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Statin Therapy Has No Significant Effect on Skin Tissue Cholesterol: Results From a Prospective Randomized Trial

Posted on: Sunday, 9 January 2005, 03:00 CST

Large-scale clinical trials have conclusively demonstrated that lowering serum cholesterol concentrations with statins slows the progression of atherosclerosis and promotes the regression and stabilization of atherosclerotic plaques, thus substantially reducing the rates of major vascular events among a wide range of patients (1-3).

Skin cholesterol (SkC) has previously been reported to be an additional independent marker of cardiovascular risk (4-8). The skin test is a quantitative interpretation of extracellular epidermal lipids, which are supplied from the circulation by a complex transport mechanism through dermal blood microcapillaries, the endothelial wall, the uppermost layers of the dermis, and the basement membrane, finally reaching the cells of the basal stratum (9). Thus, lipid-lowering therapy might also have an effect on epidermal lipid content.

Despite the growing interest in this potential new marker of cardiovascular risk, no study has investigated the effects of statins on SkC concentrations. One aim of the present study was to assess the natural midterm course of SkC concentrations prospectively. In addition, we evaluated the potential influence of statin therapy on SkC concentrations as well as potential differences between atorvastatin and simvastatin in a prospective randomized controlled trial.

Consecutive outpatients referred to the department of angiology of a tertiary care university hospital because of suspected vascular disease were eligible for the present prospective trial. Exclusion criteria included (a) current lipid-lowering therapy or lipid- lowering therapy within the last year; (b) age <18 years; (c) pregnancy; (d) psoriasis or eczema on either hand; (e) recent use (within 24 h before testing) of topical medication, as a cream or lotion, on either hand; (f) chronic liver disease or evidence of abnormal liver function (defined as an increase of transaminase activity two times above the upper reference limit of the central laboratory); (g) inflammatory muscle disease and/or an unexplained increase of creatine kinase activity three times above the upper reference limit; (h) conditions that might lead to an incomplete follow-up (i.e., life expectation <6 months); or (i) known incompatibility or allergy against statins. The study protocol was approved by the local ethics committee, and written informed consent was obtained from all patients.

At baseline and 6 weeks and 6 months after start of the study, blood samples were obtained for the determination of total plasma cholesterol (TC), serum LDL- and HDL-cholesterol (LDL-C and HDL-C), triglyceride (TGs), glucose, glycosylated hemoglobin A^sub 1c^, γ-glutamyltransferase, aspartate aminotransferase, alanine aminotransferase, and creatine kinase. SkC concentrations were also measured at baseline and at both follow-up visits by the Cholesterol 1,2,3(TM) Test (IMI International Medical Innovations Inc.) (6-8). A previous study reported a within-day imprecision (CV) of 11% and a between-day imprecision of 7% for the skin test (6). In the prestudy phase, we observed a within-day imprecision of 3.8% and a between- day imprecision of 8.6% for the right hand and 4.3% for the left hand, respectively.

The study cohort was then divided into controls (group 1) and patients requiring lipid-lowering therapy (group 2) according to the guidelines of the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III), which identifies three categories of risk (2, 10): (a) a LDL-C goal of <1000 mg/L for patients with the highest risk (coronary heart disease or coronary heart disease risk equivalents such as peripheral arterial disease, abdominal aortic aneurysm, symptomatic carotid artery disease, or diabetes mellitus); (b) a LDL-C goal of <1300 mg/L for patients with two or more cardiovascular risk factors; and (c) a LDL-C concentration of <1600 mg/L for patients with no or one risk factor. According to the literature, 40 mg of simvastatin and 20 mg of atorvastatin have similar potential in lowering serum lipids (11). Consequently, group 2 was randomly allocated according to a computer-generated randomization list to group 2a [20 mg of atorvastatin once daily (Sortis; Pfizer) or group 2b (40 mg of simvastatin once daily (Zocord; Merck, Sharp & Dohme B.V.).

Between January and April 2003, a total of 129 patients [69 men (54%) and 60 women (46%); mean (SD) age, 63.4 (12.3) years] fulfilled all study criteria and were included in the present trial and assessed at all three visits. Of these, 56 patients had diabetes mellitus (43%), 50 currently smoked cigarettes (38%), and 79 had arterial hypertension (61%). According to the randomization criteria, 44 patients (34%) had serum lipid concentrations within the reference interval and therefore served as the control group (group 1). Increased lipid concentrations required adequate treatment in the remaining 85 patients (66%). These were randomized to either atorvastatin [group 2a; 42 patients (33%)] or simvastatin [group 2b; 43 patients (33%)] treatment (2). The control and treatment groups differed significantly regarding age [60.1 (13.6) years for group 1 vs 65.1 (11.2) years for group 2; P = 0.027], whereas there were no significant differences for gender, body mass index, diabetes mellitus, current cigarette smoking, and arterial hypertension (all P >0.05). The groups differed significantly for the baseline lipids: TC, 1922 (338) vs 2484 (445) mg/L (P <0.001); LDL-C, 1041 (297) vs 1541 (391) mg/L (P <0.001); TGs, 1397 (524) vs 1804 (1034) mg/L (P = 0.016). There was no significant difference between groups for HDL-C and SkC (all P >0.05).

Table 1. Course of all investigated variables according to treatment groups.a

Fig. 1. Changes in SkC (A) and TC (B) during the 6-month study period. *, group 1 (control group); [black square], group 2a (atorvastatin); [black triangle up], group 2b (simvastatin).

