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The effects of improved metabolic risk factors on bone turnover markers after 12 weeks of simvastatin treatment with or without exercise.
Jiang, J, Boyle, LJ, Mikus, CR, Oberlin, DJ, Fletcher, JA, Thyfault, JP, Hinton, PS
Metabolism: clinical and experimental. 2014;(11):1398-408
Abstract
OBJECTIVE Emerging evidence supports an association between metabolic risk factors and bone turnover. Statins and exercise independently improve metabolic risk factors; however whether improvements in metabolic risk factor affects bone turnover is unknown. The purpose of the present study was to: 1) evaluate the relationship between metabolic risk factors and bone turnover; and 2) determine if improvements in metabolic risk factors after 12 weeks of statin treatment, exercise or the combination affect bone turnover. METHODS Fifty participants with ≥2 metabolic syndrome defining characteristics were randomly assigned to one of three groups: statin (STAT: simvastatin, 40 mg/day), exercise (EX: brisk walking and/or slow jogging, 45 minutes/day, 5 days/week), or the combination (STAT+EX). Body composition and whole body bone mineral density were measured with dual energy X-ray absorptiometry. Serum markers of bone formation (bone specific alkaline phosphatase, BAP; osteocalcin, OC), resorption (C-terminal peptide of type I collagen, CTX) and metabolic risk factors were determined. Two-factor (time, group) repeated-measures ANCOVA was used to examine changes of metabolic risk factors and bone turnover. General linear models were used to determine the effect of pre-treatment metabolic risk factors on post-treatment bone turnover marker outcomes. RESULTS Participants with ≥4 metabolic syndrome defining characteristics had lower pre-treatment OC than those with 3 or fewer. OC was negatively correlated with glucose, and CTX was positively correlated with cholesterol. STAT or STAT+EX lowered total and LDL cholesterol. The OC to CTX ratio decreased in all groups with no other significant changes in bone turnover. Higher pre-treatment insulin or body fat predicted a greater CTX reduction and a greater BAP/CTX increase. CONCLUSION Metabolic risk factors were negatively associated with bone turnover markers. Short-term statin treatment with or without exercise lowered cholesterol and all treatments had a small effect on bone turnover.
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Niacin and statin combination therapy for atherosclerosis regression and prevention of cardiovascular disease events: reconciling the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) trial with previous surrogate endpoint trials.
Michos, ED, Sibley, CT, Baer, JT, Blaha, MJ, Blumenthal, RS
Journal of the American College of Cardiology. 2012;(23):2058-64
Abstract
Despite substantial risk reductions targeting low-density lipoprotein cholesterol with statins, there remains significant residual risk as evidenced by incident and recurrent cardiovascular disease (CVD) events among statin-treated patients. Observational studies have shown that low levels of high-density lipoprotein cholesterol (HDL-C) are associated with increased CVD risk. It remains unclear whether strategies aimed at increasing HDL-C in addition to background statin therapy will further reduce risk. The AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) trial, which compared combined niacin/simvastatin with simvastatin alone, failed to demonstrate an incremental benefit of niacin among patients with atherosclerotic CVD and on-treatment low-density lipoprotein cholesterol values <70 mg/dl, but this study had some limitations. Previously, small randomized, clinical trials of niacin plus statins showed that modest regression of carotid atherosclerosis is possible in individuals with CVD, CVD risk equivalents, or atherosclerosis. This viewpoint summarizes these imaging trials studying niacin and places them in the context of the failure of AIM-HIGH to support the HDL-C-increasing hypothesis.
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Association between the changes in renal function and serum uric acid levels during multifactorial intervention and clinical outcome in patients with metabolic syndrome. A post hoc analysis of the ATTEMPT study.
