of
phenytoin capsules at doses of 30, 60, or 100 mg.
Phenytoin-assigned subjects initiated therapy with a 100-mg capsule
in the morning and a combination of various doses in the evening, for a
total dose of 300 mg/d. Blood levels of phenytoin monitored by an
independent observer were maintained between 7.5 and 15 µg/mL. When
phenytoin levels were outside this range, the regimen was modified by
the observer and levels were rechecked at the next scheduled visit.
While the 100-mg morning capsule remained constant throughout the
study, the evening dose varied from 100 to 300 mg. Phenytoin levels
were also monitored in placebo subjects to confirm that serum
concentrations were <2.5 µg/mL.
Compliance was assessed by requesting that the subjects return any unused pills and by measurement of blood phenytoin levels.
Laboratory Assessment
After a 12-hour overnight fast, venous blood was collected and
submitted for hematology (including complete white blood cell count and
differential) and chemistry analysis. The chemistry
parameters included aspartate aminotransferase (AST),
-glutamyltransferase (GGT), alkaline phosphatase, lactate
dehydrogenase, albumin, bilirubin, and plasma TG levels. TG
analyses for both sites were performed by the University of Alabama
hospital clinical laboratory. All other chemistry tests were performed
by the hospital clinical laboratories at the respective sites.
Lipoprotein cholesterol analysis was performed at the University of Alabama Lipoprotein Core Facility and, in the latter part of the study, by Atherotech Inc (Birmingham, Ala). The methodology, personnel, and equipment were the same at both sites. Direct measurements of TC, VLDL-C, IDL-C, LDL-R, HDL-C with fractionation of subclasses, and Lp(a)-C were performed by using the VAP method.11 The Lipoprotein Core Facility and Atherotech Inc are certified by the US Public Health Service under the Clinical Laboratory Improvement Amendments (CLIA) program. The VAP method separates Lp(a) and IDL-C from true LDL-C; as a result, LDL-R levels are lower than when measurements are performed with other methods (eg, ß-quantitation). A recent analysis of control repeats in separate rotors (n=12) demonstrated coefficients of variation of TC, 3.2%; VLDL-C, 10.9%; LDL-R, 6.7%; and HDL-C, 6.6%.
Safety Assessments and Medication Compliance
At each visit, all adverse events were reported. Weight, blood
pressure, and heart rate were recorded at each visit. Physical
examinations and electrocardiograms were performed at
baseline and during blinded therapy. Compliance to medication was
monitored by subtracting the difference between the number of tablets
prescribed for the specified interval and the number returned during
the subsequent visit.
Statistical Analysis
The change in HDL-C from baseline to completion of the
blinded-therapy phase was the primary efficacy
parameter. Changes in TC, VLDL-C, IDL-C, LDL-R, Lp(a)-C,
and TG were the secondary efficacy parameters. The mean of
two fasting samples obtained at weeks 11 and 12 during placebo or
phenytoin administration and two baseline measurements were used for
paired two-tailed t tests. For comparisons between the
groups, a paired two-tailed, two-sample t test was
used. The designated level of significance was P<.05.
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Results |
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Forty-one subjects (21 and 20 at the Baltimore and Birmingham sites, respectively) were randomized, and 39 subjects completed the study. One subject dropped out after developing a nonspecific rash; he was receiving placebo. A second subject fractured his femur and could not maintain the scheduled appointments. Of the 39 subjects completing the study, there were 2 women and 2 blacks.
Table 2 provides mean lipid and lipoprotein levels and
selected clinical characteristics of the 39 participants at baseline.
Six subjects had a history of CAD and 19 had a family history of
premature CAD (eg, first-degree relative with CAD <55 years).
Measurements of TC, VLDL-C, IDL-C, LDL-R, Lp(a)-C, and TG are
summarized in Fig 1. Compared with dietary baseline,
phenytoin-treated subjects experienced small but statistically
insignificant increases in TC, VLDL-C, and Lp(a)-C. A significant
increase was observed in total HDL-C (Fig 2) in the
phenytoin group compared with the placebo group at week 11
(P<.05) and remained significant when weeks 11 and 12 were
combined. The HDL2 subfraction was significantly
higher in the phenytoin group compared with the placebo group. While
not observed during the first month of therapy, this effect became
evident during the third month of therapy. HDL3 was not
significantly different between the groups at any time point. No
significant differences in TG were seen between the groups (Fig 3).
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In paired t test analysis, lipoprotein values were
averaged at weeks -2 and -1 (dietary baseline) and at weeks
11 and 12 (completion of blinded therapy) for each subject, and percent
changes were determined for each lipoprotein fraction. The paired
comparisons are presented in Table 3. There were
no significant paired percent changes in the placebo group; in the
phenytoin- treated subjects, TC, IDL-C, HDL-C, and
HDL2 levels were significantly increased at the
completion of blinded therapy compared with the dietary baseline. After
adjustment for placebo, however, the only paired percent increases that
remained significant among phenytoin-treated subjects were HDL-C
(P<.05) and HDL2
(P<.025).
