Months Of Atorvastatin Research Articles

Influence of Baseline Psychological Health on Muscle Pain During Atorvastatin Treatment.

3-hydroxy-3-methylglutaryl coenzyme A reductase reductase inhibitors (statins) are generally well tolerated, with statin-associated muscle symptoms (SAMS) the most common side effect (~10%) seen in statin users. However, studies and clinical observations indicate that many of the self-reported SAMS appear to be nonspecific (ie, potentially not attributable to statins). Mental health and well-being influence self-perception of pain, so we sought to assess the effect of baseline well-being and depression on the development of muscle pain with 6 months of atorvastatin 80 mg/d (ATORVA) or placebo in healthy, statin-naive adults. The Psychological General Well-being Index (n = 83) and Beck Depression Inventory (n = 55) questionnaires were administered at baseline in participants (aged 59.5 ± 1.2 years) from the effect of Statins on Skeletal Muscle Function and Performance (STOMP) trial (NCT00609063). Muscle pain (Short-Form McGill Pain Questionnaire [SF-MPQ]), pain that interferes with daily life (Brief Pain Inventory [BPI]), and pain severity (BPI) were then measured before, throughout, and after treatment. At baseline, there were no differences in well-being (Psychological General Well-being Index), depression (Beck Depression Inventory), or pain measures (SF-MPQ and BPI) (P values ≥ .05) between the placebo and ATORVA groups. Baseline well-being correlated negatively with baseline BPI pain severity (r = -0.290, P = .008). Baseline depression correlated with baseline pain (SF-MPQ; r = 0.314, P = .020). Baseline well-being and depression did not predict the change in pain severity or interference after 6 months among the total sample or between groups (P values ≥ .05). Baseline well-being and depression were not significant predictors of pain after 6 months of ATORVA (P values ≥ .05). Thus, they do not appear to increase the risk of SAMS in otherwise healthy adults.

The effect of atorvastatin on pancreatic beta cell requirement in women with polycystic ovary syndrome.

BackgroundThere is an increased risk of developing T2DM in women with polycystic ovary syndrome (PCOS), and there is evidence that statins improve metabolic parameters in these patients. However, there are some data to show that statins increase the risk of incipient diabetes.Materials and methodsWe have previously shown that 12 weeks of atorvastatin improves insulin resistance when measured using HOMA-IR. This post hoc analysis was designed to look at the effect of atorvastatin on pancreatic β cell function using HOMA-β in the same study. In this randomised, double-blind placebo controlled study, 40 medication-naïve patients with PCOS were randomised to either atorvastatin 20 mg daily or placebo for 3 months. A 3-month extension study for both groups of patients was undertaken with metformin 1500 mg daily after completing initial 3 months of atorvastatin or placebo.ResultsThere was a significant reduction in HOMA-β (240 ± 3.2 vs 177 ± 2.3; P value <0.01) after 12 weeks of atorvastatin treatment, which was maintained by metformin in the subsequent 12 weeks. There were no changes in HOMA-β after the placebo or after subsequent metformin treatment.There was no linear correlation between reduction in HOMA-β with improvement of free androgen index (FAI) (r2 = 0.02; P = 0.72), testosterone (r2 = 0.13; P = 0.49), SHBG (r2 = 0.22; P = 0.48), hsCRP (r2 = 0.19; P = 0.64), triglycerides (r2 = 0.09; P = 0.12), total cholesterol (r2 = 0.11; P = 0.32) or LDL-C (r2 = 0.19; P = 0.38).ConclusionTreatment with atorvastatin for 12 weeks in women with PCOS significantly reduced HOMA-β. This could be potentially due to fall in β-cell requirement with improvement of insulin resistance rather than a reduction of β-cell function.

Testosterone is associated with insulin resistance index independently of adiposity in women with polycystic ovary syndrome

Objective: To study the associations between androgens, glucose homeostasis, inflammation and statin treatment in women with polycystic ovary syndrome (PCOS).Design and methods: Oral glucose tolerance tests, androgens, hs-CRP and interleukin-1 receptor antagonist (IL-1Ra) were analyzed at baseline and after 6 months of atorvastatin (20 mg/d) or placebo treatment in 27 women with PCOS.Results: Testosterone associated with insulin resistance measured with ISIMatsuda independently of BMI, age and SHBG concentrations and the full model, including IL-1Ra, hs-CRP and HDL-C, also showed independency of BMI and waist circumference (p ≤ .042). Free androgen index (FAI) associated with ISIMatsuda independently of adiposity (p ≤ .025) but in the full model with waist circumference the association was insignificant. ISIMatsuda decreased with testosterone >1.2 nmol/l compared with lower levels at baseline (p = .043) and at six months (p = .003). Accordingly, 30-minute insulin levels were increased with moderately elevated testosterone independently of adiposity (p ≤ .046). Increased fasting glucose and AUC insulin associated with statin treatment independently of adiposity and the associations attenuated after adjusting for testosterone.Conclusions: Moderately elevated testosterone concentrations together with obesity-related inflammatory factors modify glucose homeostasis by increasing insulin resistance and early insulin secretion.