Athyros, VG, Karagiannis, A, Ganotakis, ES, Paletas, K, Nicolaou, V, Bacharoudis, G, Tziomalos, K, Alexandrides, T, Liberopoulos, EN, Mikhailidis, DP, et al
Current medical research and opinion. 2011;(8):1659-68
Abstract
AIM: To assess the effects of long-term multifactorial intervention on renal function and serum uric acid (SUA) levels and their association with estimated cardiovascular disease (eCVD) risk and actual CVD events. METHODS This prospective, randomized, target-driven study included 1123 subjects (45.6% men, age 45-65 years) with metabolic syndrome (MetS) but without diabetes or CVD. Patients were randomized to multifactorial treatment. Atorvastatin was titrated from 10-80 mg/day aiming at a low density lipoprotein cholesterol (LDL-C) target of <100 mg/dl (group A) or an LDL-C target of <130 mg/dl (group B). Changes in estimated glomerular filtration rate (eGFR) and SUA levels were recorded in all patients and in the subgroup with stage 3 chronic kidney disease (CKD; eGFR = 30-59 ml/min/1.73 m(2); n = 349). We used ANOVA to compare changes within the same group, unpaired Student t-test to compare results between groups at specific time points, and log-rank test to compare event free survival. RESULTS The eCVD-risk reduction was greater in group A. In the overall study population, eGFR increased by 3.5% (p < 0.001) and SUA levels fell by 5.6% (p < 0.001). In patients from group A with stage 3 CKD (group A1; n = 172), eGFR increased by 11.1% (p < 0.001) from baseline and by 7.5% (p < 0.001) in group B1 (n = 177; p < 0.001 vs. the change in group A1). The corresponding fall in SUA levels was 10.7% in group A1 (p < 0.001 vs. baseline) and 8.3% in group B1 (p < 0.001 vs. baseline and group A1). These changes were mainly attributed to atorvastatin treatment. Among the CKD stage 3 patients there were no CVD events in group A1, while 6 events occurred in group B1 (p = 0.014). CONCLUSIONS Multifactorial intervention in patients with MetS without established CVD improved renal function and reduced SUA levels. These changes were more prominent in stage 3 CKD patients and might have contributed to the reduction in eCVD risk and clinical events. Original study registration number [ClinicalTrials.gov ID: NCT00416741].
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Effect of atorvastatin, vitamin E and C on nonalcoholic fatty liver disease: is the combination required?
Arendt, BM, Allard, JP
The American journal of gastroenterology. 2011;(1):78-80
Abstract
Nonalcoholic fatty liver disease is associated with the metabolic syndrome. The current standard of care, healthy diet and weight loss, has limited effect. The benefits of pharmacological treatments are unclear due to the difficulty of using liver histology as the main outcome in large randomized controlled trials (RCTs). In this issue, an RCT with atorvastatin and antioxidants (vitamins E+C) vs. placebo shows improvement in liver steatosis based on computed tomography scans. The questions are is this beneficial effect due to the combined treatment or the effect of an individual compound; does this intervention improve nonalcoholic steatohepatitis.
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Predictors of new-onset diabetes in patients treated with atorvastatin: results from 3 large randomized clinical trials.
Waters, DD, Ho, JE, DeMicco, DA, Breazna, A, Arsenault, BJ, Wun, CC, Kastelein, JJ, Colhoun, H, Barter, P
Journal of the American College of Cardiology. 2011;(14):1535-45
Abstract
OBJECTIVES We sought to examine the incidence and clinical predictors of new-onset type 2 diabetes mellitus (T2DM) within 3 large randomized trials with atorvastatin. BACKGROUND Statin therapy might modestly increase the risk of new-onset T2DM. METHODS We used a standard definition of diabetes and excluded patients with prevalent diabetes at baseline. We identified baseline predictors of new-onset T2DM and compared the event rates in patients with and without new-onset T2DM. RESULTS In the TNT (Treating to New Targets) trial, 351 of 3,798 patients randomized to 80 mg of atorvastatin and 308 of 3,797 randomized to 10 mg developed new-onset T2DM (9.24% vs. 8.11%, adjusted hazard ratio [HR]: 1.10, 95% confidence interval [CI]: 0.94 to 1.29, p = 0.226). In the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) trial, 239 of 3,737 patients randomized to atorvastatin 80 mg/day and 208 of 3,724 patients randomized to simvastatin 20 mg/day developed new-onset T2DM (6.40% vs. 5.59%, adjusted HR: 1.19, 95% CI: 0.98 to 1.43, p = 0.072). In the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial, new-onset T2DM developed in 166 of 1,905 patients randomized to atorvastatin 80 mg/day and in 115 of 1,898 patients in the placebo group (8.71% vs. 6.06%, adjusted HR: 1.37, 95% CI: 1.08 to 1.75, p = 0.011). In each of the 3 trials, baseline fasting blood glucose, body mass index, hypertension, and fasting triglycerides were independent predictors of new-onset T2DM. Across the 3 trials, major cardiovascular events occurred in 11.3% of patients with and 10.8% of patients without new-onset T2DM (adjusted HR: 1.02, 95% CI: 0.77 to 1.35, p = 0.69). CONCLUSIONS High-dose atorvastatin treatment compared with placebo in the SPARCL trial is associated with a slightly increased risk of new-onset T2DM. Baseline fasting glucose level and features of the metabolic syndrome are predictive of new-onset T2DM across the 3 trials.
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Eligibility for statin therapy by the JUPITER trial criteria and subsequent mortality.
