Effect of atorvastatin on asthma control and airway inflammation: a randomised controlled trial

Hothersall, Eleanor Jane (2008) Effect of atorvastatin on asthma control and airway inflammation: a randomised controlled trial. MD thesis, University of Glasgow.

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Statins are inhibitors of the rate-limiting enzyme, 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, in cholesterol biosynthesis. As such, they have been widely used in clinical practice as cholesterol lowering agents to reduce morbidity and mortality from coronary artery disease. There is evidence from clinical studies and in vitro experiments that statins have additional anti-inflammatory properties in atherosclerotic disease, which are unrelated to their lipid lowering activity.

Clinical studies have previously suggested that statins might show a beneficial clinical effect in inflammatory diseases, such as rheumatoid arthritis and multiple sclerosis. Furthermore, preliminary data obtained in models of pulmonary inflammation suggest that the effects manifest in rheumatoid patients can be achieved also in asthma. A proof of concept study was designed to test the hypothesis that atorvastatin improves asthma control and airway inflammation in adults with asthma.

Fifty four adults with allergic asthma were recruited to a 22-week crossover randomised controlled trial comparing the effect on asthma control and airway inflammation of oral atorvastatin 40 mg daily with that of a matched placebo. Each treatment was administered for 8 weeks separated by a 6-week washout period. The primary outcome was morning peak expiratory flow. Secondary outcomes included spirometry, asthma control questionnaire (ACQ) score, asthma quality of life questionnaire (AQLQ), provocation concentration to methacholine (PC20) and inflammatory markers: exhaled nitric oxide, sputum differential cell count, sputum supernatant and serum inflammatory markers such as interleukin-6 (IL-6), IL-5, IL-8, sICAM-1, TNF-α, leukotriene B4 (LTB4) and high sensitivity C-reactive protein (hsCRP), and blood lymphocyte proliferation.

At 8 weeks, the change in mean morning PEF, as compared with baseline, did not differ between the atorvastatin and placebo treatment periods [mean difference -0.5 L/min, 95% CI -10.6 to 9.6, p=0.921]. No statistically significant effect of atorvastatin was seen in evening PEF, or methacholine responsiveness (PC20). Out of all spirometry results, only post-salbutamol FVC showed a statistically significant result, which was slightly lower in the atorvastatin group [treatment difference -0.1L, 95% CI -0.2 to 0.0, p=0.037]. There was also no change in ACQ or AQLQ.

No change was seen in exhaled nitric oxide. The total cell counts recovered from sputum were similar after atorvastatin compared to after placebo treatment. After 8 weeks, the mean absolute and relative sputum macrophage count was significantly reduced after atorvastatin compared to placebo [mean absolute difference -44.9x104 cells, 95% CI -80.1 to -9.7, p=0.029]. There was a reciprocal increase in the relative proportion of sputum neutrophils [mean proportion difference 13.1%, 95% CI 1.8 to 24.4, p=0.025], but there were no significant changes in the absolute count of these cells or the counts and proportions of the other sputum cell phenotypes under atorvastatin treatment.

The sputum concentrations of inflammatory cytokines and mediators were similar after atorvastatin compared to after placebo treatment other than LTB4 which was significantly reduced [mean difference -88.1 pg/mL, 95% CI -156.4 to -19.9, p=0.014].

No significant difference was seen in the concentration of any serum marker of inflammation between atorvastatin and placebo treatment periods. The change in hsCRP was of borderline significance [mean difference -0.65 mg/L, 95% CI -1.38 to 0.09, p=0.082], but there were no changes in sICAM-1, TNF-α, IL-5, IL-6 and IL-8. There was no significant difference in lymphocyte proliferation.

The biochemical effects of atorvastatin therapy were reflected in significant reduction in concentration of serum lipids; cholesterol (mean difference -1.71 mmol/l, 95% CI -1.94 to -1.48 p<0.0001), and HDL-cholesterol (mean difference -0.14 mmol/l, 95% CI -0.26 to -0.02 p=0.026), but not triglycerides. There were significant, albeit modest, increases in mean bilirubin, AST and ALT. There was no difference in compliance, assessed by number of tablets returned and by biochemical results.

There was no correlation between changes in LTB4 or IL-8 and sputum macrophage count, sputum neutrophil count, or PEF. The only correlation observed between the variables that were compared was between sputum macrophages and neutrophils.

Adverse event rates were similar in patients taking atorvastatin compared with placebo. Equal numbers of patients were lost to follow-up in both arms of the study. One patient died of unrelated causes while taking the placebo medication.

There were no clinically important improvements in a range of clinical indices of asthma control after eight weeks of treatment with atorvastatin despite expected changes in serum lipids. There were however changes in airway inflammation and in particular, a reduction in the absolute sputum macrophage count after atorvastatin compared to placebo and an associated reduction in sputum LTB4 and a trend towards lower CRP.

The lack of any evidence of clinical benefit of atorvastatin in allergic asthma confirms and extends the findings of a smaller randomised placebo controlled crossover trial of simvastatin in 16 subjects with asthma, which showed no change in clinical outcomes or inflammatory markers.

It is unlikely that altering duration of treatment, washout period or type of statin used would have changed the outcome of the study. However, as all patients were receiving inhaled corticosteroid as part of their asthma therapy, it is possible that this may have masked any modest anti-inflammatory effects of the statin. Baseline asthma inflammation may also have been too low to show any significant improvement.

Despite the postulated anti-inflammatory actions of statins, it seems that they may not be appropriate for the inflammatory phenotype associated with atopic asthma. The reduction in alveolar macrophage count found in patients with allergic asthma may however have relevance to the treatment of chronic lung diseases such as COPD in which alveolar macrophage function has been implicated in the pathogenesis.

Item Type: Thesis (MD)
Qualification Level: Doctoral
Keywords: Asthma, statin, atorvastatin, randomised controlled trial, inflammation, respiratory medicine, macrophages
Subjects: R Medicine > RM Therapeutics. Pharmacology
Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Supervisor's Name: Thomson, Professor Neil C
Date of Award: 5 December 2008
Depositing User: Dr Eleanor J Hothersall
Unique ID: glathesis:2008-360
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 17 Nov 2008
Last Modified: 14 Feb 2022 15:54
URI: https://theses.gla.ac.uk/id/eprint/360

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