Abstract
Background
Chronic obstructive pulmonary disease (COPD) is a leading cause of all-cause mortality, frequently accompanied by comorbidities such as cardiovascular disease and diabetes. Statins, commonly prescribed for hyperlipidemia, also exhibit anti-inflammatory properties that may benefit patients with COPD. This study aimed to evaluate the impact of statin utilization on all-cause mortality among COPD patients with data from the National Health and Nutrition Examination Survey (NHANES) and applying Mendelian randomization (MR) analysis to explore potential causal associations.
Methods
This study obtained data using the NHANES (2007–2018) database, which contained information on COPD patients with active statin prescriptions and the associated mortality data. All-cause mortality was defined as the primary outcome in this study. Cox regression models were used to determine the association between statin use and mortality, adjusting for demographic and clinical variables. MR analysis, leveraging genetic variants associated with statin use, was employed to assess potential causality.
Results
In the study of 2,416 COPD patients, the use of statins was linked to a 41% decrease in all-cause mortality [hazard ratio (HR) =0.59, 95% confidence interval (CI): 0.36–0.98]. Mediation analysis further revealed that C-reactive protein (CRP) partially mediated the protective effect of statins on all-cause mortality in COPD patients, accounting for 5.5% of the total effect. MR analysis indicated that statin use was associated with a 17% decrease in the risk of COPD (OR =0.83, 95% CI: 0.78–0.90).
Conclusions
Statins may reduce all-cause mortality in COPD patients, indicating potential therapeutic benefits beyond cholesterol management. Nonetheless, further research is needed to confirm these results.
Keywords: Chronic obstructive pulmonary disease (COPD), statins, all-cause mortality, Mendelian randomization (MR), National Health and Nutrition Examination Survey (NHANES)
Highlight box.
Key findings
• Statin use was associated with significantly reduced all-cause mortality in chronic obstructive pulmonary disease (COPD) patients.
• C-reactive protein partially mediated the protective effect of statins on all-cause mortality in patients with COPD.
• Mendelian randomization (MR) analysis suggested a causal protective effect of statins against COPD development.
What is known and what is new?
• COPD is one of the leading causes of morbidity and mortality worldwide and is exacerbated by comorbidities such as cardiovascular disease and diabetes. Although statins can lower low-density lipoprotein cholesterol and have anti-inflammatory effects, their clinical impact on COPD mortality and their causal role in disease progression remain unclear.
• Our study indicates that statin use is significantly associated with reduced all-cause mortality in patients with COPD. Importantly, MR analysis revealed a potential causal relationship, suggesting that statins may have a protective effect against the development of COPD.
What is the implication, and what should change now?
• Statins may offer therapeutic repurposing potential for COPD by targeting inflammation or neutrophil activity. Future rigorously designed randomized trials are needed to validate their mortality benefits and elucidate underlying biological mechanisms.
Introduction
Chronic obstructive pulmonary disease (COPD) is characterized by chronic, progressive airflow limitation and airway inflammation and has become one of the leading causes of morbidity and mortality worldwide (1,2). An estimated 212.3 million people are affected by COPD globally, with 3.3 million related deaths, and this trend is expected to worsen as the global population ages (3). COPD patients often suffer from multiple comorbidities, particularly cardiovascular diseases (CVD) (4). Studies have shown that the risk of cardiovascular-related mortality in COPD patients is more than twice that in non-COPD patients, with this risk increasing as the disease progresses (5). Moreover, diabetes reduces the survival rate of COPD patients by 21% (6). Given the adverse impact of CVD and other comorbidities on the prognosis of patients with COPD, all-cause mortality has become a key indicator for assessing health outcomes in this population (7).
Hydroxy-3-methylglutaryl-CoA reductase (HMGCR) inhibitors, commonly known as statins, not only lower serum low-density lipoprotein cholesterol (LDL-C) levels, but also reduce the risk of cardiovascular events. In addition, statins have been shown to possess anti-inflammatory and immune-modulatory properties (8,9). Recently, more studies have begun to explore the effectiveness of these drugs in treating COPD (10). Preliminary studies have reported some positive outcomes. For example, a single center randomized controlled trial showed that simvastatin significantly extended the time to the first exacerbation and reduced exacerbation rates in COPD patients (11). However, there has been controversy regarding the efficacy of statins as adjunctive therapy for COPD. A network meta-analysis confirmed the potential benefits of statins in reducing mortality risk in COPD patients and improving biomarkers such as C-reactive protein (CRP) and pH levels (12). Ingebrigtsen et al. identified a link between statin use and a lower risk of COPD exacerbation (13), but another study detected no significant association between statin use and the rate of COPD exacerbations (14). Moreover, a prospective cohort study initially observed an association between statin use and improved overall survival. However, after adjusting for immortal time bias, this association was no longer statistically significant (15).