Abstract 15951: Psychosocial Wellbeing Does Not Affect Muscle Pain and Quality of Life During Atorvastatin Treatment

Introduction: HMG-CoA reductase inhibitors (statins) are generally well-tolerated, although muscle weakness and pain have been reported in ~10% of statin users. However, many self-reported muscle side effects are non-specific. As mental health influences self-perception of pain, we sought to assess the effect of baseline well-being and depression on self-reported muscle pain and quality of life (QOL) after 6 months of atorvastatin (ATORVA) 80 mg/d or placebo in healthy, statin-naïve adults. Hypothesis: We hypothesized that lower levels of well-being and higher levels of depression would result in higher self-reported pain that interferes with QOL after statin therapy. Methods: The Psychological General Well-Being Index (Well-Being; n=82) and Beck Depression Inventory (Depression; n=55) were administered at baseline in subjects (aged 59.5+1.2 yrs) from STOMP (Effect of Statins on Skeletal Muscle Performance; Clinical Trials #NCT00609063). Muscle pain (Short-Form McGill Pain Questionnaire [SF-MPG]) and pain that interferes with QOL (Brief Pain Inventory [BPI]), were also measured before and after drug treatment. Results: At baseline, there were no group differences in Well-Being, Depression, or pain measures between groups (ps ≥0.05). Baseline Well-Being correlated with baseline BPI pain severity (r=-0.309, p&lt;0.01) and BPI pain interference with QOL (r=-0.271, p&lt;0.05); including both affective and activity subcomponents (ps&lt;0.05). Baseline Depression correlated with baseline pain (r=0.313, p&lt;0.05). Pain severity and interference with QOL scores were not different between statin users and controls after 6 mo of ATORVA (ps≥0.05). Baseline Well-Being and Depression were not significant predictors of pain after 6 mo of ATORVA (ps≥0.05 for overall effects and interactions). Conclusions: Lower levels of psychosocial well-being and higher levels of depression are associated with greater non-specific muscle pain, however, they are not associated with statin-associated muscle side effects or QOL after 6 mo of ATORVA in otherwise healthy adults. Trial Registration: NCT00609063

S16 A Randomised Controlled Trial Of Atorvastatin As A Stable Treatment In Bronchiectasis

Background Bronchiectasis is characterised by chronic cough, sputum production, and recurrent chest infections. Pathogenesis is poorly understood, but excess neutrophilic airway inflammation is seen. Evidence suggests that statins have pleiotropic effects; therefore these drugs could be a potential anti-inflammatory treatment for patients with bronchiectasis. We did a proof-of-concept randomised controlled trial to establish if atorvastatin could reduce cough in patients with bronchiectasis. In addition, we wanted to establish the anti-inflammatory mechanisms of statins contributing to this. Methods Patients aged 18–79 years were recruited from the Royal Infirmary of Edinburgh. Participants had clinically significant bronchiectasis confirmed by chest CT and two or more chest infections in the preceding year. Individuals were randomly allocated to receive either atorvastatin (80 mg) or a placebo, orally once a day for 6 months. Primary endpoint was reduction in cough from baseline to 6 months, measured by the Leicester Cough Questionnaire (LCQ) score (range 3–21; 3 severe cough; minimum clinically important difference, 1·3 units). Findings (i) RCT 30 individuals were assigned atorvastatin and 30 were allocated placebo. There was evidence of a difference in baseline to 6-month change in LCQ between the treatment groups, with a significant improvement in the statin treated group, with a mean difference 2.2, 95% CI for difference (0.5, 3.9) p = 0.01. When analysed as proportion of improvement in LCQ, in the statin treated group 40% patients had a 1.3 Units or more improvement in the LCQ compared with 17% in the placebo group; difference in proportion 23% (95% CI for difference 1%, 45%), p = 0.04. There was significantly increased number of apoptotic airway neutrophils [mean difference of 8.9 (11.7); p = 0.04] with a trend towards a decreased total number of neutrophils in the sputum; p = 0.09; in statin treated group. (ii) In vitro studies Statins enhance apoptosis of neutrophils in vitro due to a reduction in stimuli induced increase in calcium flux. Interpretation 6 months of atorvastatin improved cough on a quality-of-life scale in patients with bronchiectasis. Multicentre studies are now needed to assess whether long-term statin treatment can reduce exacerbations. Further studies are needed to establish if statins regulate Ca 2+ flux by altering the intracellular or extracellular pathways.

