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1.
Effect on Fasting Serum Glucose Levels of Adding Ezetimibe to Statins in Patients With Nondiabetic Hypercholesterolemia.
Toth, PP, Catapano, AL, Farnier, M, Foody, J, Tomassini, JE, Jensen, E, Polis, AB, Hanson, ME, Musliner, TA, Tershakovec, AM
The American journal of cardiology. 2016;(12):1812-1820
Abstract
Statin therapy is associated with a slightly increased risk of developing diabetes mellitus and insulin resistance in patients without diabetes. Ezetimibe combined with statins may be considered for high-risk patients who do not achieve optimal low-density lipoprotein cholesterol lowering on statin monotherapy or who are statin intolerant. Changes in fasting serum glucose (FSG) levels during ezetimibe, ezetimibe/statin, and statin treatments were assessed using data pooled from clinical trials in hypercholesterolemic and heterozygous familial hypercholesterolemic patients, who were or were not receiving statin therapy. Study types included first-line trials in statin-naive/wash-out patients and second-line add-on and uptitration studies in patients on stable statin therapy. Similar analyses of FSG changes were performed separately for each study type in patients who were nondiabetic at baseline. Across all study types and treatments, mean FSG increases from baseline were small (0.5 to 3.7 mg/dl with ezetimibe/statin; 0.2 to 4.6 mg/dl with statins) and decreased over time; between-treatment differences (0.3 to 1.4 mg/dl) were nonsignificant for all comparisons. Proportions of patients with elevated FSG ≥126 mg/dl during therapy were low and similar for all treatments in the overall cohort (1.2% to 4.3%). Elevations were highest (3.3% to 25.7%) among patients with baseline factors characteristic of metabolic syndrome and prediabetes, including higher FSG, body mass index, and triglyceride levels, and numerically lower baseline high-density lipoprotein cholesterol; however, these factors were not related to FSG increases. Changes in low-density lipoprotein cholesterol, body mass index, high-density lipoprotein cholesterol, triglycerides, and apolipoprotein B were not significantly correlated with FSG increases. In conclusion, statin therapy was associated with small FSG increases, and the addition of ezetimibe did not further increase FSG levels beyond those of statins when given to patients who are statin naive or those on statin therapy.
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2.
The effects of statins on benign prostatic hyperplasia in elderly patients with metabolic syndrome.
Zhang, X, Zeng, X, Dong, L, Zhao, X, Qu, X
World journal of urology. 2015;(12):2071-7
Abstract
PURPOSE To evaluate the effects of simvastatin and atorvastatin in elderly male patients with benign prostatic hyperplasia (BPH) accompanied by metabolic syndrome (MetS). METHODS Eligible patients aged >60 year with BPH accompanied by MetS were randomly assigned to receive 40 mg of simvastatin daily, 20 mg of atorvastatin daily or placebo (control group) treatment for 12 months. Serum lipids, interleukin 6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), prostate-specific antigen, prostate volume (PV) and the International Prostate Symptom Score (IPSS) were tested before and after treatment. RESULTS The levels of serum total cholesterol (TC), triglycerides, low-density lipoprotein cholesterol, hs-CRP, IL-6 and IPSS was decreased, serum high-density lipoprotein cholesterol (HDL-C) was increased, and PV was reduced in the patients following treatments with statins. The PV of the patients who received simvastatin were reduced more than those of the patients who received atorvastatin. The decrease in PV was more significant in the obesity patients than in the normal weight patients and in the hyperlipidemia patients than in the normal-lipid patients following the statin interventions. The reduction in PV was positively related to the decreases in the levels of TC and IL-6 and to the increase in the level of HDL-C. CONCLUSIONS Simvastatin and atorvastatin significantly reduced PV, improved lower urinary tract symptoms, and slowed the clinical progression of BPH possibly by lowering cholesterol and anti-inflammatory factors.
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3.
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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4.
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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5.
High-dose statin monotherapy versus low-dose statin/ezetimibe combination on fasting and postprandial lipids and endothelial function in obese patients with the metabolic syndrome: The PANACEA study.
