Effects Of Statins On Chronic Obstructive Pulmonary Disease Complicated With Pulmonary Hypertention And Its Adverse Drug Reactions Based On Gene Polymorphism: A Systematic ReVIEW

Objectives:To explore certain problems related to the pleiotropic effects and safety of statins by systematic review and meta-analysis, including:1. the effectiveness of statins in treatment of chronic obstructive pulmonary disease (COPD) complicated with pulmonary hypertension (PH); 2. the association between SLCO1B1 521T>C polymorphism and the risk of statin-induced adverse drug reactions (ADRs).Methods:The following steps were carried out to completing the study:establishing inclusion and exclusion criteria, setting out searching strategies for databases, screening literatures, extracting information, assessing methodological quality, qualitative and quantitative analysis and interpreting results. Data were analyzed using the RevMan 5.3 or Stata 12.0 software.Results:1. The effectiveness of statins on COPD complicated with PH:A total number of 28 RCTs were included. Among them,11 studies were assessed as high quality studies and the remaining were of low quality. The results revealed that the improvement of life quality, the increase of 6MWD (MD=50.00,95%CI:34.17,65.83) and the level of NO (SMD=0.82,95%CI:0.56,1.08) and the decrease of Borg dyspnea score (MD=-3.37,95%CI:-4.61,-2.4), sPAP (MD=-5.01595%CI:-7.63,-2.39), mPAP (MD=-3.92,95%CI:-4.64,-3.20), ET-1 (SMD=-0.65,95%CI:-0.87,-0.43), IL-6 (SMD=-0.92,95%CI:-1.25,-0.60) and hs-CRP (SMD=-1.09, 95%CI:-1.54,-0.64) were more obvious in the statins group than in the controls. The effects on FEV1% (MD=2.92,95%CI:-2.83,8.68) and FEV,/FVC (MD=0.15,95%CI:-5.13,5.43) showed no significantly different between the statins and the control groups. The rate of ADRs was significantly higer among the patients receiving statins compared to the controls (OR=4.76,95%CI:1.01,22.48). Subgroup analyses by the type of statins, dose and duration of treatment respectively showed that the outcomes of 6MWD, sPAP, mPAP and ET-1 were in accordance with the total meta-analyses.2. The association between SLCO1B1 521T>C polymorphism and the risk of statin-induced ADRs:four case-control studies and eight cohort studies including 9532 samples were included, of whom 2176 developing ADRs. All included studies were of high quality except one. A significant association between the SLCO1B1521T>C polymorphism and the risk of ADRs caused by various statins in the homozygote comparison (CC vs. TT:OR=5.56,95%CI:3.15,9.80; HR=1.43,95%CI:1.02,2.02); the dominant model (TC+CC vs. TT:OR= 2.52,95%CI:1.33,4.81), the recessive model (CC vs. TT+TC:OR=3.10, 95%CI:1.87,5.11) and the additive model (Addtive:OR=2.29,95%CI: 1.51,3.48). The association remained in the synthesis of studies with different designs as well as in the simvastatin subgroup. While no significant relationship was found in other specific statin group.Conclusion:1. Statins could significantly improve the exercise capacity and reduce the pulmonary arterial pressure of patients with COPD complicated with PH, probably by increasing NO, decreasing ET-1 and inflammatory factors like IL-6 and hs-CRP. However, the effects on the improvement of dyspnea, pulmonary function and the security need to be verified by RCTs with larger sample size and strict design and implementation, as well as the different curative effects of the statin type, dose and duration of treatment.2. SLCOIBI 521C can significantly increase the risk of simvastatin-induced ADRs. No significant association was found between other statin and the polymorphism. However, the reliability of the result might be affected by the small number of original studies. More well-designed epidemiology studies with multiple ethnicities are needed to detect the association of SLCOIBI polymorphism and the risk of specific statin-induced adverse effects and the gene-environmental interactions.