Due to the absence of explicit clinical guidelines on statin use in COPD and the small sample sizes in relevant studies, this research leverages data from the National Health and Nutrition Examination Survey (NHANES) and employs Mendelian randomization (MR) to assess the role of statins in COPD and explore potential mechanisms of action. As a national program encompassing a broad population in the United States, NHANES provides rich longitudinal cohort data, allowing us to examine the relationship between statin use and mortality in COPD patients. Moreover, using MR analysis that employs genetic variation as instrumental variables (IVs), we seek to confirm the causal link between statin use and COPD at the genetic level. This approach helps reduce common biases found in traditional observational studies (16,17). Furthermore, analyzing natural genetic variation in drug target genes can serve as a tool to assess their molecular inhibitory effects on various diseases (18,19). This study specifically utilizes genetic variation in HMGCR, which is the pharmacological target of statins, to represent the biological effect of statin therapy. By modeling the enzyme’s inhibition by statins, we investigate the potential causal influence of statins on COPD. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1-2794/rc).
Methods
Data sources
This study primarily utilized data from the NHANES, collected by the National Center for Health Statistics (NCHS) of the U.S. Centers for Disease Control and Prevention (CDC) between 2007 and 2018. The dataset spanned six survey cycles and included detailed demographic information, laboratory test results, and questionnaire data. Additionally, the MR analysis incorporated data from the FinnGen consortium’s genome-wide association study (GWAS) on statins, which involved 68,782 COPD cases and 150,010 healthy controls. This project received funding primarily from the pharmaceutical industry, along with contributions from all European ancestry participants who provided informed consent. The GWAS summary data for LDL-C were supplied by the Global Lipids Genetics Consortium (GLGC). Data for COPD were provided by BioBank Japan, which included 4,017 confirmed COPD cases and 162,653 non-COPD controls, all diagnosed using detailed criteria. Sakaue et al. first published the results of this study in 2021 (20). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.
Cohort study design and participant screening
We included adult patients with COPD diagnosed by a physician with a record of prescription medication use in the NHANES database from 2007 to 2018. We excluded participants with incomplete information, particularly those with missing COPD data, unknown mortality status, incomplete prescription medication records, those under 40 years, or missing key covariate data. COPD is defined by meeting at least one of the following criteria: (I) a forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) ratio of less than 0.7 in pulmonary function tests; (II) answering “yes” to the question “Has a doctor ever told you that you have COPD?”; (III) answering “yes” to the question “Has a doctor ever told you that you have chronic bronchitis?”; or (IV) answering “yes” to the question “Has a doctor ever told you that you have emphysema?” (21). The study aimed to assess all-cause mortality, represented by participant deaths from any cause. By linking to the National Death Index (NDI) data at the end of 2019, we accurately obtained the mortality status and primary causes of death for COPD patients (22). Additionally, all individuals who had used statins, alone or in combination, were classified into the statin use group.
Based on previous studies, this study comprehensively considered the influence of various covariates, including gender, age, race, education level, poverty-to-income ratio (PIR), body mass index (BMI), smoking, alcohol consumption, use of respiratory agents, diabetes, hypertension, CVD, dyslipidemia, triglycerides (TG), total cholesterol (TC), LDL, high-density lipoprotein (HDL), neutrophils, lymphocytes, eosinophils, and CRP (Appendix 1).
MR analysis design and IV selection
A two-sample MR analysis was conducted to investigate the potential causal relationship between statin use and COPD. In this analysis, statin use was designated as the exposure and COPD as the outcome. Single nucleotide polymorphisms (SNPs) strongly associated with statin use were selected as IVs.
To ensure the reliability of the analysis, this study strictly adhered to the three core assumptions of the two-sample MR design: (I) the selected IVs must be strongly associated with the exposure (P<5×10−8, F-statistic >10); (II) the IVs should be independent of any confounding factors; and (III) the IVs should affect the outcome solely through the exposure, without influencing it via alternative pathways (23).