Westerink, J, Deanfield, JE, Imholz, BP, Spiering, W, Basart, DC, Coll, B, Kastelein, JJ, Visseren, FL
Atherosclerosis. 2013;(1):118-24
Abstract
BACKGROUND Low-dose statin therapy in combination with ezetimibe, an inhibitor of intestinal cholesterol absorption, lowers plasma LDL-cholesterol levels to a similar degree as high-dose statin monotherapy. This study assessed whether similar LDL-cholesterol lowering with simvastatin/ezetimibe combination therapy improves fasting and postprandial arterial endothelial function compared to high-dose statin therapy alone. METHODS Multicenter, double-blind, crossover trial in 100 abdominally obese patients with the metabolic syndrome, randomized to 6 weeks' treatment with simvastatin 80 mg or simvastatin/ezetimibe 10/10 mg. Flow mediated dilatation (FMD) and peripheral arterial tonometry (EndoPAT) as well as plasma lipids were measured in the fasting state and after an oral lipid load at baseline and after both treatments. RESULTS Fasting LDL-cholesterol levels (3.57 mmol/L at baseline) were reduced to 1.79 mmol/L following treatment with simvastatin 80 mg and 1.81 mmol/L with simvastatin/ezetimibe 10/10 mg, respectively. Plasma lipids were similar at 4 h after an oral lipid load following both treatments for 6 weeks. Fasting endothelial function was also similar with both treatments when assessed by FMD (adjusted mean ± SE: 4.35 ± 0.19 vs. 4.43 ± 0.18; P = 0.777) and EndoPAT (2.12 ± 0.05 vs 2.20 ± 0.05; P = 0.304). After an oral fat load, changes in endothelial function were also comparable for both treatments as assessed by FMD (-0.34 ± 0.21 vs. -0.43 ± 0.20; P = 0.766) and EndoPAT (0.00 ± 0.07 vs. -0.04 ± 0.08; P = 0.712). CONCLUSION Treatment with simvastatin/ezetimibe 10/10 mg induced no difference in endothelial function in the fasting and postprandial state compared to simvastatin 80 mg while attaining similar LDL-c levels in obese patients with metabolic syndrome.
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6.
Age, abdominal obesity, and baseline high-sensitivity C-reactive protein are associated with low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B responses to ezetimibe/simvastatin and atorvastatin in patients with metabolic syndrome.
Robinson, JG, Ballantyne, CM, Hsueh, WA, Rosen, JB, Lin, J, Shah, AK, Tomassini, JE, Lowe, RS, Tershakovec, AM
Journal of clinical lipidology. 2013;(4):292-303
Abstract
BACKGROUND Treatment response to lipid-lowering therapy can vary in patients with the metabolic syndrome (MetS) due to various patient demographic and baseline characteristics. OBJECTIVE This study assessed the relationships between baseline characteristics and changes in lipid variables, high-sensitivity C-reactive protein (hs-CRP) and attainment of prespecified low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) levels in MetS patients treated with ezetimibe/simvastatin and atorvastatin. METHODS This is a post-hoc analysis of a multicenter, double-blind, randomized, 6-week parallel study in >1000 hypercholesterolemic subjects (median age of 59 years) with MetS and moderately high/high coronary heart disease risk who were treated with ezetimibe/simvastatin (10/20 and 10/40 mg) or atorvastatin (10, 20, 40 mg). Factors that could affect these treatments were assessed by multivariate analysis. RESULTS Increasing age, abdominal obesity (waist circumference ≥ 40/35 inches for men/women), and lower baseline hs-CRP were significant predictors of greater reductions in LDL-C, non-HDL-C, apolipoprotein B, total cholesterol, triglycerides, and very-low-density lipoprotein cholesterol but not for changes in HDL-C or apolipoprotein AI; effects of race and baseline triglycerides, non-HDL-C, LDL-C, or HDL-C levels were more limited. Age ≥ 65 years (versus <65 years) was also associated with significantly greater attainment of all LDL-C and non-HDL-C targets, whereas abdominal obesity, gender (female > male) and lower baseline LDL-C, non-HDL-C, triglycerides, and hs-CRP were associated with improved attainment for some of these targets. Blood pressure, fasting glucose, Homeostasis Model Assessment of Insulin Resistance tertiles, and diabetes did not predict response for any efficacy variable. Ezetimibe/simvastatin treatment (versus atorvastatin) was a significant predictor for change in most efficacy variables. CONCLUSIONS Treatment responses to ezetimibe/simvastatin and atorvastatin in at-risk patients with the MetS were related to age (≥ 65 years), abdominal obesity, and lower baseline hs-CRP. Ezetimibe/simvastatin treatment was found to be consistently more effective than atorvastatin at the specified dose comparisons across these subgroups. The clinical value of predictive factors requires further study in outcome trials.
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7.
The efficacy and safety of ezetimibe/simvastatin combination compared with intensified lipid-lowering treatment strategies in diabetic subjects with and without metabolic syndrome.
