High dose atorvastatin associated with increased risk of significant hepatotoxicity in comparison to simvastatin in UK GPRD cohort

Background and Aims: Occasional risk of serious liver dysfunction and autoimmune hepatitis during atorvastatin therapy has been reported. We compared the risk of hepatotoxicity in atorvastatin relative to simvastatin treatment. Methods: The UK GPRD identified patients with a first prescription for simvastatin [164,407] or atorvastatin [76,411] between 1997 and 2006, but with no prior record of liver disease, alcohol-related diagnosis, or liver dysfunction. Incident liver dysfunction in the following six months was identified by biochemical value and compared between statin groups by Cox regression model adjusting for age, sex, year treatment started, dose, alcohol consumption, smoking, body mass index and comorbid conditions. Results: Moderate to severe hepatotoxicity [bilirubin >60μmol/L, AST or ALT >200U/L or alkaline phosphatase >1200U/L] developed in 71 patients on atorvastatin versus 101 on simvastatin. Adjusted hazard ratio [AHR] for all atorvastatin relative to simvastatin was 1.9 [95% confidence interval 1.4–2.6]. High dose was classified as 40–80mg daily and low dose 10–20mg daily. Hepatotoxicity occurred in 0.44% of 4075 patients on high dose atorvastatin [HDA], 0.07% of 72,336 on low dose atorvastatin [LDA], 0.09% of 44,675 on high dose simvastatin [HDS] and 0.05% of 119,732 on low dose simvastatin [LDS]. AHRs compared to LDS were 7.3 [4.2–12.7] for HDA, 1.4 [0.9–2.0] for LDA and 1.5 [1.0–2.2] for HDS. Conclusions: The risk of hepatotoxicity was increased in the first six months of atorvastatin compared to simvastatin treatment, with the greatest difference between high dose atorvastatin and low dose simvastatin. The numbers of events in the analyses were small

Randomized double-blind placebo-controlled trial of 40 mg/day of atorvastatin in reducing the severity of sepsis in ward patients (ASEPSIS Trial)

Introduction: Several observational studies suggest that statins modulate the pathophysiology of sepsis and may prevent its progression. The aim of this study was to determine if the acute administration of atorvastatin reduces sepsis progression in statin naïve patients hospitalized with sepsis. Methods: A single centre phase II randomized double-blind placebo-controlled trial. Patients with sepsis were randomized to atorvastatin 40 mg daily or placebo for the duration of their hospital stay up to a maximum of 28-days. The primary end-point was the rate of sepsis progressing to severe sepsis during hospitalization. Results: 100 patients were randomized, 49 to the treatment with atorvastatin and 51 to placebo. Patients in the atorvastatin group had a significantly lower conversion rate to severe sepsis compared to placebo (4% vs. 24% p = 0.007.), with a number needed to treat of 5. No significant difference in length of hospital stay, critical care unit admissions, 28-day and 12-month readmissions or mortality was observed. Plasma cholesterol and albumin creatinine ratios were significantly lower at day 4 in the atorvastatin group (p < 0.0001 and p = 0.049 respectively). No difference in adverse events between the two groups was observed (p = 0.238). Conclusions: Acute administration of atorvastatin in patients with sepsis may prevent sepsis progression. Further multi-centre trials are required to verify these findings. Trial Registration: International Standard Randomized Control Trial Registry ISRCTN64637517

The role of metformin response in lipid metabolism in patients with recent-onset type 2 diabetes: HbA1c level as a criterion for designating patients as responders or nonresponders to metformin

Background: In this study, we investigated whether response to metformin, the most frequently drug for diabetes treatment, influences the therapeutic effects of antilipidemic medication in newly diagnosed patients with type 2 diabetes mellitus (T2DM). Methods: A total of 150 patients with T2DM were classified into two groups following 3 months of metformin therapy (1000mg twice daily): responders (patients showing >1% reduction in HbA1c from baseline) and nonresponders (patients showing <1% reduction in HbA1c from baseline). The patients received atorvastatin 20 mg, gemfibrozil 300 mg, or atorvastatin 20 mg and gemfibrozil 300 mg daily. Principal Findings: HbA1c and fasting glucose levels were significantly different between baseline and 3 months among responders receiving atorvastatin; however, these differences were not statistically significant in nonresponders. Atherogenic ratios of low-density lipoprotein cholesterol to high-density lipoprotein cholesterol (LDL-C/HDL-C; p = 0.002), total cholesterol to HDL-C (TC/HDL-C; p<0.001) and AIP (the atherogenic index of plasma; p = 0.004) decreased significantly in responders receiving atorvastatin than in nonresponders. Moreover, responders receiving atorvastatin showed a significant increase in HDL-C levels but nonresponders receiving atorvastatin did not (p = 0.007). The multivariate model identified a significant association between metformin response (as the independent variable) and TG, TC, HDL-C and LDL-C (dependent variables; Wilk's λ = 0.927, p = 0.036). Conclusions: Metformin response affects therapeutic outcomes of atorvastatin on atherogenic lipid markers in patients newly diagnosed with T2DM. Metformin has a greater impact on BMI in responders of metformin compared to nonresponders. Adoption of better therapeutic strategies for reducing atherogenic lipid markers may be necessary for metformin nonresponders. © 2016 Kashi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Effects of short-term treatment with atorvastatin in smokers with asthma - a randomized controlled trial