Abstract 320: Long-term Atorvastatin, But Not Pravastatin, Treatment Leads To Repressed Mitochondrial Gene Expression And Altered Cardiac Ultrastructure

Statins reduce low-density lipoprotein cholesterol (LDL-C) and decrease cardiovascular events. Although statins are generally well tolerated, the FDA warns that statins may induce skeletal muscle side effects, cognitive changes and increased fasting glucose levels. Skeletal muscle biopsies from patients with statin myopathy have revealed defects in mitochondrial ultrastructure. Impaired mitochondrial function has been postulated as a key cause of statin-induced myopathy and hepatotoxicity. Long-term statin effects on cardiac muscle are currently unknown. Wild type mice received atorvastatin, pravastatin or vehicle daily for seven months by oral gavage. Atorvastatin and pravastatin reduced LDL-C compared to vehicle. Echocardiography at two-week intervals showed no differences in %FS, %EF, circumferential fiber shortening and ventricular wall thicknesses between atorvastatin, pravastatin and vehicle treated mice. After seven months of atorvastatin, pravastatin or vehicle administration cardiac muscles (n=21-29) were analyzed, and only atorvastatin treated hearts revealed: A) swollen and misaligned mitochondria and accumulation of protein aggregates by transmission electron microscopy (n=4, each), and B) repression of mitochondrial and endoplasmatic reticulum related genes by genome-wide expression profiling. In cultured ventricular myocytes, atorvastatin, but not pravastatin; 1) down-regulated survival pathways via inhibition of ERK1/2T202/Y204, AktSer473 and mTOR signaling (p70 S6 kinaseThy421/Ser4240 and S6 RPSER 235/236), 2) reduced protein expression of caveolin-1, dystrophin, epithermal growth factor receptor and insulin receptor β, 3) decreased RhoA activation, and 4) induced apoptosis. LDL-C reduction by atorvastatin, but not pravastatin, was associated with a repression of mitochondrial and endoplasmic reticulum related genes, an accumulation of protein aggregates, and swollen mitochondria. This is the first report demonstrating that long-term atorvastatin treatment causes adverse effects on cardiac muscle with preserved cardiac function. Whether these changes predispose atorvastatin treated hearts to contractile dysfunction after hemodynamic stress needs further investigation.

Atorvastatin as a stable treatment in bronchiectasis: a randomised controlled trial

Bronchiectasis is characterised by chronic cough, sputum production, and recurrent chest infections. Pathogenesis is poorly understood, but excess neutrophilic airway inflammation is seen. Accumulating evidence suggests that statins have pleiotropic effects; therefore, these drugs could be a potential anti-inflammatory treatment for patients with bronchiectasis. We did a proof-of-concept randomised controlled trial to establish if atorvastatin could reduce cough in patients with bronchiectasis. Patients aged 18-79 years were recruited from a secondary-care clinic in Edinburgh, UK. Participants had clinically significant bronchiectasis (ie, cough and sputum production when clinically stable) confirmed by chest CT and two or more chest infections in the preceding year. Individuals were randomly allocated to receive either high-dose atorvastatin (80 mg) or a placebo, given orally once a day for 6 months. Sequence generation was done with a block randomisation of four. Random allocation was masked to study investigators and patients. The primary endpoint was reduction in cough from baseline to 6 months, measured by the Leicester Cough Questionnaire (LCQ) score, with a lower score indicating a more severe cough (minimum clinically important difference, 1·3 units). Analysis was done by intention-to-treat. The trial is registered with ClinicalTrials.gov, number NCT01299181. Between June 23, 2011, and Jan 30, 2011, 82 patients were screened for inclusion in the study and 22 were excluded before randomisation. 30 individuals were assigned atorvastatin and 30 were allocated placebo. The change from baseline to 6 months in LCQ score differed between groups, with a mean change of 1·5 units in patients allocated atorvastatin versus -0·7 units in those assigned placebo (mean difference 2·2, 95% CI 0·5-3·9; p=0·01). 12 (40%) of 30 patients in the atorvastatin group improved by 1·3 units or more on the LCQ compared with five (17%) of 30 in the placebo group (difference 23%, 95% CI 1-45; p=0·04). Ten (33%) patients assigned atorvastatin had an adverse event versus three (10%) allocated placebo (difference 23%, 95% CI 3-43; p=0·02). No serious adverse events were recorded. 6 months of atorvastatin improved cough on a quality-of-life scale in patients with bronchiectasis. Multicentre studies are now needed to assess whether long-term statin treatment can reduce exacerbations. Chief Scientist's Office.

