copd is a lifestyle - related disease of the lungs that is primarily caused by regular smoking.1 it is an inflammatory disease associated with damage to the alveolar septa and increased levels of inflammatory mediators , such as c - reactive protein ( crp ) , interleukin-6 , interleukin-1 , and tumor necrosis factor- ( tnf- ) in the lung periphery.2 this local inflammation in the lungs spills into the systemic circulation , where it causes systemic inflammation.3 research has suggested that the systemic effects of copd can also cause comorbidities , such as cardiovascular diseases.3,4 thus , copd has attracted attention as a systemic disease.3,5 the systemic inflammation of copd is suggested to be involved in the pathogenesis of ischemic heart diseases and arteriosclerosis.6 several reports demonstrated that athosclerotic plaques in copd patients show a low - grade inflammation similar to that in the peripheral lungs.3,7,8 actually , the cause of death for 20%30% of patients with copd is cardiovascular disease , and death due to cardiovascular disease is highly evident in patients with mild or moderate copd.9,10 however , the precise mechanism of arteriosclerotic cardiovascular diseases and their effective preventive strategy in patients with copd are still unknown . thus , it is associated with the pathology of cardiovascular diseases and is a factor that governs the severity of cardiovascular disease . long - acting inhaled anticholinergics , such as tiotropium , are used in curing copd , and the uplift trial examined the usefulness of these medications . the results of this trial and a subanalysis indicated that patients using tiotropium had improved respiratory function and a decreased risk of cardiovascular complications , such as myocardial infarction.11,12 in other words , research has suggested that copd is a therapeutic target for the improvement of prognosis in patients with cardiovascular diseases . various epidemiological studies have indicated that crp is a factor that predicts cardiovascular events , such as myocardial infarction.1315 in addition , a study that examined systemic inflammation in patients with copd reported that these patients had increased levels of inflammatory markers , such as circulating neutrophils , fibrinogen , tnf- , and crp.5 1-antitrypsin  low - density lipoprotein ( at - ldl ) complex is a recently identified oxidized ldl . at - ldl is found in human serum and at sites of atherosclerotic lesions , and the levels of at - ldl in the blood indicate the activity of foam cells in atherosclerotic lesions.16,17 serum amyloid a ( saa ) bonds to high - density lipoprotein . when reactive oxygen species from inflammatory cells are activated by inflammation in blood vessels , they bond saa to ldl to form a complex known as saa - ldl . saa - ldl is a potential marker that can be used to predict and thus prevent the occurrence of coronary events.18 curcumin is a polyphenol naturally found in turmeric and has anti - inflammatory and antioxidant activities . turmeric has been used as a remedy in traditional indian and chinese medicine for over 6,000 years . it is also extensively used as a spice , flavoring agent , food preservative , and food color . curcumin has a number of biological activities , such as anti - inflammatory and anticancer actions.19,20 over the past few years , some useful effects of curcumin in treating various disorders have been identified.1921 we previously reported the use of curcumin in two rat models of chronic heart failure following hypertensive heart disease and myocardial infarction.22 curcumin was effective at inhibiting the progression of heart failure . because of its various biological activities , curcumin may be used clinically . however , the drawbacks of curcumin are a very limited absorbability when ingested and a poor bioavailability . thus , we used a drug delivery system to develop a highly absorbable curcumin preparation ( theracurmin ; theravalues corporation , kioi , tokyo , japan ) to increase its absorption in the intestinal tract . natural curcumin forms extremely large granules in an aqueous solution , but theracurmin is a preparation that features coated , extremely fine microparticles of curcumin . with such a drug delivery system , curcumin is consistently dispersed in an aqueous solution , thus improving its absorption by the intestinal tract.23 curcumin is reported to have anti - inflammatory activity as it inhibits nuclear factor-b ( nf-b ) as well as antioxidant activity as it eliminates reactive oxygen species.24 thus , curcumin may inhibit inflammation and oxidative stress , both implicated in increasing the risk of cardiovascular diseases . accordingly , our objective was to evaluate the efficacy of theracurmin in patients with mild copd by examining its effects on oxidative stress markers and inflammatory markers . the purpose of this trial was fully explained to potential subjects verbally and in writing . once potential subjects provided written informed consent , they were allowed to participate in this trial . the subjects were men or women ( age , 2085 years ) who met the following criteria : 1 ) patients with copd at stage 0 , i , or ii according to the definition by the japanese respiratory society and 2 ) patients who have never smoked at least for the past 4 months . we enrolled patients with copd ( including those being treated for the condition ) who were classified as having stage i ( mild ) or stage ii ( moderate ) copd based on the classification system of the japanese respiratory society . during observation , the quantity and frequency of the dose remained unchanged for the patients being