&lt;b&gt;Background&lt;/b&gt; The immune modulating properties of statins may benefit smokers with asthma. We tested the hypothesis that short-term treatment with atorvastatin improves lung function or indices of asthma control in smokers with asthma.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Methods&lt;/b&gt; Seventy one smokers with mild to moderate asthma were recruited to a randomized double-blind parallel group trial comparing treatment with atorvastatin (40 mg per day) versus placebo for 4 weeks. After 4 weeks treatment inhaled beclometasone (400 ug per day) was added to both treatment arms for a further 4 weeks. The primary outcome was morning peak expiratory flow after 4 weeks treatment. Secondary outcome measures included indices of asthma control and airway inflammation.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Results&lt;/b&gt; At 4 weeks, there was no improvement in the atorvastatin group compared to the placebo group in morning peak expiratory flow [-10.67 L/min, 95% CI -38.70 to 17.37, p=0.449], but there was an improvement with atorvastatin in asthma quality of life score [0.52, 95% CI 0.17 to 0.87 p=0.005]. There was no significant improvement with atorvastatin and inhaled beclometasone compared to inhaled beclometasone alone in outcome measures at 8 weeks.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusions&lt;/b&gt; Short-term treatment with atorvastatin does not alter lung function but may improve asthma quality of life in smokers with mild to moderate asthma. Clinicaltrials.gov identifier: NCT0046382

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

Background There 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 is some data to show that statins increase the risk of incipient diabetes. Material and Methods We 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 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. Results There was a significant reduction in HOMA-β (240±3.2vs.177±2.3; pvalue&lt;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). Conclusion Treatment with atorvastatin for 12 weeks in women with PCOS significantly reduced HOMA-β. This could be potentially due to fall in βcell requirement with improvement of insulin resistance rather than a reduction of βcell function

The effects of atorvastatin in mustard gas exposed patients with chronic obstructive pulmonary disease: A randomized controlled trail

Background: Statins have anti-inflammatory effects in patients with chronic obstructive pulmonary disease. This study designed to evaluate the effects of atorvastatin on serum highly sensitive C-reactive protein (hs-CRP) and pulmonary function in sulfur mustard (SM) exposed patients with chronic obstructive pulmonary disease. Methods: In a double blind clinical trial, 50 patients with chronic obstructive pulmonary disease due to sulfur mustard and high hs-CRP, randomly entered in this study. 45 patients completed the study (n=22, placebo and n=23, atorvastatin). Serum hs-CRP, pulseoximetry, spirometery and six-minute walk distance test (6MWDT) were measured, COPD assessment test (CAT) and St George's respiratory questionnaire (SGRQ) were completed by patients at the beginning of trial and after 9 weeks of prescription of 40 mg/day atorvastatin or placebo. At 4th week, pulseoximetry, spirometry and 6MWDT were measured. Results: At 4th week, there was no improvement in the atorvastatin group compared to the placebo group in SPO2, FEV1, and 6MWDT (p=0.79, p=0.12, p=0.12 respectively). At 9th week, there was no improvement with atorvastatin in serum hs-CRP, SPO2, FEV1 and 6MWDT compared to the placebo (p=0.35, p=0.28, p=0.94, p=0.43 respectively) but there was an improvement with atorvastatin in quality of life (with CAT score, P<0.001 and SGRQ total score, P=0.004). Conclusion: Atorvastatin does not alter serum hs-CRP and lung functions but may improve quality of life in SM-injured patients with chronic obstructive pulmonary disease

Redemptive benefit of atorvastatin in the risk factors of coronary artery disease

Cardiovascular disease, in particular coronary artery disease (CAD), is the principal cause of mortality in developed countries. The classical acute phase protein, C-reactive protein (CRP) is an exquisitely sensitive systemic marker of disease with broad clinical utility for monitoring and differential diagnosis. In recent years, acute phase reactants have been shown to predict future cardiovascular events in individuals with and without established CAD. Atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, substantially reduce cardiovascular morbidity and mortality, and recently their anti-inflammatory properties have been investigated. The present study was therefore designed to determine the effects of atorvastatin on CRP in patients with CAD. Ninety two patients with or without or at the risk of CAD were recruited for the study, of which 35 belongs to control (untreated) and 57 were test group, in which, 30 of them received daily with 20 mg/day of atorvastatin and the remaining 27 were untreated. The patients were followed for over a period of 6 weeks. For entire study population, CRP along with lipid profile, SGOT, SGPT, urea and creatinine were measured 1st day and at the end of 6th week of the treatment. For patients with or at risk of CAD, the reduced rate of progression of atherosclerosis associated with intensive atorvastatin treatment, as compared with control is significantly related to greater reduction in the levels of both atherogenic lipoproteins and CRP. This may be important with respect to the early benefits of atorvastatin therapy