Cushman, M, McClure, LA, Lakoski, SG, Jenny, NS
The American journal of cardiology. 2010;(1):77-81
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Abstract
Justification for the Use of Statins in Primary Prevention: An Intervention Trial Using Rosuvastatin (JUPITER) reported reduced cardiovascular and all-cause mortality with statin treatment in patients with elevated C-reactive protein (CRP) and average cholesterol levels who were not eligible for lipid-lowering treatment on the basis of existing guidelines. The aim of this study was to determine the prevalence of eligibility and mortality in a general population sample on the basis of eligibility for statin treatment using the JUPITER criteria. The study group consisted of 30,229 participants in the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort, an observational study of US African American and white participants aged > or =45 years, enrolled in their homes from 2003 to 2007 and followed biannually by telephone. Among 11,339 participants age eligible for JUPITER and without vascular diagnoses or using lipid-lowering treatment, 21% (n = 2,342) met JUPITER entry criteria. Compared with JUPITER participants, they had similar low-density lipoprotein cholesterol and CRP levels, were more often women, were more often black, had metabolic syndrome, and used aspirin for cardioprotection. Over 3.5 years of follow-up, the mortality rate in REGARDS participants eligible for JUPITER was 1.17 per 100 patient-years (95% confidence interval 0.94 to 1.42). Compared with those otherwise JUPITER eligible who had CRP levels <2 mg/L (n = 2,620), those with CRP levels > or =2 mg/L had a multivariate-adjusted relative risk of 1.5 (95% confidence interval 1.1 to 2.2) for total mortality. In conclusion, 21% not otherwise eligible would be newly eligible for lipid lowering treatment on the basis of JUPITER trial eligibility.
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Comparative study of low doses of rosuvastatin and atorvastatin on lipid and glycemic control in patients with metabolic syndrome and hypercholesterolemia.
Park, JS, Kim, YJ, Choi, JY, Kim, YN, Hong, TJ, Kim, DS, Kim, KY, Jeong, MH, Chae, JK, Oh, SK, et al
The Korean journal of internal medicine. 2010;(1):27-35
Abstract
BACKGROUND/AIMS: This multicenter, open-labeled, randomized trial was performed to compare the effects of rosuvastatin 10 mg and atorvastatin 10 mg on lipid and glycemic control in Korean patients with nondiabetic metabolic syndrome. METHODS In total, 351 patients who met the modified National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria for metabolic syndrome with low-density lipoprotein cholesterol (LDL-C) levels > or = 130 mg/dL were randomized to receive either rosuvastatin 10 mg (n = 173) or atorvastatin 10 mg (n = 178) for over 6 weeks. RESULTS After 6 weeks of treatment, greater reductions in total cholesterol (- 35.94 +/- 11.38 vs. - 30.07 +/- 10.46%, p < 0.001), LDL-C (48.04 +/- 14.45 vs. 39.52 +/- 14.42%, p < 0.001), non-high-density lipoprotein cholesterol (- 42.93 +/- 13.15 vs. - 35.52 +/- 11.76%, p < 0.001), and apolipoprotein-B (- 38.7 +/- 18.85 vs. - 32.57 +/- 17.56%, p = 0.002) levels were observed in the rosuvastatin group as compared to the atorvastatin group. Overall, the percentage of patients attaining the NCEP ATP III goal was higher with rosuvastatin as compared to atorvastatin (87.64 vs. 69.88%, p < 0.001). Changes in glucose and insulin levels, and homeostasis model assessment of insulin resistance index were not significantly different between the two groups. The safety and tolerability of the two agents were similar. CONCLUSIONS Rosuvastatin 10 mg was more effective than atorvastatin 10 mg in achieving NCEP ATP III LDL-C goals in patients with nondiabetic metabolic syndrome, especially in those with lower NCEP ATP III target level goals.
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Comparison of the effects of atorvastatin and simvastatin in women with polycystic ovary syndrome: A prospective, randomized study.
Kaya, C, Pabuccu, R, Cengiz, SD, Dünder, I
Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association. 2010;(3):161-6
Abstract
UNLABELLED Polycystic ovary syndrome (PCOS) is associated with hyperandrogenism, insulin resistance (IR), and chronic inflammation. Simvastatin improves endocrine/clinical aspects of PCOS and decreases systemic inflammation in PCOS. There have been no comparative studies carried out regarding the effects of different statin treatment in PCOS. We aimed to assess the effects of two different statin treatments on various metabolic, endocrine, oxidative and inflammatory factors in PCOS. DESIGN Prospective, randomized clinical trial METHODS Sixty-four (64) women with PCOS were included in the study. Group 1 had (atorvastatin, 20lmg daily; n=32) or group 2 had (simvastatin, 20l mg daily n=32). The metabolic, endocrine, inflammatory and oxidative profiles were evaluated. RESULTS Group 1 resulted in a significant reduction in the HOMA index and fasting insulin (-26.9+/-9.6%, -26.2+/-10.8%, P<0.01, respectively).CRP levels decreased by 63.6+/-15.9% in group 1 (P<0.01), whereas in the group 2 it decreased by 34.6+/-10.7% (P<0.05). Serum levels of LH declined by 19.1+/-4.5% (P<0.05) in the group 1 and by 39.3+/-11.9% (P<0.01) in the group 2. FAI decreased by -20+/-9.9% in group 1 (P<0.05) and it decreased by -38.7+/-13.8% in the group 2 (P<0.01). MDA levels decreased by 32.6+/-9.6% in group 1 (P<0.05), whereas in the group 2 it decreased by 30.3+/-10.9% (P<0.01). HOMA index and fasting insulin showed a reduction but not reached statistically significance in the group 2 (8.3+/-1.9%, 3.0+/-0.8%, P>0.05, respectively). CONCLUSION Both the statins are effective in reducing inflammation, hyperandrogenemia, oxidative stress and metabolic parameters. While atorvastatin has more noticeable effects on fasting insulin and insulin sensitivity, simvastatin has a dominant effect on total T in PCOS women.