During the selection of IVs, we chose SNPs strongly associated with statin use [P<5×10−8, r2<0.001, genetic distance of 10,000 kilobase (kB)]. SNPs potentially related to confounding factors or disease outcomes were excluded using the LDTrait tool, and the F-statistic for each SNP was calculated to assess its validity as an IV (24). The SNP was only considered a valid IV if its F-statistic exceeded 10. Additionally, to ensure the accuracy of the analysis, we harmonized the alleles between the exposure and outcome datasets and excluded any palindromic sequences.
This study used HMGCR, the target gene of statins, as a proxy for the exposure. We selected SNPs within 100 kB pairs of the HMGCR gene significantly associated with lower LDL-C levels in the GLGC GWAS and achieved genome-wide significance (P<5×10−8) as IVs. Additionally, we selected SNPs with a linkage disequilibrium coefficient R2<0.3 through linkage disequilibrium analysis.
Statistical analysis
This cohort study presents continuous variables as medians with interquartile ranges, while categorical variables are presented as percentages. The Cox proportional hazards model was used to calculate the hazard ratio (HR) and 95% confidence interval (CI) for statin use and all-cause mortality, with multivariable adjustments based on the univariate Cox regression analysis results. Additionally, subgroup analyses were stratified by age, gender, year, and various comorbidities to identify subgroups with a higher sensitivity to treatment response. The analysis accounted for the U.S. population structure using weighting factors, and complex survey sample data were processed with the “survey” package in R 4.3.3 software. Sample weights were recalculated and applied according to NHANES reporting guidelines. The mediation package of R software was used for mediation analysis. A P value of less than 0.05 was considered statistically significant.
We employed five genetic association methods to explore the relationship between statin use and COPD: MR-Egger regression, the weighted median method, inverse variance weighting (IVW), the simple model, and the weighted model. The robustness of the study was ensured through several validation steps. First, Cochran’s Q test assessed heterogeneity between studies and then examined heterogeneity through the symmetry of funnel plots. Additionally, the MR-Egger intercept and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) global tests were employed to detect potential pleiotropy. MR-PRESSO was further used to identify and exclude outliers, updating the result estimates accordingly. Sensitivity analysis was performed using leave-one-out testing, where individual SNPs were sequentially removed to assess their impact on the overall results and determine the influence of individual SNPs on the association. All statistical analyses were conducted using R software (version 4.3.3) and the TwoSampleMR package, with a significance threshold set at a P value of less than 0.05.
Results
Cohort selection
A total of 59,842 participants were selected from the NHANES database between 2007 and 2018. Of these, 2,883 individuals diagnosed with COPD by a physician had prescription medication records, and available mortality data were included for further analysis. After excluding 467 participants with missing key covariate data, 2,416 participants remained in the final analysis (Figure 1). This represents an estimated population of 16,578,300 individuals in the United States.
Figure 1.
Flowchart of the cohort selection process. COPD, chronic obstructive pulmonary disease; NHANES, National Health and Nutrition Examination Survey.
Baseline characteristics of cohort study participants
The baseline characteristics of the study participants are presented in Table 1. Among the participants, 74.69% were between 40 and 69 years old, 55.21% were female, and 82.09% were non-Hispanic white. The prevalence of current smokers was 30.44%, and 43.08% of participants were classified as obese. Statin use was reported by 7.13% of participants. The median survival time for the cohort was 7.07 years. Among those who died from various causes, the most common comorbidities were CVD, diabetes, and hypertension, accounting for 38.62%, 35.04%, and 20.64%, respectively.
Table 1. Baseline characteristics of COPD participants by all-cause mortality status in the NHANES 2007–2018.