treated for copd , and the patients had stable disease with no acute exacerbation . this trial was reviewed and approved by the ethics committee of the kyoto medical center . based on the philosophy of the ethical principles originating in the declaration of helsinki , this trial protected the rights and welfare of subjects . to ensure the scientific nature and reliability of this trial and to ensure safety , this trial was conducted in accordance with the principles of good clinical practice and strictly adhered to the ministry of health , labor , and welfare s ethical guidelines for clinical research . we conducted this double - blind , parallel - group , randomized trial from october 2012 to september 2014 . once the written informed consent was obtained , the subjects were randomly assigned to one of the two groups ( the theracurmin [ theravalues corporation , kioi , tokyo , japan ] group or the placebo group ) . the subjects took three capsules of theracurmin ( theracurmin is sold as a health supplement ) or a placebo ( 90 mg in total , 30 mg per capsule ) twice a day ( after breakfast and dinner , total dose : 180 mg ) . the primary end points were oxidative stress markers and inflammatory markers ( crp , saa - ldl , and at - ldl ) . parametric data , ie , continuous data , were expressed as mean  standard deviation . as part of statistical analysis , a mann  whitney u - test was used to compare continuous data between the two groups . for analysis of three or more matched groups , friedman test was performed followed by the wilcoxon signed - rank test with bonferroni correction as a post hoc test . all analyses were done using spss version 22.0 for windows ( ibm corporation , armonk , ny , usa ) , with p<0.05 indicating statistical significance . the purpose of this trial was fully explained to potential subjects verbally and in writing . once potential subjects provided written informed consent , they were allowed to participate in this trial . the subjects were men or women ( age , 2085 years ) who met the following criteria : 1 ) patients with copd at stage 0 , i , or ii according to the definition by the japanese respiratory society and 2 ) patients who have never smoked at least for the past 4 months . we enrolled patients with copd ( including those being treated for the condition ) who were classified as having stage i ( mild ) or stage ii ( moderate ) copd based on the classification system of the japanese respiratory society . during observation , the quantity and frequency of the dose remained unchanged for the patients being treated for copd , and the patients had stable disease with no acute exacerbation . this trial was reviewed and approved by the ethics committee of the kyoto medical center . based on the philosophy of the ethical principles originating in the declaration of helsinki , this trial protected the rights and welfare of subjects . to ensure the scientific nature and reliability of this trial and to ensure safety , this trial was conducted in accordance with the principles of good clinical practice and strictly adhered to the ministry of health , labor , and welfare s ethical guidelines for clinical research . we conducted this double - blind , parallel - group , randomized trial from october 2012 to september 2014 . once the written informed consent was obtained , the subjects were randomly assigned to one of the two groups ( the theracurmin [ theravalues corporation , kioi , tokyo , japan ] group or the placebo group ) . the subjects took three capsules of theracurmin ( theracurmin is sold as a health supplement ) or a placebo ( 90 mg in total , 30 mg per capsule ) twice a day ( after breakfast and dinner , total dose : 180 mg ) . the primary end points were oxidative stress markers and inflammatory markers ( crp , saa - ldl , and at - ldl ) . parametric data , ie , continuous data , were expressed as mean  standard deviation . as part of statistical analysis , a mann  whitney u - test was used to compare continuous data between the two groups . for analysis of three or more matched groups , friedman test was performed followed by the wilcoxon signed - rank test with bonferroni correction as a post hoc test . all analyses were done using spss version 22.0 for windows ( ibm corporation , armonk , ny , usa ) , with p<0.05 indicating statistical significance . of the 48 subjects enrolled , four dropped out : one because of soft stool ( placebo group ) , one because of gastrointestinal bleeding ( theracurmin group ) , one because of muscle aches ( placebo group ) , and one because of a rash on the back ( placebo group ) . five subjects withdrew their consent ( four in the placebo group and one in the theracurmin group ) because they would not like to take the trial medication of their own free will despite a lack of symptoms , leaving 39 subjects in the final analysis . the placebo group comprised 17 subjects ( 15 men and two women ) , and the theracurmin group comprised 22 subjects ( 19 men and three women ) . there were no significant differences between the two groups in terms of sex , age , systolic blood pressure , diastolic blood pressure , glycated hemoglobin , blood sugar , triglyceride , ldl - cholesterol , high - density lipoprotein - cholesterol , uric acid , -glutamyl transpeptidase , creatinine , crp , saa - ldl , and percent forced expiratory volume in 1 second . the patients in the placebo group had a significantly higher body mass index than those in the theracurmin group ( p=0.046 ) . the theracurmin group had significantly higher levels of at - ldl than did the placebo group ( p=0.037 ) . the percent changes in parameters between the baseline