Jimenez, JG, Rosen, JB, Pirags, V, Massaad, R, Hanson, ME, Brudi, P, Triscari, J
Diabetes, obesity & metabolism. 2013;(6):513-22
Abstract
AIMS: The objective was to assess the consistency of effect of switching to ezetimibe/simvastatin 10/20 mg versus doubling the baseline statin dose (to simvastatin 40 mg or atorvastatin 20 mg) or switching to rosuvastatin 10 mg across subgroups of subjects with (n = 617) and without (n = 191) metabolic syndrome (MetS). METHODS This was a post hoc analysis of a randomized, double-blind, 6-week study of adults 18-79 years with cardiovascular disease and diabetes mellitus with low-density lipoprotein cholesterol (LDL-C) ≥70 and ≤160 mg/dl. The percent change in LDL-C and other lipids was estimated within each subgroup separately. Safety and tolerability were assessed. RESULTS In subjects with MetS, percent changes in LDL-C and other lipids were greater with ezetimibe/simvastatin versus doubling baseline statin or numerically greater versus switching to rosuvastatin, except high-density lipoprotein cholesterol and apolipoprotein (Apo) AI (mean percent changes in LDL-C were: -22.49% ezetimibe/simvastatin, -9.64% doubled baseline statin and -19.20% rosuvastatin). In subjects without MetS, percent changes in LDL-C, total cholesterol and Apo B were greater with ezetimibe/simvastatin versus doubling baseline statin or numerically greater versus switching to rosuvastatin (mean percent changes in LDL-C were: -25.14% ezetimibe/simvastatin, -4.75% doubled baseline statin and -19.75% rosuvastatin). Safety profiles were generally similar. CONCLUSION These results showed that switching to ezetimibe/simvastatin 10/20 mg was more effective at reducing LDL-C, total cholesterol and Apo B versus doubling the baseline statin dose to simvastatin 40 mg or atorvastatin 20 mg or switching to rosuvastatin 10 mg regardless of MetS status. These results were generally similar to those of the full cohort.
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8.
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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9.
Long-term efficacy and safety of ezetimibe/simvastatin coadministered with extended-release niacin in hyperlipidaemic patients with diabetes or metabolic syndrome.
Fazio, S, Guyton, JR, Lin, J, Tomassini, JE, Shah, A, Tershakovec, AM
Diabetes, obesity & metabolism. 2010;(11):983-93
Abstract
AIMS: To assess the efficacy and safety of ezetimibe/simvastatin (E/S) plus extended-release niacin (N) in hyperlipidaemic patients with diabetes mellitus (DM), metabolic syndrome (MetS) without DM (MetS/non-DM) or neither (non-DM/non-MetS). METHODS A subgroup analysis of a double-blind, 64-week trial of 1220 randomized patients who received E/S (10/20 mg) + N (to 2 g) or E/S (10/20 mg) for 64 weeks, or N (to 2 g) for 24 weeks then E/S (10/20 mg) + N (2 g) or E/S (10/20 mg) for 40 additional weeks. The evaluable populations of this analysis included n = 765 patients at 24 weeks and n = 574 at 64 weeks. Among those receiving N, only those who attained the 2-g dose were included in the analysis. RESULTS E/S+N improved levels of low-density lipoprotein cholesterol, other lipids and lipoprotein ratios compared with N and E/S at 24 weeks and E/S at 64 weeks. The combination increased high-density lipoprotein cholesterol and apolipoprotein AI comparably to N and more than E/S. E/S+N reduced high-sensitivity C-reactive protein (hsCRP) levels more effectively than N and similarly to E/S. E/S+N was generally well tolerated. Discontinuations due to flushing with N and E/S+N were comparable and greater than E/S in all subgroups. Fasting glucose trended higher for N vs. E/S. Glucose elevations from baseline to 12 weeks were highest for patients with DM (24.9 mg/dl for N, 21.2 mg/dl for E/S+N, 17.5 mg/dl for E/S); fasting glucose then declined to pretreatment levels at 64 weeks in all subgroups. New-onset DM was more frequent among MetS patients than those without MetS during the first 24 weeks and trended higher among those assigned to N-containing regimens [n = 5(5.1%) for N, n = 2(1.7%) for E/S, n = 21(8.8%) for E/S+N]; during the 24-64 week extension study, diabetes was diagnosed in five additional patients in the E/S(cumulative incidence of 5.9%) and one in the E/S+N (cumulative incidence of 9.2%). Treatment-incident elevations in uric acid levels were increased among subjects assigned to N-containing regimens, but there were no effects on symptomatic gout. CONCLUSION Combination E/S+N is a safe treatment option for hyperlipidaemic patients including those with DM and MetS, but requires monitoring of glucose and potentially uric acid levels.
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10.
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.