| Variable | Total (n=2,416) | All-cause mortality | P value | |
|---|---|---|---|---|
| No (n=1,899) | Yes (n=517) | |||
| Survival time (years) | 7.07 [0.16] | 7.50 [0.18] | 4.91 [0.22] | <0.001 |
| Age | <0.001 | |||
| >69 years | 801 (25.31) | 506 (20.17) | 295 (50.82) | |
| 40–69 years | 1,615 (74.69) | 1,393 (79.83) | 222 (49.18) | |
| Gender | 0.008 | |||
| Female | 1,239 (55.21) | 1,030 (56.83) | 209 (47.17) | |
| Male | 1,177 (44.79) | 869 (43.17) | 308 (52.83) | |
| Race | 0.001 | |||
| Mexican American | 158 (2.25) | 134 (2.34) | 24 (1.78) | |
| Non-Hispanic Black | 446 (7.59) | 371 (7.88) | 75 (6.15) | |
| Non-Hispanic White | 1,488 (82.09) | 1,121 (81.03) | 367 (87.38) | |
| Other | 324 (8.07) | 273 (8.75) | 51 (4.69) | |
| Marital | 0.002 | |||
| Married | 1,384 (64.85) | 1,115 (66.72) | 269 (55.56) | |
| Unmarried | 1,032 (35.15) | 784 (33.28) | 248 (44.44) | |
| Education | <0.001 | |||
| Below high school | 657 (17.94) | 484 (16.39) | 173 (25.65) | |
| College graduate or above | 406 (23.04) | 350 (24.99) | 56 (13.36) | |
| High school/some college | 1,353 (59.02) | 1,065 (58.62) | 288 (60.99) | |
| PIR | <0.001 | |||
| High | 577 (37.23) | 497 (39.81) | 80 (24.39) | |
| Low | 809 (21.59) | 605 (19.93) | 204 (29.85) | |
| Medium | 849 (34.02) | 645 (33.08) | 204 (38.70) | |
| Unknown | 181 (7.16) | 152 (7.18) | 29 (7.06) | |
| Smoking status | 0.007 | |||
| Current smoker | 738 (30.44) | 572 (30.27) | 166 (31.24) | |
| Never smoker | 691 (28.73) | 588 (30.22) | 103 (21.30) | |
| Past smoker | 987 (40.84) | 739 (39.50) | 248 (47.46) | |
| Drinking status | >0.99 | |||
| No | 758 (26.91) | 606 (26.89) | 152 (27.01) | |
| Yes | 1,658 (73.09) | 1,293 (73.11) | 365 (72.99) | |
| BMI | 0.001 | |||
| Low weight | 42 (1.85) | 23 (1.36) | 19 (4.31) | |
| Normal weight | 539 (22.19) | 391 (21.38) | 148 (26.22) | |
| Obese | 1,076 (43.08) | 872 (43.20) | 204 (42.47) | |
| Overweight | 759 (32.88) | 613 (34.06) | 146 (27.01) | |
| Hypertension | 0.008 | |||
| No | 1,957 (84.36) | 1,558 (85.37) | 399 (79.36) | |
| Yes | 459 (15.64) | 341 (14.63) | 118 (20.64) | |
| Diabetes | <0.001 | |||
| No | 1,651 (74.03) | 1,330 (75.86) | 321 (64.96) | |
| Yes | 765 (25.97) | 569 (24.14) | 196 (35.04) | |
| CVD | <0.001 | |||
| No | 1,698 (73.85) | 1,399 (76.36) | 299 (61.38) | |
| Yes | 718 (26.15) | 500 (23.64) | 218 (38.62) | |
| Dyslipidemia | 0.40 | |||
| No | 1,399 (58.40) | 1,111 (58.82) | 288 (56.36) | |
| Yes | 1,017 (41.60) | 788 (41.18) | 229 (43.64) | |
| Asthma | 0.07 | |||
| No | 1,562 (65.62) | 1,202 (64.64) | 360 (70.52) | |
| Yes | 854 (34.38) | 697 (35.36) | 157 (29.48) | |
| Cancer | 0.09 | |||
| No | 1,932 (77.65) | 1,542 (78.52) | 390 (73.33) | |
| Yes | 484 (22.35) | 357 (21.48) | 127 (26.67) | |
| Respiratory agents | <0.001 | |||
| No | 1,979 (83.14) | 1,588 (84.79) | 391 (74.94) | |
| Yes | 437 (16.86) | 311 (15.21) | 126 (25.06) | |
| Statin use status | 0.03 | |||
| Not taking statins | 2,242 (92.87) | 1,753 (92.26) | 489 (95.87) | |
| Taking statins | 174 (7.13) | 146 (7.74) | 28 (4.13) | |
| Total cholesterol (mg/dL) | 191.00 (163.00, 222.00) | 192.00 (165.00, 222.00) | 182.00 (154.00, 213.00) | <0.001 |
| Triglyceride (mg/dL) | 134.00 (93.00, 200.00) | 132.00 (94.00, 201.00) | 141.00 (90.00, 195.00) | 0.70 |
| HDL (mg/dL) | 51.00 (41.00, 62.00) | 51.00 (42.00, 62.00) | 49.00 (39.00, 63.00) | 0.20 |
| LDL (mg/dL) | 107.00 (107.00, 110.00) | 107.00 (107.00, 111.00) | 107.00 (98.00, 108.00) | 0.06 |
| Neutrophils (1,000 cells/UL) | 4.40 (3.40, 5.50) | 4.30 (3.40, 5.40) | 4.90 (3.80, 6.20) | <0.001 |
| Lymphocyte (1,000 cells/UL) | 1.90 (1.60, 2.50) | 2.00 (1.60, 2.50) | 1.80 (1.40, 2.30) | <0.001 |