Response to statin therapy in obstructive sleep apnea syndrome: a multicenter randomized controlled trial.

Rationale. Accumulated evidence implicates sympathetic activation as inducing oxidative stress and systemic inflammation, which in turn lead to hypertension, endothelial dysfunction, and atherosclerosis in obstructive sleep apnea (OSA). Statins through their pleiotropic properties may modify inflammation, lipid profile, and cardiovascular outcomes in OSA. Methods. This multicenter, randomized, double-blind study compared the effects of atorvastatin 40 mg/day versus placebo over 12 weeks on endothelial function (the primary endpoint) measured by peripheral arterial tone (PAT). Secondary endpoints included office blood pressure (BP), early carotid atherosclerosis, arterial stiffness measured by pulse wave velocity (PWV), and metabolic parameters. Results. 51 severe OSA patients were randomized. Key demographics for the study population were age 54 ± 11 years, 21.6% female, and BMI 28.5 ± 4.5 kg/m2. In intention to treat analysis, mean PAT difference between atorvastatin and placebo groups was 0.008 (−0.29; 0.28), P = 0.979. Total and LDL cholesterol significantly improved with atorvastatin. Systolic BP significantly decreased with atorvastatin (mean difference: −6.34 mmHg (−12.68; −0.01), P = 0.050) whereas carotid atherosclerosis and PWV were unchanged compared to the placebo group. Conclusion. In OSA patients, 3 months of atorvastatin neither improved endothelial function nor reduced early signs of atherosclerosis although it lowered blood pressure and improved lipid profile. This trial is registered with NCT00669695.

Effects of Atorvastatin on Cerebral Blood Flow in Middle-Aged Adults at Risk for Alzheimer’s Disease: A Pilot Study

Hypercholesterolemia in midlife increases risk for Alzheimer's disease (AD) and contributes to cerebrovascular dysregulation - an early finding in preclinical AD pathology. Statins improve vascular reactivity, but it is unknown if they increase regional cerebral blood flow (CBF) in individuals at risk for AD. In a randomized, controlled, double-blind pilot study, 16 asymptomatic middle-aged adults with parental history of AD were randomized to atorvastatin or placebo daily for 4 months. At baseline and month 4, regional CBF was measured using arterial spin-labeling magnetic resonance imaging and endothelial function was measured using brachial artery ultrasound. At baseline, participants with low HDL-cholesterol, higher global vascular risk, and greater endothelial dysfunction had reduced regional CBF in areas of the brain related to memory and learning (all p < 0.03). Using voxel-based analysis, 4 months of atorvastatin increased CBF in bilateral hippocampi, fusiform gyrus, putamen and insular cortices compared to placebo. In this pilot study, atorvastatin increased regional CBF in persons at risk for AD. Further research is warranted to confirm whether statins increase CBF in areas of the brain related to memory and learning and whether such perfusion changes are associated with a delay in the onset of AD. http://clinicaltrials.gov Identifier: NCT00751907.

Atorvastatin Reduces Malondialdehyde Concentrations in Patients with Polycystic Ovary Syndrome

It has been shown that there is an increase in oxidative stress in polycystic ovary syndrome (PCOS). Statins are considered to have a pleiotropic effect other than their lipid-lowering effect. These effects may be mediated in part by reducing oxidative stress. This randomized, double-blind, placebo-controlled study was conducted to assess the effect of atorvastatin on serum malondialdehyde (MDA) concentrations as a marker of oxidative stress in patients with PCOS. Forty medication-naïve patients with PCOS were randomized to either atorvastatin 20 mg daily or placebo for 3 months. A 3-month extension study for both groups of patients was undertaken with metformin 1500 mg daily after completing initial 3 months of atorvastatin or placebo. There was a significant decrease of MDA concentrations with atorvastatin [mean (sem)] [0.29 (0.04) vs. 0.25 (0.02) μmol/liter; P < 0.01] compared with placebo [0.28 (0.02) vs. 0.29 (0.12) μmol/liter; P = 0.52]. Three months treatment with metformin resulted in further reduction of MDA levels with atorvastatin compared with baseline [0.25 (0.02) baseline vs. 0.23 (0.03) μmol/liter for atorvastatin treated; P = 0.02]. There was also a significant correlation between the reduction in MDA with a reduction in high-sensitivity C-reactive protein (r = 0.71, P < 0.01), an increase in 25-hydroxyvitamin D (25OHD; r = -0.68, P = 0.02), and a reduction in testosterone levels (r = 0.63, P = 0.01). Multiple linear regression analysis revealed Δ25OHD, ΔC-reactive protein, and Δtestosterone were independent predictors of changes in MDA after atorvastatin treatment. No correlation was observed between the reductions in serum MDA concentrations with changes in the lipid parameters. Twelve weeks of atorvastatin led to a significant reduction in oxidative stress as determined by MDA concentrations among patients with polycystic ovary syndrome that was independently predicted by changes in testosterone, 25OHD, and high-sensitivity C-reactive protein.

