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CLINICAL STUDIES |
From the Department of Clinical Pharmacology, University of Bonn, Germany (Ms Thelen, Dr Lütjohann); Department of Internal Medicine (Dr Päivä) and Laboratory of Atherosclerosis Genetics, Department of Clinical Chemistry, Centre for Laboratory Medicine, University Hospital of Tampere and Medical School, University of Tampere, Tampere, Finland (Dr Laaksonen, Dr Lehtimäki); and the Department of Neurology, Erasme Hospital, Free University of Brussels, Belgium (Dr Laaksonen).
Address for reprints: Dieter Lütjohann, PhD, Department of Clinical Pharmacology, University of Bonn, Sigmund-Freud-Str. 25, D-53105 Bonn, Germany; e-mail: dieter.luetjohann{at}ukb.uni-bonn.de.
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ABSTRACT |
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Key Words: Brain cholesterol • statins • lathosterol • 24S-hydroxycholesterol • 27-hydroxycholesterol
In this study, we asked whether high-dose treatment with simvastatin or atorvastatin has an influence on a surrogate marker of brain cholesterol homeostasis, 24(S)-hydroxycholesterol (24S-OH-Chol), in patients with moderately elevated plasma cholesterol levels. 24S-OH-Chol is an oxysterol, which derives exclusively from the brain in humans.6,7 Cholesterol is converted to 24S-OH-Chol by an enzyme of the cytochrome P 450 family, CYP46A1, which is mainly present in neurons.8 This oxysterol is regarded as the main elimination product of brain cholesterol. It is able to penetrate the blood-brain barrier and plays a key role in brain cholesterol homeostasis. Cholesterol itself is not able to cross the blood-brain barrier and is synthesized in situ.9 Thus, measurement of plasma 24S-OH-Chol allows us to investigate the impact of statins on brain cholesterol metabolism.
27-Hydroxycholesterol (27-OH-Chol) is another oxysterol produced by sterol 27-hydroxylase (CYP27A1), which is widely distributed in different organs and tissues. Like 24S-OH-Chol, it seems to be a regulator of cholesterol homeostasis.10 In the circulation, oxysterols are transported by lipoproteins such as cholesterol.11 Thus, the ratio of the concentrations of 24S-OH-Chol to cholesterol indicates changes in brain cholesterol metabolism, excluding the influence of statins on lipoproteins.
In a previous open-label study, aggressive simvastatin treatment led to a significant decrease of the ratio of 24S-OH-Chol to cholesterol in patients with hyperlipidemia, implicating a potential effect on brain cholesterol metabolism.12 In our present study, we compared the effect of high doses of simvastatin and atorvastatin on plasma 24S-OH-Chol and its ratio to cholesterol in a controlled trial in patients with slightly elevated plasma cholesterol levels.
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SUBJECTS AND METHODS |
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Participants
Plasma samples were taken from an earlier randomized, placebo-controlled, double-blind intervention study with simvastatin and atorvastatin.13 Forty-four subjects aged between 30 and 69 years (16 men and 18 women) were recruited from the University Hospital of Tampere and Primary Health Care Centres of neighboring municipalities of Tampere (Table I). Their average plasma total cholesterol concentration was 5.8 ± 0.9 mmol/L and plasma triglycerides below 4.5 mmol/L. The patients were instructed to adhere to their normal diet during the study. Patients with familial hypercholesterolemia and patients with plasma total cholesterol >8.0 mmol/L in the initial screening were excluded as well as women of childbearing potential. Other exclusion criteria were use of concurrent lipid-altering medication or antioxidant vitamins, renal or hepatic dysfunction, and use of medication known to affect the metabolism of atorvastatin or simvastatin. Blood was collected at baseline and after 2 weeks and 2 months of the treatment.
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Assays
Plasma Sterols
Cholesterol was determined by gas-liquid chromatography-flame ionization detection (GC-FID) and lathosterol, and the oxysterols 24S-OH-Chol and 27-OH-Chol were determined by GC-mass spectrometry (MS) as described previously.13 The variability of within-day and between-day accuracy and precision for all analytes was lower than 4% of the respective nominal and mean values, respectively. The limit of detection for the oxysterols 24S- and 27-hydroxycholesterol was 2 to 4 ng/mL.
Statistical Analyses
Statistical analyses were carried out using SPSS 12.0 for Windows (SPSS Inc, Chicago). Effect of treatment over time on plasma sterol concentrations was tested by repeated analysis of variance with age and gender as covariants (RANCOVA). The unpaired t test was performed on baseline, intermediate, and endpoint values between the placebo and the treatment groups, respectively. The 2-paired Student t test was used to compare differences between baseline and endpoint values in each group. In addition, for some variables of interest, Pearson's correlation coefficients were also calculated. Data are presented as mean ± SD unless otherwise stated. A P value of less than .05 was considered statistically significant.
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RESULTS |
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After 2 months, simvastatin (80 mg/day) and atorvastatin (40 mg/day) treatment resulted in a significant lowering of 35% (P < .001, between groups over time, RANCOVA) of total cholesterol determined by GC-FID (Table III).
The ratio of lathosterol to cholesterol, a surrogate plasma marker of endogenous cholesterol synthesis, decreased significantly by about 65% (P < .001, between groups over time, RANOVA) during statin treatment (Table IV). The full effect of the different statins on cholesterol concentrations and the lathosterol to cholesterol ratio was actually achieved after 2 weeks.
Although absolute amounts of 24S- and 27-hydroxycholesterol were decreased significantly by 30% and 28%, respectively (P < .001 for both), group-over-time changes for the ratios of 24S-OH-Chol and 27-OH-Chol revealed no significant changes (RANCOVA). Due to atorvastatin treatment, the ratio of 24S-OH-Chol to cholesterol increased by 22% (P = .009) after 2 weeks and by 14% (P < .001) after 2 months, whereas there was no change in this ratio during simvastatin treatment.
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Here, the observation that the ratio of 24S-OH-Chol to cholesterol increases during atorvastatin treatment, whereas the ratio of 27-OH-Chol to cholesterol was not affected by statin treatment, indicates that under the present conditions, brain cholesterol homeostasis is not significantly affected. Notably, 27-OH-Chol is transported by the same lipoproteins like cholesterol and 24S-OH-Chol.11 The absolute levels of 27-OH-Chol were significantly reduced in the same range as levels of 24S-OH-Chol and cholesterol. Although 27-OH-Chol is produced ubiquitously, statin treatment seems to have no effect on the formation of this cholesterol metabolite and less or even no effect on the formation of the cholesterol brain metabolite 24S-OH-Chol. This might indicate that even high doses of statins do not alter oxidative degradation of whole-body cholesterol in a distinct way. It remains questionable whether statins have an impact on brain cholesterol metabolism.
Animal studies with high doses of statins support the theory that statins do decrease cholesterol levels in the cortical part of the brain15 or decrease whole-brain cholesterol synthesis.16 Because cholesterol has been linked to AD pathology,17,18 it is of interest to investigate the benefit of statin administration in prospective studies to confirm results from retrospective studies.1-3 Nevertheless, there are also studies that do not support a beneficial effect of statin therapy for patients with AD,19,20 and there have even been reports of cognitive impairment and memory loss in the context with chronic statin intake.21,22
The present results suggest that atorvastatin (40 mg) and simvastatin (80 mg) do have a slightly different effect on the brain cholesterol metabolism, at least in the short term. It is important to evaluate whether this difference is visible also during continuous treatment because it may affect the efficiency of these compounds in the treatment and prevention of AD, and it may also cause differences in the longterm safety profile.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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REFERENCES |
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