and after 6 months of theracurmin or placebo administration are listed in table 2 . there were no significant differences in the percent changes in crp and saa - ldl ( primary end points ) between the groups . however , the percent change in all primary end points increased in the placebo group but decreased in the theracurmin group . the levels of at - ldl , which is oxidatively modified ldl , were also a primary end point . the percent change in at - ldl was significantly lower in the theracurmin group compared with that in the placebo group ( p=0.020 ) . curcumin significantly decreased the blood levels of at - ldl in patients with mild copd . systemic inflammation in copd is known to be associated with a risk of cardiovascular diseases.25 copd itself is a risk factor for arteriosclerosis , and the systemic effects of copd are known to cause various comorbidities , such as a 1.5- to 2-fold increase in the risk of ischemic heart disease.26 currently , because there is no definitive treatment for copd and no treatment to restore the lung function , bronchodilators and steroids are used to treat copd by improving respiratory function . however , some of these medications , such as 2-agonists , worsen comorbidities such as myocardial infarction that are caused by the systemic effects of copd . the 2-agonists are used as bronchodilators to treat patients with asthma or copd and are thought to cause fewer adverse reactions in the cardiovascular system than 1-agonists ; however , 2-agonists are reported to increase heart rate and lower potassium levels , potentially increasing the cardiovascular risk for patients with asthma or copd.27 a study examining steroids and the occurrence of cardiovascular events reported that steroids significantly increased the risk of a cardiovascular event.28 curcumin was used in the current trial , and no studies have reported serious adverse reactions to curcumin . curcumin is a highly safe natural herbal product , and a study has suggested that curcumin may be effective in treating numerous disorders , such as heart disease , malignancies , lifestyle - related diseases , neurological disorders , inflammatory diseases , and infections.1922 a comparison of at - ldl levels in smokers and nonsmokers indicated that at - ldl levels are significantly elevated in smokers.29 at - ldl is an oxidatively modified ldl , and at - ldl levels quickly drop as a result of smoking cessation , which suggests that at - ldl promotes atherosclerosis and is closely related to smoking . based on these findings , it may be a useful marker to assess cardiovascular risk . given that at - ldl levels decreased significantly as a result of taking theracurmin , curcumin may prevent the onset of arteriosclerosis in copd and consequently reduce the cardiovascular risk . the baseline at - ldl levels were significantly higher in the theracurmin group , but levels of at - ldl and other inflammatory markers and oxidative stress markers , such as crp and saa - ldl , tended to decrease in the theracurmin group , suggesting that the inflammation in copd is likely to be inhibited by theracurmin . many studies have reported that curcumin has anti - inflammatory and antioxidant activities.3032 tnf- , cyclooxygenase-2 ( cox-2 ) , stat , cyclin d1 , and nf-b are related to inflammation , and curcumin displays anti - inflammatory action by inhibiting tnf- , cox-2 , stat , cyclin d1 , and nf-b signaling . curcumin displays antioxidant activity because the ch2 located in the center of the molecule and hydroxyl groups in the benzene rings eliminate reactive oxygen species.30,33 these actions of curcumin may be related to the mechanism by which curcumin inhibits oxidized ldl . a retrospective cohort study of 854 patients with copd examined differences in the mortality rate depending on whether patients were treated with statins.34 in this study , the hazard ratio for death of patients taking statins was 0.57 ( 95% confidence interval 0.380.87 ) compared with patients not taking statins . the study reported that treatment with statins was associated with an improvement in the survival rate after the exacerbation of copd . a cohort study of 11,212 patients reported that angiotensin - converting enzyme inhibitors and angiotensin ii receptor blockers improved the prognosis for patients with copd.35 cardiovascular events are complications of copd , and treatment must inhibit cardiovascular events to improve the prognosis for patients with copd . we examined blood inflammatory markers and respiratory function in patients with mild copd over 6 months . compared with the placebo , theracurmin significantly decreased the blood levels of the inflammatory marker at - ldl and tended to decrease ( albeit not significantly ) levels of crp and saa - ldl . however , as a limitation , this trial had a small sample and was conducted over a short period of time ( 6 months ) . a long - term study with cardiovascular events as a primary end point and numerous patients with copd if a natural product that is inexpensive and safe can be used to prevent and treat cardiovascular disease , then such a treatment could greatly benefit public health and welfare and reduce medical expenses in the process . in patients with copd and inflammatory disease , the current trial indicated that theracurmin might reduce levels of at - ldl , a complex that promotes arteriosclerosis . copd is an inflammatory disease , and curcumin may help to prevent ischemic disorders ( eg , myocardial infarction ) , which are a comorbidity of copd . this study suggests that curcumin could help in preventing the development of vascular events in patients with copd .