Virtual Histology Findings and Effects of Varying Doses of Atorvastatin on Coronary Plaque Volume and Composition in Statin-Naive Patients

While statin induces plaque regression, its effects, particularly with different doses on plaque virtual histology composition, remain unknown. In this prospective, randomized, double-blinded study, 40 consecutive statin-naive patients with stable angina requiring percutaneous coronary intervention (PCI) were randomized to 2 arms (20 patients each) receiving 6 months of atorvastatin 10 mg or 40 mg daily. The primary end-point was (VH-IVUS) changes from baseline to 6 months, as assessed by a core laboratory. Fifty-four VH-IVUS lesions were analyzed from the 10 mg group and 57 from the 40 mg group. Overall, plaque volume was reduced by 4.28% (-5.10±14.93 mm(3), P<0.001), absolute VH-IVUS fibrous volume by 10.54% (-4.87±10.74 mm(3), P<0.001), and relative percentage fibrous component by 3.29±7.84% (P<0.001), while relative percentage dense calcium increased by 1.50±3.08% (P<0.001), and necrotic core by 3.19±7.82% (P<0.001). Beneficial changes were more substantial in the higher dose (40 mg) group, with significantly more percentage plaque volume regression (-1.50±3.85% vs. 0.38±4.05% increase in the 10 mg group, P=0.014), less relative percentage necrotic core expansion (1.68±7.57% vs. 4.78±7.82% in the 10 mg group, P=0.037), and without occurrence of major adverse cardiac events (vs. 6 patients in the 10 mg group, P=0.020). In statin-naive patients requiring PCI, 6 months of atorvastatin induced a significant percentage of plaque volume reduction and substantial modification of VH-IVUS composition. In addition, these effects appeared to vary with different doses of atorvastatin, showing significantly better limitation of relative percentage necrotic core expansion at a higher dose.

Atorvastatin therapy decreases androstenedione and dehydroepiandrosterone sulphate concentrations in patients with polycystic ovary syndrome: randomized controlled study

Hyperandrogenaemia in polycystic ovary syndrome (PCOS) represents a composite of raised serum concentrations of testosterone, androstenedione, dehydroepiandrosterone (DHEA) and DHEA sulphate (DHEAS). In patients with PCOS, testosterone and androstenedione are primarily derived from the ovaries and DHEAS is a metabolite predominantly from the adrenals. It has been shown that atorvastatin reduces testosterone concentrations in patients with PCOS. The objective was to study the effect of atorvastatin on serum androstenedione and DHEAS concentrations in patients with PCOS. A randomized, double-blind, placebo-controlled study was performed. Forty medication-naive patients with PCOs were randomized to either atorvastatin 20mg daily or placebo for three months. Subsequently, a three-month extension study for all patients was undertaken with metformin 1500 mg daily. The main outcome measures were change in androstenedione and DHEAS concentrations. The mean (SD) baseline androstenedione (5.7 [0.8] versus 5.6 [1.3] nmol/L; P = 0.69) and DHEAS (7.1 [1.0] versus 7.2 [1.2] μmol/L; P = 0.72) concentrations were comparable between two groups. There was a significant reduction of androstenedione (5.7 [0.8] versus 4.7 [0.7] nmol/L; P = 0.03) and DHEAS (7.1 [1.0] versus 6.0 [0.9] μmol/L; P = 0.02) with three months of atorvastatin while there were no significant changes with placebo. Three months' treatment with metformin maintained the reduction of androstenedione and DHEAS concentrations with atorvastatin compared with baseline. There were no changes in either DHEAS or androstenedione concentrations in the initial placebo group after 12 weeks of metformin. Twelve weeks of atorvastatin significantly reduced both DHEAS and androstenedione contributing to the total reduction of androgen concentrations and indicating that the reduction of the hyperandrogenaemia could be partly due to the action of atorvastatin at both the ovary and the adrenal gland in PCOS.

