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Comparison of the Effects of Pravastatin and Lovastatin On Comparison of the Effects of Pravastatin and Lovastatin on Sleep Disturbance in Hypercholesterolemic Subjects Downloaded from https://academic.oup.com/sleep/article/22/1/117/2731686 by guest on 29 September 2021 Bruce L. Ehrenberg,1 Stefania Lamon-Fava,3 Kate E. Corbett,1 Judith R. McNamara,3 Gerard E. Dallal,4 and Ernst J. Schaefer2,3 (1) Department of Neurology and the (2) Division of Endocrinology, Diabetes, Metabolism, and Molecular Medicine†, New England Medical Center, Boston, Mass; (3) the Lipid Metabolism Laboratory and (4) Division of Biostatistics, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Mass Summary: We have studied the effects of two cholesterol-lowering medications, lovastatin and pravastatin, on different sleep parameters in hypercholesterolemic subjects. These medications are 3-hydroxy-methylglutaryl coenzyme A inhibitors. Only subjects who had complained of sleep disturbance while on previous treatment with lovastatin were enrolled. Sixteen subjects (11 men and 5 women) underwent a randomized, double-blind, three-way crossover treatment with lovastatin, pravastatin, and placebo. Each phase of the study lasted 4 weeks. A placebo wash-out period of 4 weeks separated each treatment phase. At the end of each treatment phase, subjects were admitted to the sleep laboratory for 2 consecutive nights. No statistical differences were detected during treatment with lovastatin, pravastatin, and placebo for sleep parame- ters such as total sleep time, total awake time, wake time after sleep onset, efficiency of sleep, and percent of different phas- es of sleep. Our study suggests that lovastatin and pravastatin do not have a significant effect on sleep parameters in hyper- cholesterolemic subjects that could explain their complaints of insomnia. Nevertheless, the subjects did have moderate sleep disturbances that could account for insomnia and most likely predate the use of HMG-CoA reductase inhibitors. Key words: Hydroxy-methylglutaryl coenzyme A; lovastatin; pravastatin; hypercholesterolemia HYDROXY-METHYLGLUTARYL coenzyme A (HMG- has not been detected in cerebrospinal fluid.4 It has also CoA) reductase is a key enzyme in the early steps of the been shown that the rate of transport of lovastatin in extra- intracellular synthesis of cholesterol. Inhibitors of this hepatic cells is 100-fold greater than that of pravastatin.5 enzyme have been developed and have become the most Some studies have indicated that treatment with lovas- widely used medications in the treatment of elevated plas- tatin may be associated with increased wake time after ma cholesterol levels, or hypercholesterolemia.1 Lovastatin sleep onset6 or with impaired daytime performance7 when (Mevacor®) and pravastatin (Pravachol®) belong to this compared to pravastatin. It has been hypothesized that group of medications. The chemical composition of lovas- these effects of lovastatin may be caused by its lipophilici- tatin differs slightly from that of pravastatin due to the pres- ty and a direct action in the central nervous system. ence of a methyl instead of a hydroxyl group side chain.2,3 The purpose of this study was to test the hypothesis This difference, though small, is sufficient to confer differ- that lovastatin and pravastatin differ in their effect on sev- ent physico-chemical characteristics to these molecules: eral sleep parameters in a group of hypercholesterolemic lovastatin is lipophilic and has been shown to cross the men and women who had previously complained of sleep blood-brain barrier, while pravastatin is hydrophilic and disturbance while on lovastatin. METHODS Accepted for publication August, 1998 Subjects Address correspondence and requests for reprints to Bruce L. Ehrenberg, MD, Department of Neurology, New England Medical Center, 750 Washington Subjects were recruited from a population of patients Street, Box #4, Boston, MA 02111 attending our Lipid Clinic and being treated with lovas- SLEEP, Vol. 22, No. 1, 1999 117 Lovastatin and pravastatin in sleep—Ehrenberg et al tatin. Subjects were asked to complete a 13-question sleep questionnaire.8 We only recruited subjects who had three or Table 1.