| Eosinophils (1,000 cells/UL) | 0.20 (0.10, 0.30) | 0.20 (0.10, 0.30) | 0.20 (0.10, 0.30) | 0.90 |
| C-reactive protein (mg/L) | 2.70 (1.70, 3.70) | 2.70 (1.70, 3.60) | 2.70 (2.00, 4.90) | 0.01 |
Data are presented as median [standard error], n (%), or median (interquartile range). Note: “All-cause mortality yes/no” represents mortality status based on National Death Index (NDI) linkage, where “Yes” indicates participants confirmed deceased by the end of 2019, and “No” indicates those still alive as of that date. BMI, body mass index; COPD, chronic obstructive pulmonary disease; CVD, cardiovascular diseases; HDL, high-density lipoprotein; LDL, low-density lipoprotein; NHANES, National Health and Nutrition Examination Survey; PIR, poverty-to-income ratio.
Association between statin use and all-cause mortality in COPD patients
The detailed results of the univariate and multivariate Cox regression analyses are presented in Table S1. The multivariate Cox regression analysis revealed that in COPD patients, diabetes was associated with a 34% increased risk of all-cause mortality (HR =1.34, 95% CI: 1.04–1.74). CVD was linked to a 52% increased risk (HR =1.52, 95% CI: 1.19–1.94). High neutrophil count (HR =1.15, 95% CI: 1.08–1.22) and elevated CRP levels (HR =1.01, 95% CI: 1.00–1.02) were significantly associated with increased all-cause mortality in COPD patients. Initial univariate analysis indicated a 46% reduction in all-cause mortality risk (HR =0.54, 95% CI: 0.32–0.90) associated with statin use. This protective association was further confirmed by weighted multivariate analysis, which showed a 41% reduction in all-cause mortality risk (HR =0.59, 95% CI: 0.36–0.98) after adjusting for covariates. Five different analytic models were employed to assess the robustness of the model (Table 2), all of which indicated a significant association between statin use and reduced all-cause mortality. Specifically, in Model 3, after adjusting for demographic characteristics and comorbidities such as diabetes and CVD, statin use was significantly related to a 48% reduction in all-cause mortality (HR =0.52, 95% CI: 0.32–0.86). In Model 5, which accounted for additional variables such as age, sex, marital status, education level, BMI, hypertension, diabetes, CVD, TC, LDL, and neutrophil count, the protective effect of statins was even more pronounced, with a 50% reduction in all-cause mortality risk (HR =0.50, 95% CI: 0.31–0.82).
Table 2. Multi-model analysis of all-cause mortality in COPD patients.
| Variables | Model 1 | Model 2 | Model 3 | Model 4 | Model 5 | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | HR (95% CI) | P | HR (95% CI) | P | HR (95% CI) | P | |||||
| Statin use status | ||||||||||||||
| Not taking statins | 1.00 (Reference) |
1.00 (Reference) |
1.00 (Reference) |
1.00 (Reference) |
1.00 (Reference) |
|||||||||
| Taking statins | 0.54 (0.32–0.90) |
0.01 | 0.53 (0.32–0.87) |
0.01 | 0.52 (0.32–0.86) |
0.01 | 0.50 (0.31–0.83) |
0.007 | 0.50 (0.31–0.82) |
0.006 | ||||
Model 1: crude; Model 2: adjusted for age, marital, education, PIR, gender, BMI; Model 3: adjusted for age, marital, education, PIR, gender, BMI, hypertension, diabetes, CVD, dyslipidemia, asthma, cancer; Model 4: adjusted for age, marital, education, PIR, gender, BMI, hypertension, diabetes, CVD, TC, LDL; Model 5: adjusted for age, marital, education, PIR, gender, BMI, hypertension, diabetes, CVD, TC, LDL, neutrophils. BMI, body mass index; CI, confidence interval; COPD, chronic obstructive pulmonary disease; CVD, cardiovascular diseases; HR, hazard ratio; LDL, low-density lipoprotein; PIR, poverty-to-income ratio; TC, total cholesterol.