Distinct effects of pitavastatin and atorvastatin on lipoprotein subclasses in patients with Type 2 diabetes mellitus

Effects of pitavastatin and atorvastatin on the lipid profile and lipoprotein subclasses were compared in patients with Type 2 diabetes with dyslipidaemia. Patients with Type 2 diabetes with hypercholesterolaemia and/or hypertriglyceridaemia were randomized to receive pitavastatin 2 mg (n = 16) or atorvastatin 10 mg (n = 15) for 6 months, and blood lipid and lipoprotein profiles and cholesterol and triglyceride contents of 20 lipoprotein subclasses, determined by high-performance liquid chromatography, were compared. At baseline, cholesterol in VLDL and LDL subclasses were increased equally in two groups of patients with diabetes as compared with normolipidaemic control subjects. As compared with baseline, serum levels of total cholesterol, LDL cholesterol, non-HDL cholesterol, LDL cholesterol:HDL cholesterol ratio and apolipoprotein B were decreased after 1, 3 and 6 months of treatment with atorvastatin and pitavastatin. Serum triglyceride levels were decreased after 1, 3 and 6 months of atorvastatin, but only at 3 months of pitavastatin. Serum HDL cholesterol was increased after 1, 3 and 6 months of pitavastatin, whereas HDL cholesterol was even decreased after 6 months of atorvastatin. Cholesterol levels of most VLDL and LDL subclasses were decreased equally in both groups. However, only pitavastatin increased cholesterol of medium HDL subclass. Serum triglyceride and triglyceride contents in VLDL and LDL subclasses were decreased only by atorvastatin. The impact on lipoprotein subclass profiles was different between pitavastatin and atorvastatin. It may be beneficial to determine lipoprotein subclass profile and select the appropriate statin for each profile in patients with diabetes with an additional cardiovascular risk such as low HDL cholesterol or hypertriglyceridaemia.

Atorvastatin Increases 25-Hydroxy Vitamin D Concentrations in Patients with Polycystic Ovary Syndrome

It has been shown that many women with polycystic ovary syndrome (PCOS) are 25-hydroxyvitamin D (25OHD) insufficient. Both statin treatment and vitamin D supplementation have been shown to improve biochemical hyperandrogenemia, insulin resistance, and markers of inflammation in patients with PCOS, raising the possibility that some of the statin effects are mediated through vitamin D. We conducted this randomized, double-blind placebo controlled study to assess the effect of atorvastatin on serum 25OHD concentrations in patients with PCOS. Forty medication-naive patients with PCOS were randomized to either atorvastatin 20 mg daily or placebo for 3 months. After completing the initial 3 months of atorvastatin or placebo, both groups of patients participated in a 3-month extension study with metformin 1500 mg daily. We measured changes in 25OHD concentrations by use of tandem mass spectrometry. Mean (SD) baseline 25OHD concentrations were comparable between the 2 groups [45.9 (2.4) vs 44.8 (1.8) nmol/L; P = 0.7]. There was a significant increase in 25OHD concentrations with atorvastatin [45.9 (2.4) vs 60.8 (3.5) nmol/L] compared with placebo [44.8 (1.8) vs 41.8 (3.2) nmol/L; P = 0.02]. Three-month treatment with metformin maintained the improvement of 25OHD with atorvastatin compared to baseline [45.9 (2.4) vs 61.8 (3.5), P ≤ 0.01). There were no significant changes in 25OHD concentrations in the placebo group after 12 weeks of metformin. Among patients with polycystic ovary syndrome, 12 weeks of atorvastatin led to a clinically significant rise in 25OHD concentrations. This may represent a beneficial pleiotropic effect of statins on 25OHD concentrations.

Higher Baseline LDL-C Levels Amplify the Short-Term Benefit of Early Intensive Statin Treatment in Acute Coronary Syndrome

Some randomized studies have shown a delay of up to a few years in the statin-related survival advantage, whereas others have demonstrated an early survival benefit for some patients. We examined the short-term effects of statins in patients with acute coronary syndrome (ACS), stratified according to baseline LDL-C. Patients with ACS (n = 180) were randomized to receive 6 months of atorvastatin (20 mg) in the Extended-ESTABLISH trial. Six months after ACS onset, all patients were treated with statins to achieve an LDL-C value of < 100 mg/dL. Patient outcomes were analyzed with respect to LDL-C at the time of ACS onset: high baseline (≥ 100 mg/dL, n = 124) or low baseline (< 100 mg/dL, n = 56) LDL-C. The cumulative incidence rates of major adverse cardiac and cerebrovascular events (MACCE) did not significantly differ between the early-statin and control groups in the high baseline groups at 6 months (p = 0.158), whereas a significant benefit of early intensive statins appeared 1 year (p = 0.034) later. In contrast, we found no significant short-term benefits of statins after either 6 months or 1 year in the low baseline group. Multivariate analysis showed that early intensive atorvastatin therapy was associated with a lower risk of MACCE at 1 year in the high baseline group (OR, 0.25; 95% CI, 0.05 to 0.83; p = 0.035). The effects of 6 months of intensive lipid-lowering therapy appear after 1 year in patients with ACS and baseline LDL-C ≥ 100 mg/dL.

