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Simvastatin impairs exercise training adaptations.
Mikus, CR, Boyle, LJ, Borengasser, SJ, Oberlin, DJ, Naples, SP, Fletcher, J, Meers, GM, Ruebel, M, Laughlin, MH, Dellsperger, KC, et al
Journal of the American College of Cardiology. 2013;(8):709-14
Abstract
OBJECTIVES This study sought to determine if simvastatin impairs exercise training adaptations. BACKGROUND Statins are commonly prescribed in combination with therapeutic lifestyle changes, including exercise, to reduce cardiovascular disease risk in patients with metabolic syndrome. Statin use has been linked to skeletal muscle myopathy and impaired mitochondrial function, but it is unclear whether statin use alters adaptations to exercise training. METHODS This study examined the effects of simvastatin on changes in cardiorespiratory fitness and skeletal muscle mitochondrial content in response to aerobic exercise training. Sedentary overweight or obese adults with at least 2 metabolic syndrome risk factors (defined according to National Cholesterol Education Panel Adult Treatment Panel III criteria) were randomized to 12 weeks of aerobic exercise training or to exercise in combination with simvastatin (40 mg/day). The primary outcomes were cardiorespiratory fitness and skeletal muscle (vastus lateralis) mitochondrial content (citrate synthase enzyme activity). RESULTS Thirty-seven participants (exercise plus statins: n = 18; exercise only: n = 19) completed the study. Cardiorespiratory fitness increased by 10% (p < 0.05) in response to exercise training alone, but was blunted by the addition of simvastatin resulting in only a 1.5% increase (p < 0.005 for group by time interaction). Similarly, skeletal muscle citrate synthase activity increased by 13% in the exercise-only group (p < 0.05), but decreased by 4.5% in the simvastatin-plus-exercise group (p < 0.05 for group-by-time interaction). CONCLUSIONS Simvastatin attenuates increases in cardiorespiratory fitness and skeletal muscle mitochondrial content when combined with exercise training in overweight or obese patients at risk of the metabolic syndrome. (Exercise, Statins, and the Metabolic Syndrome; NCT01700530).
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Comparison of 80 versus 10 mg of atorvastatin on occurrence of cardiovascular events after the first event (from the Treating to New Targets [TNT] trial).
LaRosa, JC, Deedwania, PC, Shepherd, J, Wenger, NK, Greten, H, DeMicco, DA, Breazna, A, ,
The American journal of cardiology. 2010;(3):283-7
Abstract
Analyses of randomized clinical trials are usually restricted to examination of time to first event. However, because many patients have multiple events, this approach precludes much potentially useful clinical and economic data. To assess the effect on overall disease burden in the Treating to New Targets (TNT) study, we evaluated the effect of treatment with atorvastatin 80 versus 10 mg in the period after the occurrence of a first cardiovascular event. In TNT, 10,001 patients with stable coronary heart disease received double-blind therapy with atorvastatin 80 or 10 mg and were followed for 4.9 years. Post hoc time-to-event analysis was used to estimate separate hazard ratios for time to any first, second, third, fourth, and fifth recurrent cardiovascular events. During TNT, 3,082 patients had a first recurrent cardiovascular event, with 1,516, 698, 345, and 197 developing second, third, fourth, and fifth recurrent events, respectively. In patients receiving atorvastatin 80 mg, the relative risk of a first recurrent event was significantly decreased compared to those receiving atorvastatin 10 mg. Significant benefit with the 80-mg dose was also observed for second, third, fourth, and fifth recurrent events. Similar findings were recorded in 5,854 patients with type 2 diabetes mellitus and/or metabolic syndrome and in 3,809 patients > or = 65 years of age compared to younger patients. In conclusion, treatment with atorvastatin 80 mg continued to significantly decrease the risk of any cardiovascular event over time compared to atorvastatin 10 mg in patients who had survived previous events. In TNT, analyses limited to the primary end point significantly underestimated the decrease in total cardiovascular disease burden achieved by intensive low-density lipoprotein cholesterol lowering.
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Comparison effect of atorvastatin (10 versus 80 mg) on biomarkers of inflammation and oxidative stress in subjects with metabolic syndrome.