Subgroup analysis and interaction testing
Subgroup analysis revealed that the protective effect of statins on all-cause mortality in COPD patients varied according to different patient characteristics, including age, gender, year, and comorbid conditions (Figure 2). A significant interaction existed for asthma status (P for interaction =0.007). Among non-asthmatic COPD patients, statin use was associated with a 60% reduction in all-cause mortality (HR =0.40; 95% CI: 0.23–0.71). This benefit did not extend to asthmatic COPD patients. For dyslipidemia status, no significant interaction was found (P for interaction =0.815). Dyslipidemia patients had a 23% mortality reduction with statins (HR =0.77; 95% CI: 0.31–1.87). Non-dyslipidemia patients showed greater reduction (47%; HR =0.53; 95% CI: 0.28–1.01). CVD status interaction was non-significant (P for interaction =0.347). Statins reduced mortality by 55% in CVD patients (HR =0.45; 95% CI: 0.21–0.94). Non-CVD patients had smaller reductions (24%; HR =0.76; 95% CI: 0.39–1.50). Diabetes status interaction was also non-significant (P for interaction =0.239). Diabetics exhibited 61% lower mortality with statins (HR =0.39; 95% CI: 0.16–0.91). Non-diabetics showed 32% risk reduction (HR =0.68; 95% CI: 0.37–1.25). Analysis of age, sex, year, and other covariates demonstrated consistent protective effects without significant heterogeneity (all P for interaction >0.05).
Figure 2.
Subgroup analysis of the association between statin use and all-cause mortality in COPD patients. CI, confidence interval; COPD, chronic obstructive pulmonary disease; CVD, cardiovascular diseases; HR, hazard ratio.
Mediation analysis
The mediation analysis was conducted to evaluate the mediating role of CRP in the association between statin use and all-cause mortality in COPD patients. The model was adjusted for age, marital status, education, PIR, gender, BMI, hypertension, diabetes, CVD, TC, and LDL. As shown in Table 3, the total effect of statins on reducing all-cause mortality was significant (estimate =−0.072, 95% CI: −0.117 to −0.010). The mediation effect of CRP accounted for 5.5% of the total effect (estimate =−0.004, 95% CI: −0.008 to 0.000), while the direct effect of statins remained statistically significant (estimate =−0.068, 95% CI: −0.115 to −0.010). Additionally, mediation analysis for other inflammatory markers including neutrophils, lymphocytes and eosinophils (Table S2) showed no statistically significant mediating effects on the association between statin use and all-cause mortality in COPD patients.
Table 3. CRP as a mediator in the associations between statins and all-cause mortality in COPD patients.
| Effect type | Estimate | 95% CI | P value | |
|---|---|---|---|---|
| Lower boundary | Upper boundary | |||
| Total effect | −0.072 | −0.117 | −0.010 | 0.02 |
| Mediation effect | −0.004 | −0.008 | 0.000 | <0.001 |
| Direct effect | −0.068 | −0.115 | −0.010 | 0.04 |
| Proportion mediated | 0.055 | 0.008 | 0.200 | 0.02 |
Model was adjusted for age, marital, education, PIR, gender, BMI, hypertension, diabetes, CVD, TC, and LDL. BMI, body mass index; CI, confidence interval; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; CVD, cardiovascular diseases; LDL, low-density lipoprotein; PIR, poverty-to-income ratio; TC, total cholesterol.
MR analysis and sensitivity analysis
In the MR analysis evaluating the effect of statins on COPD risk, 47 SNPs were selected as IVs (Table S3). The results from the inverse variance-weighted method indicated that statin use was associated with a 17% lower risk of COPD [odds ratio (OR) =0.83, 95% CI: 0.78–0.90]. Consistent findings from the MR-Egger regression, weighted median method, simple model, and weighted model further supported the conclusion that statins are a protective factor, significantly lowering the risk of COPD. The Cochran Q test (P=0.46), MR-Egger intercept test (P=0.40), and MR-PRESSO global test (P=0.20) revealed no significant heterogeneity or horizontal pleiotropy bias (Figure 3). Additionally, the funnel plot (Figure S1) and leave-one-out analysis (Figure S2) did not show any substantial heterogeneity or individual SNPs exerting a strong influence on the summary estimates, indicating the robustness of the results.
Figure 3.