The SLIM Study: Slo-Niacin® and Atorvastatin Treatment of Lipoproteins and Inflammatory Markers in Combined Hyperlipidemia.

BACKGROUND: The combination of niacin and statin has proven value in hyperlipidemia management and heart disease prevention. However, the efficacy of the non-prescription time-release niacin, Slo-Niacin®, is little studied alone and not at all with atorvastatin. We gave Slo-Niacin® and atorvastatin, singly and together to determine efficacy on the combined abnormalities of triglyceride, LDL and HDL. METHODS: 42 men and women with LDL-C>130mg/dL HDL-C <45 (men or 55mg/dL (women) were randomized to 3 months of atorvastatin 10 mg/day or incremental doses of Slo-Niacin® to 1500 mg/day. The alternate drug was added in the next 3-month segment. Lipid profiles and transaminases were measured monthly and other measures at baseline and the end of each treatment sequence. RESULTS: Mean entry lipids (mg/dL) were: TG 187, LDL-C 171, and HDL-C 39. Mean BMI was 32.6 Kg/m(2). Monotherapy with Slo-Niacin® decreased median triglyceride 15%, mean LDL-C 12% and non-HDL-C 15% and increased HDL-C 8%. Atorvastatin decreased median triglyceride 26%, and mean LDL-C 36%, non-HDL-C 36% and increased HDL-C 6%. Combined therapy decreased median triglyceride 33% and mean LDL-C and non-HDL-C each 43%. HDL-C increased 10% (all p<0.001). Median remnant-like lipoprotein-C decreased 55%, mean apo-B 40%, median hsCRP 23% (all p<0.05), TNFa 12% and no change in IL-6. Mean LDL buoyancy increased 15%, apo-A-I 5% and median HDL(2)-C 20% (all p<0.05). ALT declined with Slo-Niacin® treatment alone compared to atorvastatin and also decreased when Slo-Niacin® was added to atorvastatin. Six subjects dropped out, 3 for niacin related symptoms. CONCLUSIONS: Slo-Niacin® 1.5g/day with atorvastatin 10 mg/day improved lipoprotein lipids, apoproteins and inflammation markers without hepatotoxicity. Slo-Niacin® deserves further study as a cost-effective treatment of hyperlipidemia.

The in vivo role of arginase in cutaneous microvascular dysfunction in hypercholesterolemic humans before and after statin therapy

Elevated low‐density lipoproteins (LDL) are associated with systemic vascular dysfunction evident in the cutaneous microvasculature. Our aim was to determine the role of arginase and freely exchangeable L‐arginine (L‐arg) in vivo in reduced NO‐dependent vasodilation (VD) in hypercholesteroleΔic (HC) skin before and after statin therapy. Three intradermal microdialysis (MD) fibers were placed in 5 normocholesterolemic (NC) (LDL=92 ±8 mg/dl) and 6 HC subjects before (LDL=179±6 mg/dl) and after 3 months of atorvastatin (10 mg) (LDL=100±7 mg/dl): control, arginase‐inhibited (A‐I: 5 mM BEC), and L‐arg (10 mM). Skin blood flow (SkBF) was measured while local skin heating (42°C) induced NO‐dependent VD [quantified (ΔNO) by infusing 10 mM L‐NAME after the plateau (P) in SkBF]. Cutaneous vascular conductance (CVC= flux/MAP) was normalized to max (50 mM SNP). VD was reduced in HC (HC: 77±5 vs. NC: 94±5 % max, p&lt;0.05) as was ΔNO (HC: 37±5 vs. NC: 61±6 % max, p&lt;0.05). P and ΔNO were augmented in HC with A‐I (P: 92±3, ΔNO: 65±3% max, p&lt;0.05) and L‐arg (P: 95±3, ΔNO: 75±4% max, p&lt;0.05) but not in NC. After statin therapy there was no difference between control (P: 92±2, ΔNO: 51±4% max) and A‐I (P: 97±1, ΔNO: 62±6% max, p&gt;0.05) or L‐arg (P: 94±3, ΔNO: 56±5% max, p&gt;0.05) sites. Reduced NOS substrate availability through upregulated arginase contributes to cutaneous microvascular dysfunction with HC, which is corrected with statin therapy.