The natural course of the investigated variables, as assessed in the control group, revealed a significant decrease (14.4%) in SkC from visit 2 to visit 3 (P <0.001) and a significant increase (6.7%) in LDL (P = 0.049). We observed no other significant changes concerning all investigated variables between the baseline assessment and follow-up visits (all P >0.05; Table 1 and Fig. 1).

We then analyzed the mean relative changes in the investigated variables at visits 2 and 3. Compared with baseline concentrations, we detected a significant difference in SkC concentrations for group 1 [3.2 (3.3)%] vs group 2 [-4.2 (26.7)%] after 6 weeks (P = 0.027) with no additional significant difference after 6 months (P >0.05). As expected, we observed a significant difference between groups 1 and 2 concerning the relative changes in serum lipids. We observed significant decreases in TC, LDL-C, and TG concentrations (each P <0.01 after 6 weeks and 6 months), respectively, in the statin groups, whereas there were no relative changes in HDL-C concentrations (P >0.05). There was no statistically significant difference between groups 2a and 2b in lowering SkC (12.1% vs 18.5%; P >0.05) or serum lipid concentrations (all P >0.05).

In review, the present study evaluated for the first time the natural course of SkC by follow-ups for 6 months. Compared with baseline values, SkC increased by 3% after 6 weeks and decreased after 6 months by 12%. These results suggest a significant fluctuation in SkC concentrations, which has also been observed by Zawydiwski et al. (6), who investigated 10 individuals and reported a within-day imprecision of 11% and a between-day imprecision of 7%. A substantial natural variation in SkC concentrations must therefore be considered in interpretation of the results of this novel test (7, 8).

This is the first trial investigating a potential effect of statin therapy on SkC. In the treatment groups, SkC concentrations decreased by 12% and 19%, respectively, during the follow-up period compared with baseline values. However, we also observed a 12% decrease in SkC in patients not receiving lipid-lowering treatment. A substantial effect on statins of SkC is therefore unlikely or is masked by natural fluctuations in SkC.

The similar changes in SkC concentrations in the control and treatment groups should be analyzed more precisely. Potential explanations include inappropriate drug intake as well as technical failures in test performance. The hypothesis of noncompliance with drug intake in the statin groups can be dismissed in light of the significant decrease in serum lipid concentrations (~30%). Technical failure in the execution of the skin test is also not a probable explanation because the mean (SD) SkC concentrations in our study are comparable to previously published data (6-8). Another potential explanation might be the effect of seasonal variation, but a significant effect seems unlikely, especially if we consider that SkC fluctuations of 11%, even within 1 day, have been reported and that comparable natural fluctuations of 12% were observed in the present study over the total study period of 9 months (6). Nevertheless, based on our present study design, we cannot completely exclude the hypothesis of an additional seasonal influenceon SkC.

In summary, SkC concentrations exhibit significant biological fluctuations, and statin therapy leads to comparable decreases in SkC concentrations.

We thank IMI International Medical Innovations Inc. (Toronto, Canada) for providing the tests.

References

1. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo- controlled trial. Lancet 2002;360:7-22.

2. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): final report. Circulation 2002;106:3143-421.

3. Steinberg D. Atherogenesis in perspective: hypercholesterolemia and inflammation as partners in crime. Nat Med 2002;8:1211-7.

4. De Graeve J, Bouissou H, Thiers JC, Fouet J, Valdiguie P. Is cutaneous apoprotein B a better discriminator than serum lipoproteins for atherosclerosis? Atherosclerosis 1984;52:301-7.

5. Bouissou H, De Graeve J, Solera ML, Thiers JC, Bouissou P, Puel J, et al. Cutaneous cholesterol in the young and aged coronary patient. Arch Mal Coeur Vaiss 1982;75:621-6.

6. Zawydiwski R, Sprecher DL, Evelegh M, Horsewood P, Carte C, Patterson M. A novel test for the measurement of skin cholesterol. Clin Chem 2001;47: 1302-4.

7. Sprecher DL, Goodman SG, Kannampuzha P, Pearce GL, Langer A. Skin tissue cholesterol (SkinTc) is related to angiographically- defined cardiovascular disease. Atherosclerosis 2003;171:255-8.

8. Mancini GBJ, Chan S, Frohlich J, Kuramoto L, Schulzer M, Abbott D. Association of skin cholesterol content, measured by a non- invasive method, with markers of inflammation and Framingham risk prediction. Am J Cardiol 2002;89:1313-6.

9. Lopukhin YM. The skin and atherosclerosis (a three drop test). Physicochem Asp Med Rev 1992;3:1-124.

10. Warnick GR, Myers GL, Cooper GR, Rifai N. Impact of the third cholesterol report from the Adult Treatment Panel of the National Cholesterol Education Program on the clinical laboratory. Clin Chem 2002;48:11-7.

11. Jones P, Kafonek S, Laurora I, Hunninghake D. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study). Am J Cardiol 1998;81:582-7.

DOI: 10.1373/clinchem.2004.038737

Markus Reiter,* Susan Wirth, Ali Pourazim, Mehrdad Baghestanian, Erich Minar, and Robert A. Bucek (Clinic for Internal Medicine II, Department of Angiology, University of Vienna, Whringer Grtel 18- 20, A-1090 Vienna, Austria; * author for correspondence: fax 43-1- 40400-4665, e-mail markus.reiter@akh-wien.ac.at)

Copyright American Association for Clinical Chemistry Jan 2005

Source: Clinical Chemistry

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