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Different galenic formulations of fluvastatin have equal lipid-lowering potential but differ in reducing lipemia-induced endothelial dysfunction.
Westphal, S, Abletshauser, C, Luley, C
Coronary artery disease. 2009;(1):81-5
Abstract
BACKGROUND Postprandial lipemia is known to exert a reversible detrimental effect on endothelium-dependent flow-mediated vasodilation (FMD). Fasting FMD has shown to be improved by fluvastatin. In this study, we investigated whether lipemia-induced endothelial dysfunction can be mitigated by fluvastatin in two (immediate-release and extended-release) formulations. METHODS In 27 patients with the metabolic syndrome, randomized in a three-period crossover design for 5 weeks each to 80 mg extended-release fluvastatin daily, 40 mg immediate-release fluvastatin twice daily (b.i.d.) or placebo, the fasting and postprandial lipids and FMD of the brachial artery were measured at baseline and after 5 weeks of each treatment period. Postprandial lipemia was induced by administration of whipping cream containing 33% fat (1 g fat/kg body weight). FMD was determined by two-dimensional ultrasonography of the brachial artery in the fasting state and 4 h after the fatty meal. Lipids were determined using routine methods. RESULTS Fasting triglycerides were reduced after immediate-release and extended-release fluvastatin by 16 and 23%, respectively, and postprandial triglycerides by 20 and 29%, respectively. The fasting FMD was also improved by each treatment. The postprandial FMD impairment, however, was mitigated only after 40 mg b.i.d. After 80 mg fluvastatin, the last dose of which had been administered the previous evening, the lipemic FMD impairment was the same as after the placebo. CONCLUSION Fluvastatin improves fasting FMD regardless of whether it is administered as 40 mg b.i.d. or 80 mg daily given in the evening. The lipemic FMD impairment, in contrast, is improved only by 40 mg b.i.d. when the tablet is taken in the morning of the test day. As the half-life of fluvastatin is about 2 h, we surmise that an improvement occurs only when sufficient amounts of fluvastatin are present in the bloodstream.
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Atorvastatin and fenofibrate have comparable effects on VLDL-apolipoprotein C-III kinetics in men with the metabolic syndrome.
Chan, DC, Watts, GF, Ooi, EM, Ji, J, Johnson, AG, Barrett, PH
Arteriosclerosis, thrombosis, and vascular biology. 2008;(10):1831-7
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OBJECTIVE The metabolic syndrome (MetS) is characterized by insulin resistance and dyslipidemia that may accelerate atherosclerosis. Disturbed apolipoprotein (apo) C-III metabolism may account for dyslipidemia in these subjects. Atorvastatin and fenofibrate decrease plasma apoC-III, but the underlying mechanisms are not fully understood. METHODS AND RESULTS The effects of atorvastatin (40 mg/d) and fenofibrate (200 mg/d) on the kinetics of very-low density lipoprotein (VLDL)-apoC-III were investigated in a crossover trial of 11 MetS men. VLDL-apoC-III kinetics were studied, after intravenous d(3)-leucine administration using gas chromatography-mass spectrometry and compartmental modeling. Compared with placebo, both atorvastatin and fenofibrate significantly decreased (P<0.001) plasma concentrations of triglyceride, apoB, apoB-48, and total apoC-III. Atorvastatin, not fenofibrate, significantly decreased plasma apoA-V concentrations (P<0.05). Both agents significantly increased the fractional catabolic rate (+32% and +30%, respectively) and reduced the production rate of VLDL-apoC-III (-20% and -24%, respectively), accounting for a significant reduction in VLDL-apoC-III concentrations (-41% and -39%, respectively). Total plasma apoC-III production rates were not significantly altered by the 2 agents. Neither treatment altered insulin resistance and body weight. CONCLUSIONS Both atorvastatin and fenofibrate have dual regulatory effects on VLDL-apoC-III kinetics in MetS; reduced production and increased fractional catabolism of VLDL-apoC-III may explain the triglyceride-lowering effect of these agents.