Utilidad de la citometría de flujo para valorar el efecto de la atorvastatina sobre la función plaquetaria y la movilización del Ca 2+ en pacientes hiperlipémicos

Introduction Thrombotic events are common in hyperlipemic patients in which platelet activation play a decisive role. The presence of activated platelets, as described in a previous paper, is a major risk factor for thrombosis in patients with a high plasma cholesterol and it is therefore of great interest to have a lipid lowering drug that, in addition to normalising plasma lipids, also decreases this activation of circulating platelets. The main aims of this study are to assess whether the increased platelet activation in hypercholesterolemic patients is accompanied by changes in cytoplasmic free calcium mobilisation in platelets and the formation of platelet microaggregates, and whether these changes are normalised by treatment with atorvastatin. Material and methods To achieve these aims 30 hypercholesterolemia patients and 40 normolipemic controls were recruited. The percentage of CD62 positive platelets, the number of spontaneously formed platelet microaggregates (MAP/5000 platelets) and the free calcium mobilization in platelets were evaluated in citrated blood . An EPICS-XL flow cytometer and the antibodies and fluorochromes CD61.PE, CD62.FITC and FLUO3-AM were used for this study. The patients were evaluated before and after two months of atorvastatin (20 mg/day) treatment. Results The results show that atorvastatin treatment significantly decreases the plasma concentration of total and LDL-Cholesterol and triglycerides. In parallel a decrease was noted in the percentage of activated circulating CD62 positive platelets (2.41±1.55% to 1.45±1.06%, P<0.05) and also in the number of spontaneously formed MAP (390±43 to 322±48, P<0.05). These changes were accompanied by the normalization in the free calcium mobilization in platelets. Conclusions As a conclusion it is noted that the flow cytometry of whole blood is a useful technique for evaluating aspects such as those raised in this study. Hypercholesterolemia patients showed more spontaneous platelet activation, which was accompanied by the formation of platelet microaggregates and changes in the cytoplasmic free calcium mobilization, which were normalised by treatment with atorvastatin, which has not been previously reported in the literature.

Effect of intensive statin therapy on arterial elasticity in patients with coronary artery disease

Objective — Reduced arterial compliance is an independent predictor of cardiovascular mortality and is commonly encountered in patients with coronary artery disease. Statins may produce cholesterol-independent effects which can result at least in part from direct improvement of the arterial function. In this study, we sought to determine the effect of intensive statin therapy according to the Adult Treatment Panel III guidelines on arterial compliance in dyslipidaemic patients with angiographically-proven CAD selected for medical treatment.Methods — Patients (n = 33) received atorvastatin 40 mg/day for 6 months. Large arterial compliance and small arterial compliance were measured at baseline and after 6 months of atorvastatin treatment.Results — After treatment, the large artery elasticity index (LAEI) increased from 11.85 ± 3.46 to 13.80 ± 3.95 ml/mm Hg x 100 (P < 0.001) and the small artery elasticity index (SAEI) increased from 3.84 ± 1.97 to 4.97 ± 1.98 ml/mm Hg (P= 0.03).There was no correlation between the change in either LAEI or SAEI and other baseline variables or changes in lipid levels.Conclusion — Our findings suggest that intensive statin therapy according to the Adult Treatment Panel III guidelines improves arterial elasticity in CAD patients selected for medical treatment.The beneficial vascular effect of atorvastatin on arterial elasticity was independent of lipid parameters.

A 6 month randomized, double blind, placebo controlled, multi-center trial of high dose atorvastatin on myocardial perfusion abnormalities by positron emission tomography in coronary artery disease

In coronary artery disease (CAD), statins decrease morbidity and mortality but changes in myocardial perfusion abnormalities remain poorly defined. We completed a randomized, double blind, placebo controlled, multi-center trial of 145 patients, 43 to 86 years old, with CAD from seven community and academic centers for cardiac positron emission tomography (PET) randomized to 6 months of atorvastatin 80 mg daily (72 patients) or placebo (73 patients). PET scans were obtained at baseline, 6 weeks and 6 months using N-13 ammonia or Rb-82 at rest and after dipyridamole or adenosine stress, submitted to the core PET laboratory in Houston. Change in stress induced perfusion defects from baseline to follow-up PET scans was scored by two independent, double blinded readers and by automated quantitative software. Total and LDL cholesterol decreased by 37% and 51%, respectively in atorvastatin but not placebo groups (P < .05). The primary endpoint, quantitative severity (lowest mean quadrant activity), showed no significant difference between treatment and placebo. The secondary endpoint, predefined blinded visual change scores, improved significantly after atorvastatin compared to placebo at six months (P = .02). Ad-hoc subgroup analysis showed interaction between quantitative defect size and treatment response with perfusion defects in the upper tertile of size by automated software improving more in atorvastatin than placebo groups (P = .016). The primary endpoint, quantitative severity of myocardial perfusion abnormalities by PET, did not improve after 6 months of atorvastatin 80 mg daily compared to placebo. The secondary endpoint of predefined blinded visual change scores significantly improved, as did a subgroup in the upper tertile of defect size, compared to placebo.