Statins-COPD MR analysis and sensitivity analysis. CI, confidence interval; COPD, chronic obstructive pulmonary disease; MR, Mendelian randomization; MR-PRESSO, Mendelian Randomization Pleiotropy RESidual Sum and Outlier; OR, odds ratio; SNP, single nucleotide polymorphism.
Six SNPs were selected as IVs in the MR analysis investigating the relationship between HMGCR expression and COPD risk (Table S4). Neither the MR-Egger method nor the IVW method found a significant causal association between HMGCR expression and COPD risk. The Cochran Q test (P=0.94) and the MR-Egger intercept test (P=0.63) also indicated no significant heterogeneity or horizontal pleiotropy bias (Figure 4).
Figure 4.
HMGCR-COPD MR analysis and sensitivity analysis. CI, confidence interval; COPD, chronic obstructive pulmonary disease; HMGCR, hydroxy-3-methylglutaryl-CoA reductase; MR, Mendelian randomization; OR, odds ratio; SNP, single nucleotide polymorphism.
Discussion
This study, which uses NHANES data, indicates a possible link between statin use and lower all-cause mortality in COPD patients. This link remained statistically significant even after accounting for various confounding factors. These results align with patterns seen in earlier research. Lu et al. found in a network meta-analysis that statins could lower the risk of all-cause mortality (relative risk =0.72, 95% CI: 0.63–0.84) (12). Furthermore, a cohort study conducted by Xia et al. indicated that statin therapy is linked to reduced 30-day mortality in patients with severe COPD (OR =0.7, 95% CI: 0.57–0.85) (25). A meta-analysis by Horita et al. that incorporated observational studies indicated a trend of decreased mortality (HR =0.81, 95% CI: 0.75–0.86) (26). Our research reinforces the prevailing belief that statins could enhance the prognosis of COPD in a broad population sample.
Subgroup analysis and interaction tests indicated that the protective effects of statins differ among various COPD patient characteristics. Particularly, patients with a sole COPD diagnosis experienced greater benefits from statin therapy than those with asthma-COPD overlap (ACO). This variation could be linked to essential pathophysiological differences between the two conditions (27,28). COPD mainly results from neutrophil inflammation and oxidative stress, often caused by long-term exposure to harmful particles, which leads to progressive small airway fibrosis and emphysema. Conversely, ACO features asthma-related eosinophilic inflammation layered over the structural changes seen in COPD, frequently resulting in significant airway hyperresponsiveness and extensive remodeling (29,30). Previous studies have shown the potential of statins to reduce airway fibrosis and improve small airway function, particularly in patients with COPD alone (31). However, extensive airway remodeling in patients with ACO may limit the benefits of statin therapy (32). Thus, careful consideration must be given to managing this overlapping syndrome when evaluating statin therapy for patients with ACO.
This study is the first to employ a MR approach based on genetic data to investigate the effects of statins on COPD patients. Our MR analysis provides genetic-level evidence suggesting an association between statin use and a reduced risk of COPD. By utilizing genetic variants associated with statin use as IVs, we could accurately infer causal relationships, effectively mitigating biases commonly encountered in traditional observational studies, such as immortal time bias, as previously discussed by Yadav et al. (33,34). Crucially, this MR finding supports a causal role of statin-related pathways in the pathogenesis of COPD.
The present findings indicated that this pathway regulates factors beyond LDL-C. Based on the biological role of statins in targeting HMGCR, we selected genetic variants associated with HMGCR expression as proxies for exposure (35). However, both IVW-MR and MR-Egger analyses failed to demonstrate a significant causal relationship between HMGCR expression and COPD. This finding is consistent with the study by Freyberg et al., which reported that low LDL-C levels were associated with increased COPD exacerbations and specific mortality risk, indicating that the protective effect of statins against COPD may be independent of the LDL-C regulatory pathway (36). It also aligns with the work of Khan et al. (37), who systematically demonstrated that statins exert anti-COPD effects by inhibiting nuclear factor-κB (NF-κB) signaling, NOD-like receptor protein 3 (NLRP3) inflammasome activation, and the production of pro-inflammatory cytokines. These core pathways drive airway neutrophil infiltration and parenchymal injury, which trigger the development of COPD.
