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00019616-200711000-00007MiscellaneousThe EndocrinologistThe Endocrinologist© 2007 Lippincott Williams & Wilkins, Inc.17November 2007 p 315-317The Effect of Atorvastatin Treatment on Insulin Resistance, Leptin, and Highly Sensitive C-Reactive Protein in Hypercholesterolemic PatientsPreliminary StudySari, Ramazan MD; Eray, Esin MDFrom the Akdeniz University, School of Medicine, Division of Endocrinology and Metabolism, Antalya, Turkey.Reprints: Ramazan Sari, MD, Akdeniz University, School of Medicine, Department of Internal Medicine, Division of Endocrinology and Metabolism, TR-07070, Antalya, Turkey. E-mail: [email protected] or [email protected] aim of this study was to evaluate the effect of atorvastatin treatment on insulin resistance, highly sensitive C-reactive protein, and leptin levels in hypercholesterolemic patients. Forty-two hypercholesterolemic and 24 control subjects were included in this study. Serum lipids, insulin, glucose, leptin, highly sensitive C-reactive protein, and homeostasis model assessment (HOMA-IR) were determined at baseline and after 3 months' atorvastatin treatment. Only high sensitive C-reactive protein level was decreased after treatment with atorvastatin in patients with hypercholesterolemia. These findings suggest that atorvastatin may be used as a therapy for improving the plasma lipids profile, as well as the chronic low-grade inflammatory state, in hypercholesterolemia.Hypercholesterolemia is a major risk factor for atherosclerosis and its chronic complications.1 Insulin resistance with other risk factors, including dyslipidemia, obesity, and hypertension, plays an important role in the pathogenesis of atherosclerosis.2 Insulin resistance is increasingly recognized as a chronic, low-level inflammatory state.3 High-sensitivity C-reactive protein (hs-CRP) is a sensitive marker for low-grade inflammation and is associated with increased risk of atherosclerosis and cardiovascular events.4 Increased hs-CRP levels are also associated with hyperinsulinemia and hypercholesterolemia.5,6Leptin is a peptide hormone produced by adipose cells.7 Elevated plasma leptin levels have been shown to correlate with insulin resistance, hypertension, hypercholesterolemia, and obesity. In addition to its metabolic effects, leptin plays a role in the pathogenesis of atherosclerosis.8,9Statins are well-known lipid lowering agents.10 In addition to their lipid-lowering effects, they have anti-inflammatory, antioxidant, and antithrombotic effects.11 Understanding the pleiotropic effects of statins may become important in the treatment and prevention of cardiovascular disease. The effects of statins on insulin resistance, hs-CRP, and leptin levels are not well studied. We have examined the effect of short-term atorvastatin treatment on insulin resistance, hs-CRP, and leptin levels in hypercholesterolemic patients.MATERIALS AND METHODSWe recruited 42 hypercholesterolemic patients (low-density lipoprotein cholesterol >160 mg/dL) (22 male and 20 female) and 24 control subjects (13 male and 11 female). None of the participants had kidney or liver disease, type 2 diabetes, or hypothyroidism. None of the hypercholesterolemic patients were taking lipid-lowering agents. Body weight (kilograms) and height (meters) were measured with the patient in light clothes and without shoes.Venous blood was collected for lipid profile (total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglyceride), insulin, glucose, leptin, and hs-CRP levels. Atorvastatin, 20 mg per day, was given for 3 months, and the same measurements were made again. Fasting plasma insulin level was measured by immunometric assay method (Immulite 2000 Analyzer); fasting plasma glucose level was measured by enzymatic colorimetric assay method (GLU; Roche Diagnostics GmbH, Mannheim, Germany). Insulin resistance was estimated using the homeostasis model assessment (HOMA-IR), derived from the following equation [HOMA-IR = (fasting plasma glucose level × fasting plasma insulin level)/22.5]. Fasting plasma leptin levels were measured by 2-site immunoradiometric assay method (Active Human Leptin IRMA, DSL-23100). hs-CRP levels were measured by using the nephelometric method on a BNII nephelometer (Dade Behring, Germany).Statistical AnalysisStatistical analysis was done with SPSS statistical software (SPSS 10.0 for Windows, standard version). The results are presented as mean ± SD. Mann-Whitney U test and the general linear model were used to compare the groups. Wilcoxon signed ranks test was done to compare the before and after atorvastatin treatment groups. Correlation analysis was done using Spearman's test. A P value of <0.05 was considered statistically significant.RESULTSA comparison of the baseline parameters in hypercholesterolemic patients and the control group is shown in Tables 1, 2, 3, and 4. The changes in basal parameters after atorvastatin treatment in hypercholesterolemic patients are shown in Table 5. All patients completed the study for 3 months. Treatment with 20 mg atorvastatin was well tolerated. None of the common adverse events (hospitalization, muscular, renal, and hepatocellular toxicity, elevations of creatine kinase) were noted.JOURNAL/endst/04.03/00019616-200711000-00007/table1-7/v/2021-02-17T201839Z/r/image-tiff Comparison of the Baseline Parameters in Hypercholesterolemic Patients and Control GroupJOURNAL/endst/04.03/00019616-200711000-00007/table2-7/v/2021-02-17T201839Z/r/image-tiff Comparison of the Baseline Parameters in Obese Hypercholesterolemic Patients and Control GroupJOURNAL/endst/04.03/00019616-200711000-00007/table3-7/v/2021-02-17T201839Z/r/image-tiff