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Phenytoin was well tolerated and no significant side effects were reported. No alterations were detected in complete blood counts, results of blood chemistry tests, or coagulation indexes during drug treatment. The compliance rates for drug treatment and placebo were 97% and 98%, respectively. Participants receiving phenytoin were closely monitored to maintain serum levels between 7.5 and 15 µg/mL. This range was successfully maintained in all study patients, except in one female subject who maintained low blood phenytoin levels throughout the study, despite upward adjustments in her phenytoin dosage. No correlations were observed between paired changes in lipoprotein cholesterol levels or phenytoin blood levels at weeks 11 and 12. Similarly, no correlation was found between lipoprotein changes and body mass index.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Reduction in CAD mortality reported in epileptics9 has been attributable in part to an elevation in HDL-C.7 8 To explore the effect of phenytoin in nonepileptic subjects with reduced HDL-C, 39 subjects completed a randomized double-blind, placebo-controlled study. Significant elevations in HDL-C were observed during phenytoin administration. To our knowledge, this represents the first controlled trial testing the efficacy of phenytoin in nonepileptic subjects with low HDL-C. Of particular interest was the finding that the increase was predominantly confined to the HDL2 subfraction. Among the 21 subjects assigned to phenytoin, only 3 subjects did not have an increase in the HDL2 subfraction compared with dietary baseline. The lack of a correlation between serum phenytoin levels and changes in HDL2 may have reflected the narrow range maintained due to rigorous control inherent in phenytoin dosage and blood levels. Noncompliance was a consideration in 1 female subject receiving phenytoin who maintained subtherapeutic levels of the medication throughout the treatment phase. However, increases in HDL-C and HDL2 observed in this subject were comparable to the mean within the phenytoin-treated group. The 12.4% increase in the HDL-C occurred during a relatively short period of treatment (3 months). With longer duration of phenytoin use, HDL-C increases of nearly 30% have been reported.12
Previous studies have affirmed that subjects with elevated HDL2 (eg, women, marathon runners)13 14 are at reduced risk of CAD. Conversely, reduced HDL2 coincides with primary isolated low HDL-C, a disorder characterized by an increased risk of CAD.15 Observational studies assessing the relative importance of HDL-C subfractions vis-à-vis coronary risk have yielded divergent outcomes.16 17 18 Sweetnam et al18 hypothesized that when a higher proportion of total HDL-C resided within HDL2 (ie, >35%), then this subfraction appeared to be more important than HDL3 as a predictor of CAD. That significant elevations in HDL2 occurred in subjects with low levels at baseline in the present study raises the possibility that phenytoin may have potential clinical utility in this high-risk subgroup. Unfortunately, despite the plethora of observational studies, there are no randomized clinical trials assessing the relative importance of HDL-C subfractions.
There are several potential mechanisms for the increases in HDL-C observed in the present study. Because phenytoin is an inducer of cytochrome P-450, the most elaborate hepatic microsomal protein,19 there is enhanced synthesis of apolipoprotein A-I, the primary apolipoprotein of HDL-C.15 Other microsomal inducers have also been reported to raise HDL-C.7 20 21 A second mechanism may reflect phenytoin-mediated inhibition of hepatic lipase, an enzyme that actively degrades HDL2 in hepatocytes.22 Hepatic lipase inhibitors such as estrogenic compounds enhance HDL2 by this mechanism, while androgenic compounds and progestational agents produce the opposite effect.13 Another plausible mechanism of HDL-C enhancement is via stimulation of lecithin–cholesterol acyl transferase activity, an important enzyme regulating HDL-C metabolism.23 Finally, stimulation of lipoprotein lipase activity augments release and transfer of surface components from triglyceride-rich lipoproteins (eg, chylomicrons, VLDL-C) to form HDL2 particles.24 However, with lipoprotein lipase stimulation, reduction, rather than elevation in TG, would have been anticipated.
We are aware of only one published trial that tested the efficacy of
low-dose phenytoin in nonepileptic subjects.25 Both
the doses (30 and 100 mg/d) and duration (1 month) were considerably
lower than in the present study, and no effect on HDL-C was
observed. As seen in Fig 2
, the rise in HDL-C did not
begin until after week 4. Whether the very low doses employed by
McKenney et al25 would have resulted in significant
increases in HDL-C had their study duration been lengthened cannot be
determined. However, the dose of phenytoin used in the present
study to maintain a level within a low therapeutic range (as defined
for anticonvulsant use) was well tolerated. The relatively short
duration of medication (3 months) does not preclude the possibility
that side effects observed with chronic use (eg, gingival hyperplasia)
might occur; however, these effects are usually observed with higher
phenytoin dosages.26 Similarly, cognitive
disturbances are uncommon when low serum concentrations
are maintained.27 Whether chronic maintenance of
low doses of phenytoin (as employed in the present study) minimizes
the possibility of these side effects requires further study.
Recommendations for using phenytoin as an HDL-C–raising agent must be limited at the present time until some of the aforementioned issues can be adequately addressed. Currently, the National Cholesterol Education Program recommends LDL-C lowering as the primary intervention in subjects with dyslipidemia.3 The results obtained in the present study, however, suggest that phenytoin may be useful as adjunctive therapy in patients with low HDL-C not adequately responsive to other recommended lipid-altering therapies. Alternatively, phenytoin may be considered in CAD patients with reduced HDL-C and desirable TC,28 in whom the risk of recurrent cardiovascular events is doubled.29 Prospective studies addressing the safety and long-term efficacy (eg, reduction in CAD events) of phenytoin will determine its future role in the management of low HDL-C.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by National Institutes of Health Preventive Cardiology Academic Award KO7-HL-02263-03 (Dr Miller) and a grant from Parke-Davis, division of Warner Lambert Inc.
Received August 9, 1995; accepted October 10, 1995.
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