—Design of the randomized, crossover, placebo-controlled more of the following complaints on at least 3 nights per trial of the effect of lovastatin and pravastatin on sleep disturbances. week while taking lovastatin for over 30 days: 1) sleep onset latency equal to or greater than 30 minutes; 2) five or Treatment phase more nocturnal awakenings lasting more than 1 minute, or subjective total wake time after sleep onset of 30 minutes 1 2 3 or more; 3) awakening 30 minutes or more before desired Sequence n wake-up time; 4) sleeping less than 6 hours per night; or 5) 1 Placebo Lovastatin Pravastatin 1 daytime fatigue 2-3 hours after wake-up time. A total of 20 2 Placebo Pravastatin Lovastatin 2 subjects were recruited. Three subjects were removed from 3 Lovastatin Placebo Pravastatin 4 the study prior to completion—one for developing chest 4 Lovastatin Pravastatin Placebo 3 5 Pravastatin Placebo Lovastatin 3 pain and skin rash before the randomization phase of the Downloaded from https://academic.oup.com/sleep/article/22/1/117/2731686 by guest on 29 September 2021 study, and two because of poor compliance. In addition, at 6 Pravastatin Lovastatin Placebo 3 the end of the study one subject admitted to taking pre- scribed sleep medications (benzodiazepine) throughout the study period. While inclusion of this subject’s data did not change the results, results are presented for the 16 remain- Myers Squibb Pharmaceutical Research Institute. Also, ing subjects only. All subjects had elevated blood choles- subjects were told not to take medications such as steroids, terol levels (>240 mg/dl), and six subjects had triglyceride other hypolipidemic drugs, anticoagulants, theophylline, levels >250 mg/dl. Subjects who had recently experienced barbiturates or other hypnotics, anxiolytics, and aluminum- a myocardial infarction, or had homozygous familial containing anti-acids during the study. hypercholesterolemia, non-type-II hyperlipoproteinemia, dysproteinemia, hypertension (>160/100 mm Hg), obesity Sleep Measurements (body weight >40% above ideal weight), diabetes mellitus, At the end of the placebo lead-in phase and each treat- and thyroid, kidney, or liver disease were excluded from ment phase (lovastatin, pravastatin, and placebo), subjects the study. Eleven of the 16 subjects were men, with a mean were admitted to the sleep laboratory and polysomno- age of 53.8±11.5 years, and 5 were women, all post- graphic evaluations (EEG, EOG, EKG, EMG, and four res- menopausal, with a mean age of 57.4±11.3 years. piratory monitors) on 2 consecutive nights were performed. Briefly, polysomnograms were recorded using Nihon- Study Design Kohdon EEG amplifiers connected to a Telefactor semi- Subjects were stabilized on a reduced-fat, reduced- automatic sleep scoring system. The data from each night cholesterol diet (<30% of energy as total fat, <7% as satu- were scored by direct visual analysis of each 30-second rated fat, and <200 mg/day of cholesterol) prior to entry epoch of data visualized on the reformatter’s TV screen or into the study, and were asked to follow this diet through- on tape backups. Measurements included: total sleep time out the study. The study consisted of six distinct phases, (TST), sleep efficiency (total sleep time/total time in bed, each lasting 4 weeks, for a total of 24 weeks. After an ini- or EFF), amount of wake time after sleep onset (WASO), tial single-blind period of 4 weeks during which subjects stage 1 sleep (S1), stage 2 sleep (S2), stages 3-4 sleep were given placebo tablets matching the lovastatin and (SWS), rapid eye movement (REM), irregular respiratory pravastatin tablets to establish their compliance to the reg- sleep events of apnea or hypopnea (APN), periodic leg imen, subjects were randomized in a double-blind, three- movements without arousal (PLM), periodic leg move- way crossover protocol to treatment with lovastatin, ments with arousal (PLMA), and arousals unrelated to APN pravastatin, and placebo. The dose for each study drug was or PLM (AR). In addition, we calculated the following 40 mg, given in one of three ways: 1) one active lovastatin indexes: tablet at dinner and one pravastatin-matching placebo periodic movement index (or PMI) = (PLM+PLMA)/TST tablet at bedtime; 2) one lovastatin-matching placebo tablet apnea/hypopnea index (or AHI) = APN/TST total arousal index (or TAI) = (PLMA+AR+APN)/TST. at dinner and one active pravastatin tablet at bedtime; or 3) We consider the PMI normal if lower than 10/hour, the AHI appropriate matching placebos at dinner and at bedtime. normal if lower than 5/hour, and the TAI normal if lower Each of these treatment phases lasted 4 weeks and was sep- than 5/hour. arated from the following treatment phase by an additional 4-week placebo “washout” period. The sequence of these Laboratory Measurements randomized treatments is shown in Table 1. All medication and matching placebo tablets were provided by the Bristol- Blood was drawn from each subject at the end of each SLEEP, Vol. 22, No. 1, 1999 118 Lovastatin and pravastatin in sleep—Ehrenberg et al Table 2.—Effects of lovastatin and pravastatin on sleep measurements (n=16) Placebo Lovastatin Pravastatin F P Minimum Minimum significant significant ratio difference mean+SD mean+SD mean+SD TST (h) 6.2+0.8 6.4+0.6 6.3+0.8 0.98 0.38 0.40 AW (h) 0.68+0.60 0.64+0.59 0.79+0.67 1.72 0.19 1.35
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