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Influence of metabolic syndrome factors and insulin resistance on the efficacy of ezetimibe/simvastatin and atorvastatin in patients with metabolic syndrome and atherosclerotic coronary heart disease risk.
Rosen, JB, Ballantyne, CM, Hsueh, WA, Lin, J, Shah, AK, Lowe, RS, Tershakovec, AM
Lipids in health and disease. 2015;:103
Abstract
BACKGROUND Metabolic syndrome (MetS) and insulin resistance (IR) are increasing in prevalence, are associated with higher risk for coronary heart disease (CHD), and may potentially influence the responses to lipid-altering drug therapy. This study evaluated the effects of MetS factors (abdominal obesity, depleted high-density lipoprotein cholesterol [HDL-C], and elevated triglycerides, blood pressure, and fasting glucose) and IR on ezetimibe/simvastatin and atorvastatin treatment efficacy in patients with MetS. METHODS This post-hoc analysis of a multicenter, 6-week, double-blind, randomized, parallel group study of 1128 subjects with hypercholesterolemia, MetS, and moderately high/high CHD risk evaluated the effects of baseline MetS factors/IR on percent change from baseline in lipids, apolipoproteins, and high-sensitivity C-reactive protein (hs-CRP), after treatment with the usual starting doses of ezetimibe/simvastatin (10/20 mg) versus atorvastatin (10 mg, 20 mg) and next higher doses (10/40 mg versus 40 mg). RESULTS Ezetimibe/simvastatin and atorvastatin efficacy was generally consistent across MetS factor/IR subgroups. Ezetimibe/simvastatin produced greater incremental percent reductions in LDL-C, non-HDL-C, apolipoprotein B, total cholesterol, and lipoprotein ratios for all subgroups, and larger percent increases in HDL-C and apolipoprotein AI for all but non-obese and HDL-C ≥ 40 mg/dL subgroups than atorvastatin at the doses compared. Triglycerides, very-LDL-C, and hs-CRP results were more variable but similar between treatment groups. CONCLUSION The magnitude of lipid-altering effects produced by each treatment regimen was generally similar across all MetS and IR subgroups. Ezetimibe/simvastatin produced greater percent reductions in most lipid fractions than atorvastatin at the dose comparisons studied, and all treatments were generally well tolerated. (Registered at clinicaltrials.gov: NCT00409773).
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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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Relationships between metabolic syndrome and other baseline factors and the efficacy of ezetimibe/simvastatin and atorvastatin in patients with type 2 diabetes and hypercholesterolemia.
Goldberg, RB, Guyton, JR, Mazzone, T, Weinstock, RS, Polis, AB, Tipping, D, Tomassini, JE, Tershakovec, AM
Diabetes care. 2010;(5):1021-4
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OBJECTIVE To investigate relationships between baseline factors and treatment-associated efficacy changes in type 2 diabetes. RESEARCH DESIGN AND METHODS Multivariable analyses of treatment response in 1,229 type 2 diabetic patients with hypercholesterolemia who received ezetimibe/simvastatin or atorvastatin in a randomized double-blind 6-week study. RESULTS Increasing age was related to improvements in all lipid assessments. Men had greater triglyceride and non-HDL cholesterol reductions than women, and black/Hispanic patients had less favorable lipid effects than other races/ethnicities. Increasing baseline LDL cholesterol was associated with improvements in most lipids; higher baseline non-HDL cholesterol with improved HDL cholesterol and triglycerides; higher baseline HDL cholesterol with greater non-HDL cholesterol and high-sensitivity C-reactive protein (hs-CRP) reductions; and higher baseline hs-CRP with smaller LDL cholesterol, non-HDL cholesterol, and apolipoprotein B reductions. Patients with high baseline non-HDL cholesterol or triglycerides less frequently attained LDL cholesterol targets. Obesity was inversely related to HDL cholesterol and hs-CRP changes, and higher baseline A1C to smaller apolipoprotein B reductions. Metabolic syndrome was not a significant predictor. CONCLUSIONS Treatment responses in type 2 diabetic patients were related to baseline factors, although treatment effects (ezetimibe/simvastatin being more effective than atorvastatin) remained consistent. The presence of predictive factors should be considered in planning lipid-altering therapy.
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Comparison of simvastatin and metformin in treatment of polycystic ovary syndrome: prospective randomized trial.