Atorvastatin effects on serum level of hs-CRP and lung function in chemical warfare victims with chronic obstructive pulmonary disease.

Background: Anti-Infammatory properties of Statins may be beneficial in reduction of airway inflammation and improvement of lung function in patients with chronic obstructive pulmonary disease. This study designed to evaluate the effects of atorvastatin on serum level of highly sensitive C-reactive protein (hs-CRP) and pulmonary function in chemical warfare (sulfur mustard) victims with chronic obstructive pulmonary disease. Methods ana materials: In a double blind clinical trial, 50 patients with chronic obstructive pulmonary disease due to sulfur mustard and high serum level of hs-CRP entered in this study. 45 patients completed the study (n=22, placebo and n=23, atorvastatin randomly). Serum level of hs-CRP by particle enhanced turbimetric assay, pulse oximetry, spirometry and six minute walk distance (6MWD) were measured, COPD assessment test (CAT) and St George’s respiratory questionnaire (SGRQ) were completed by patients at the beginning of trial and after 9 weeks of prescription of 40 mg/day atorvastatin or placebo. After 4 weeks, pulse oximetry, spirometry and 6MWD were measured. RESULT: After 4 weeks, there was no improvement in the atorvastatin group compared to the placebo group in SPO2, FEV1 and 6MWD (p=0.79, p=0.12 and p=0.12 respectively). After 9 weeks, there was no improvement with atorvastatin in serum level of hs-CRP, SPO2, FEV1 and 6MWD compared to the placebo (p=0.35, p=0.28, p=0.94 and p=0.43 respectively) but there was an improvement with atorvastatin in health-related quality of life (with CAT score, P<0.001 and SGRQ total score, P=0.004). Conclusion: Atorvastatin does not alter serum level of hs-CRP and lung function but may improve health-related quality of life in sulfur mustard-injured patients with chronic obstructive pulmonary disease

A mechanistic study on the phototoxicity of atorvastatin: singlet oxygen generation by a phenanthrene-like photoproduct

Atorvastatin calcium (ATV) is one of the most frequently prescribed drugs worldwide. Among the adverse effects observed for this lipid-lowering agent, clinical cases of cutaneous adverse reactions have been reported and associated with photosensitivity disorders. Previous work dealing with ATV photochemistry has shown that exposure to natural sunlight in aqueous solution leads to photoproducts resulting from oxidation of the pyrrole ring and from cyclization to a phenanthrene derivative. Laser flash photolysis of ATV, at both 266 and 308 nm, led to a transient spectrum with two maxima at λ ) 360 and λ ) 580 nm (τ ) 41 μs), which was assigned to the primary intermediate of the stilbene-like photocyclization. On the basis of the absence of a triplet-triplet absorption, the role of the parent drug as singlet oxygen photosensitizer can be discarded. By contrast, a stable phenanthrene-like photoproduct would be a good candidate to play this role. Laser flash photolysis of this compound showed a triplet-triplet transient absorption at λmax ) 460 nm with a lifetime of 26 μs, which was efficiently quenched by oxygen (kq ) 3 ((0.2) × 109 M-1 s-1). Its potential to photosensitize formation of singlet oxygen was confirmed by spin trapping experiments, through conversion of TEMP to the stable free radical TEMPO. The photoreactivity of the phenanthrene-like photoproduct was investigated using Trp as a marker. The disappearance of the amino acid fluorescence (λmax ) 340 nm) after increasing irradiation times at 355 nm was taken as a measurement of photodynamic oxidation. To confirm the involvement of a type II mechanism, the same experiment was also performed in D2O; this resulted in a significant enhancement of the reaction rate. On the basis of the obtained photophysical and photochemical results, the phototoxicity of atorvastatin can be attributed to singlet oxygen formation with the phenanthrene-like photoproduct as a photosensitizer

Photochemical behavior of the drug atorvastatin in water.

Atorvastatin undergoes a self-sensitized photooxygenation by sunlight in water. The main photoproducts, isolated by chromatographic techniques, have been identified by spectroscopic means. They present a lactam ring arising from an oxidation of pyrrole ring and an alkyl/aryl shift. A mechanism involving singlet oxygen addition and an epoxide intermediate is suggested