Comparison of the Baseline Parameters in Nonobese Hypercholesterolemic Patients and Control GroupJOURNAL/endst/04.03/00019616-200711000-00007/table4-7/v/2021-02-17T201839Z/r/image-tiff Comparison of the Baseline Parameters in Obese and Nonobese Hypercholesterolemic PatientsJOURNAL/endst/04.03/00019616-200711000-00007/table5-7/v/2021-02-17T201839Z/r/image-tiff Comparison of the Baseline Parameters and After Atorvastatin Treatment in Hypercholesterolemic PatientsDISCUSSIONHypercholesterolemia is a major risk for atherosclerosis.12 A recent study shows that atherosclerosis is a chronic inflammatory process.13 C-reactive protein is a prototypic marker for inflammation and many studies showed that hs-CRP confers a risk for coronary heart disease.14,15 Insulin resistance is a prime risk factor for atherosclerosis. Recent data indicate that there is a relationship between insulin resistance and an increased acute phase response.3 We also detected a positive correlation between HOMA-IR and hs-CRP in hypercholesterolemic patients.Elevated plasma leptin levels are known to correlate with insulin resistance and other markers of the metabolic syndrome, including obesity, hypercholesterolemia, and hypertension. Furthermore, leptin may play a role in the development of atherosclerosis.8 The relationship between leptin and hs-CRP in relation to insulin resistance and atherosclerosis is more complex. The link between these parameters may be through the common pathway of obesity and inflammation.16 In this study, we confirmed that hypercholesterolemic patients have a significantly higher leptin, hs-CRP, and HOMA-IR. Because our hypercholesterolemic patients have a higher body mass index (BMI), we adjusted these values accordingly. After adjustment for BMI, there was no difference between the 2 groups.Statins are well-known lipid-lowering agents. They have not only lipid-lowering effects but also anti-inflammatory effects.17 In our study, 20 mg per day atorvastatin treatment for 3 months decreased hs-CRP levels (33%). These results confirm findings from previous studies.17,18 The anti-inflammatory mechanisms of statins are poorly understood. Statins inhibit macrophage activity and the subsequent production of cytokines, especially IL-6.19 Statins may also reduce plasma hs-CRP levels by direct inhibition of C-reactive protein production through cytokine-independent mechanisms.20The effect of statins on insulin resistance is controversial. In our study, there was no improvement in the HOMA-IR with atorvastatin treatment. Other studies have found improvement21–23 and worsening of insulin resistance.24,25Leptin, an adipokine secreted from adipose tissue, may play a role in the development of atherosclerosis. Increased food intake and insulin resistance have been shown to rapidly increase leptin levels.8 Leptin levels in hypercholesterolemic patients and the effect of statin on plasma leptin levels are poorly studied. Elevated plasma leptin levels correlate with insulin resistance and other markers of the metabolic syndrome, including obesity, hypercholesterolemia, and hypertension.8 However, after standardization for BMI and insulin resistance, leptin levels were not different in hypercholesterolemic patients in the van der Vleuten et al26 study. Zhao and Wu9 found that atorvastatin inhibited leptin release and mRNA expression and reduced leptin levels in hypercholesterolemic rabbits. In our study, elevated leptin levels in hypercholesterolemic patients were due to higher BMI, and atorvastatin treatment did not decrease the leptin levels.The limitations of our study were a relatively short study period and a small number of patients. We also used a different atorvastatin dose (20 mg) in our study.We found a significant increase in HOMA-IR, hs-CRP, and leptin levels in obese hypercholesterolemic patients. After treatment, however, only hs-CRP levels decreased. Our findings suggest that atorvastatin may be used as a therapy for improving the plasma lipids profile, as well as the chronic low-grade inflammatory state, in obesity and dyslipidemia.REFERENCES1. Jialal L, Stein D, Balis D, et al. Effect of hydroxymethyl glutaryl coenzyme a reductase inhibitor therapy on high sensitive C-reactive protein levels. Circulation. 2001;103:1933–1935.[Context Link][Full Text][CrossRef][Medline Link]2. Peters AL. The clinical implications of insulin resistance. Am J Manag Care. 2000;6:668–674.[Context Link]3. Fernandez-Real JM, Ricart W. Insulin resistance and chronic cardiovascular inflammatory syndrome. Endocr Rev. 2003;24:278–301.[Context Link][Full Text][CrossRef][Medline Link]4. Rifai N, Ridker PM. 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Atorvastatin reduces serum leptin concentrations in hypercholesteromic rabbits. Clin Chim Acta. 2005;360:133–140.[Context Link][CrossRef][Medline Link]10. Goldstein JL, Brown MS. Regulation of low density lipoprotein receptors: implications for pathogenesis and therapy of hypercholesterolemia and atherosclerosis. Circulation. 1987;76:504–507.[Context Link][Full Text][CrossRef][Medline Link]11. Davignon J. Beneficial cardiovascular pleiotropic effects of statins. Circulation. 2004;109:39–43.[Context Link][Medline Link]12. Lundbye JB, Thompson PD. Statin use in the metabolic syndrome. Curr Atheroscler Rep. 2005;7:17–21.[Context Link][CrossRef][Medline Link]13. Van Oostrom AJ, Sijmonsma TP, Verseyden C, et al. Postprandial recruitment of neutrophils may contribute to endothelial dysfunction. J Lipid Res. 2003;44:576–583.[Context Link][CrossRef][Medline Link]14. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. 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