Banaszewska, B, Pawelczyk, L, Spaczynski, RZ, Duleba, AJ
The Journal of clinical endocrinology and metabolism. 2009;(12):4938-45
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CONTEXT Polycystic ovary syndrome (PCOS) is characterized by ovarian dysfunction and hyperandrogenism; it is also associated with increased cardiovascular risks such as adverse lipid profile and endothelial dysfunction. Metformin and, more recently, statins have been shown to improve endocrine and metabolic aspects of PCOS. OBJECTIVE The aim of the study was to compare effects of simvastatin and metformin on PCOS. DESIGN In a prospective trial, women with PCOS (n = 136) were randomized to simvastatin (S), metformin (M), or simvastatin plus metformin (SM) groups. Evaluations were performed at baseline and after 3 months. SETTING The study was conducted at an academic medical center. PRIMARY OUTCOME The change of serum total testosterone was measured. RESULTS The study was completed by 113 subjects. Total testosterone decreased significantly and comparably in all groups: by 17.1, 13.6, and 15.1%, respectively, in the S, M, and SM groups. Significant decreases were also observed in all groups with respect to body mass index, C-reactive protein, and soluble vascular cell adhesion molecule-1. DHEAS declined significantly only in the S group. None of the treatments were associated with significant changes in LH or FSH. Total cholesterol and low-density lipoprotein cholesterol significantly declined only in S and SM groups. CONCLUSIONS Simvastatin treatment was superior to metformin alone, whereas a combination of simvastatin and metformin was not significantly superior to simvastatin alone.
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Simvastatin reduces circulating plasminogen activator inhibitor 1 activity in volunteers with the metabolic syndrome.
Wang, L, Rockwood, J, Zak, D, Devaraj, S, Jialal, I
Metabolic syndrome and related disorders. 2008;(2):149-52
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BACKGROUND The Metabolic Syndrome (MS) confers an increased risk for diabetes and cardiovascular disease. We previously showed that simvastatin has concomitant benefits in reducing low-density lipoprotein (LDL)-cholesterol and inflammation in MS subjects. The levels of plasminogen activator inhibitor 1(PAI-1), soluble P-selectin (sP-selectin), and soluble CD40 ligand (sCD40L) play an important role in the development and progression of atherosclerosis. Their levels are increased in the MS. The current study was to investigate the effects of simvastatin on PAI-1, sP-selectin, and sCD40 ligand. METHODS Fifty subjects with MS were randomized into either placebo or simvastatin (40 mg/day) group for 8 weeks. Blood samples were obtained at baseline and at the end of the study. PAI-1 activity and sP-selectin and sCD40L levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS There was no baseline difference in any of the parameters studied. Compared to baseline, simvastatin significantly reduced (P < 0.05) the circulating PAI-1 activity (24.3 +/- 5.2 IU/mL at baseline vs. 21.4 +/- 3.9 IU/mL after 8 weeks of treatment). Simvastatin did not alter (P < 0.05) the levels of sP-selectin (111.4 +/- 35.9 ng/mL at baseline vs. 118.5 +/- 71.2 ng/mL after 8 weeks) or sCD40L (2.0 +/- 1.6 ng/mL at baseline vs. 1.5 +/- 1.0 ng/mL after 8 weeks). CONCLUSION Our data indicate that simvastatin therapy has significant effects on the fibrinolytic system in MS subjects as evidenced in a reduction in PAI-1 activity.
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Simvastatin (40 mg/day), adiponectin levels, and insulin sensitivity in subjects with the metabolic syndrome.
Devaraj, S, Siegel, D, Jialal, I
The American journal of cardiology. 2007;(9):1397-9
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The metabolic syndrome (MS) is characterized by low-grade inflammation and confers an increased risk for diabetes mellitus and cardiovascular disease. Statins reduce cardiovascular events in patients with the MS and have pleiotropic effects in addition to lowering low-density lipoprotein cholesterol. Because there is a paucity of data on the effect of statins on adiponectin levels and insulin sensitivity in the MS, this study was conducted to test the effect of simvastatin (40 mg/day) compared with placebo on circulating adiponectin levels and homeostasis model assessment insulin resistance in subjects with the MS in a randomized, double-blind, placebo-controlled study. Simvastatin therapy failed to affect circulating adiponectin levels or insulin sensitivity compared with placebo over 8 weeks. In conclusion, although simvastatin is anti-inflammatory, it failed to affect adiponectin levels or improve insulin sensitivity in subjects with the MS.