Singh, U, Devaraj, S, Jialal, I, Siegel, D
The American journal of cardiology. 2008;(3):321-5
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Abstract
Metabolic syndrome (MS), characterized by low-grade inflammation, confers an increased risk for cardiovascular disease. Statins, in addition to having lipid-lowering effects, have pleiotropic effects and decrease biomarkers of inflammation and oxidative stress. The Treating to New Target Study showed a greater decrease in low-density lipoprotein (LDL) cholesterol and cardiovascular events with atorvastatin 80 mg versus 10 mg in patients with MS with coronary heart disease. However, part of this benefit could be caused by the greater pleiotropic effects of the higher dose of atorvastatin. The dose-response effect of atorvastatin on biomarkers of inflammation and oxidative stress has not been investigated in subjects with MS. Thus, the dose-response effect of atorvastatin on biomarkers of inflammation (high-sensitivity C-reactive protein [hs-CRP], matrix metalloproteinase-9, and nuclear factor-kappaB [NF-kB] activity) and oxidative stress (oxidized LDL, urinary nitrotyrosine, F2-isoprostanes, and monocyte superoxide release) was tested in a randomized double-blind clinical trial in subjects with MS. Seventy subjects were randomly assigned to receive placebo or atorvastatin 10 or 80 mg/day for 12 weeks. A strong dose-response (atorvastatin 10 compared with 80 mg, p <0.05) was observed for changes in total, LDL (32% and 44% reduction), non-high-density lipoprotein (28% and 40% reduction), and oxidized LDL cholesterol (24% and 39% reduction) at atorvastatin 10 and 80 mg, respectively. Hs-CRP, matrix metalloproteinase-9, and NF-kB significantly decreased in the 80-mg atorvastatin group compared with baseline. In conclusion, this randomized trial of subjects with MS showed the superiority of atorvastatin 80 mg compared with its 10-mg dose in decreasing oxidized LDL, hs-CRP, matrix metalloproteinase-9, and NF-kB activity.
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Is atorvastatin superior to other statins? Analysis of the clinical trials with atorvastatin having cardiovascular endpoints.
Doggrell, SA
Reviews on recent clinical trials. 2006;(2):143-53
Abstract
Placebo-controlled clinical trials have shown that atorvastatin is beneficial in patients with myocardial ischemia, established coronary artery disease, hypertension and 3 other cardiovascular risk factors (e.g. left-ventricular hypertrophy, type 2 diabetes, smoking), and in diabetes, but not in patients with calcific aortic stenosis. Recently, intensive low density lipoprotein (LDL)-cholesterol lowering with atorvastatin 80 mg/day has been shown to have a greater clinical benefit than atorvastatin 10 mg/day in patients with coronary heart disease and one other high-risk factor (previous myocardial infarction, coronary revascularization or angina), and to be superior to moderate lipid lowering with pravastatin (40 mg/day) in patients with an acute coronary syndrome. However, a smaller study comparing lovastatin 5 mg/day with atorvastatin 80 mg/day was unable to detect any difference in outcomes in patients with stable coronary disease, despite the greater LDL-cholesterol lowering with the atorvastatin, possibly because it was not powered to do so. In a retrospective cohort study, atorvastatin 10 mg/day, pravastatin 20 mg/day, simvastatin 20 mg/day, lovastatin 20 mg/day and fluvastatin 20 mg/day had similar efficacy as secondary prevention after acute myocardial infarction. At present, the evidence from clinical trials is favouring the intensity of the effect on LDL-cholesterol and/or C-reactive protein (CRP) with atorvastatin 80 mg, rather than the use of atorvastatin per se, when greater benefits are observed with the 80 mg dose of atorvastatin compared to other statins. Thus, at present, it is not clear whether atorvastatin is superior to other statins in some indications (coronary heart disease, acute coronary syndromes) or whether it is the intensive lipid lowering that is responsible for the superiority. Atorvastatin has little or no ability to increase high density lipoprotein (HDL)-cholesterol, and this may be a disadvantage in patients with metabolic syndrome or diabetes, where low HDL-cholesterol is a key feature. Thus, other statins should probably be preferred to atorvastatin in patients with diabetes/metabolic syndrome. Alternatively, atorvastatin can be used in combination with a fibrate to increase HDL-cholesterol in patients with diabetes/metabolic syndrome.
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Emerging therapeutic strategies for the management of dyslipidemia in patients with the metabolic syndrome.
Davidson, MH
The American journal of cardiology. 2004;(11A):3C-11C
Abstract
The benefits of lipid-lowering therapy in significantly reducing cardiovascular events has been established in many at-risk populations. However, patients with the metabolic syndrome (MS) pose a challenge for clinical management. A high degree of residual risk exists in patients with the MS or diabetes mellitus, and this is of growing importance because of the increasing prevalence of obesity and its associated comorbidities in the world. As the MS has emerged as a major risk factor for both cardiovascular disease and diabetes, targeting treatment to achieve aggressive goals becomes paramount. This article reviews emerging therapeutic strategies for the management of dyslipidemia in patients with the MS.