Furthermore, this genetic evidence for reduced COPD incidence provides critical mechanistic support for the observational finding that statin use is associated with decreased all-cause mortality in COPD patients. The biological link underlying these two observations is that statins exert sustained suppression on systemic inflammation. This inflammation itself serves as both an initiator of COPD development and a key driver of elevated mortality risk. As emphasized by Hirano et al. (38), COPD is not an isolated lung disease but a systemic disorder characterized by systemic inflammation as the central link connecting extrapulmonary multi-organ damage and adverse outcomes. Chronic inflammation, through persistent activation of systemic immune responses, not only exacerbates airway inflammation and lung tissue remodeling but also induces or aggravates multiple comorbidities. These comorbidities, together with acute disease exacerbations, constitute the primary causes of increased mortality in COPD patients, with impacts extending far beyond simple declines in lung function. Khan et al. (37) further elaborated on the mechanism of statin action. By inhibiting the mevalonate pathway to reduce isoprenoid intermediates, statins disrupt Rho GTPase-dependent inflammatory cascades. This mechanism exerts a consistent protective effect across different stages of COPD. In the pathogenic stage, it attenuates early airway inflammation to prevent disease initiation. In patients with established disease, this anti-inflammatory effect slows disease progression, reduces the frequency of acute exacerbations, and alleviates cardiovascular comorbidities.
Collectively, these findings underscore the necessity of prioritizing alternative mechanisms, particularly the anti-inflammatory pathways of statins, to fully elucidate their beneficial effects in COPD patients. In COPD patients, elevated inflammatory markers are closely linked to disease progression and poor prognosis (39). CRP, a biomarker synthesized by the liver in response to the inflammatory cytokine IL-6, is elevated in parallel with COPD severity and all-cause mortality (40-42). These findings align with our multivariate regression analysis, which demonstrated that higher neutrophil counts, and CRP levels significantly increase all-cause mortality in COPD patients. The mediation analysis (Table 3) further verified that CRP partially mediates the protective effect of statins on all-cause mortality in COPD patients, accounting for 5.5% of the total effect. This finding directly links the anti-inflammatory properties of statins to improved survival outcomes. Furthermore, He et al. (43), in a large-scale cohort study using UK Biobank data, provided complementary evidence for our conclusions. Their work revealed that CRP is not only significantly positively associated with COPD risk but also mediates the association between the triglyceride-glucose (TyG) index and COPD (mediation proportion: 15.6%), directly validating the pivotal bridging role of inflammation in linking metabolic imbalance to COPD pathogenesis. Therefore, statins exert their mortality benefit at least partially by inhibiting the systemic inflammatory cascade that drives disease progression, acute exacerbations, and comorbid cardiovascular events. This further highlights the role of inflammatory pathways in the statin-mediated reduction in COPD incidence and improvement in prognosis.
Several limitations of this study should be acknowledged. First, the NHANES database lacks detailed information on statin doses and formulations to explore dose-response relationships and the comparative anti-inflammatory effects of different statin classes. Second, although confounding factors were corrected by multivariate regression, unmeasured covariates may still affect the accuracy of the results. Third, self-reported COPD status and the exclusion of approximately 16% of participants due to missing data introduced recall and selection biases, respectively. Fourth, the reliance on GWAS data from European and East Asian populations limits generalizability to other populations globally. Fifth, due to the lack of immune cell inflammatory markers and expression quantitative trait loci (eQTL) data, the MR analysis focused only on the HMGCR pathway and ignored other potential statin mechanisms. Finally, MR remains vulnerable to genetic tools, population selection, and measurement bias (44-47). The MR analysis suggests a possible causal relationship between statins and COPD risk reduction, but it focused on the incidence of COPD rather than mortality and thus requires confirmation in randomized, controlled trials (48).
Conclusions
This study, utilizing data from the NHANES cohort, identified a statistically significant association between statin use and a reduction in all-cause mortality among patients COPD. The mediation analysis revealed that CRP partially mediates the protective effect of statins on all-cause mortality in COPD patients. However, due to the inherent limitations associated with observational studies, this association should be interpreted with caution. MR analysis also indicated a potential causal relationship, suggesting that statin use may reduce the risk of developing COPD. These results underscore the necessity for additional well-structured clinical trials to enhance our understanding of the therapeutic potential of statins in the management of COPD.
Supplementary
The article’s supplementary files as
Acknowledgments
We appreciate the people who contributed to the NHANES data that we studied on.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.
Footnotes
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1-2794/rc
Funding: This work was supported by the Medical and Health Science and Technology Project of Zhejiang Province (grant No. 2024KY129); The Clinical Research Project of Zhejiang TCM Science and Technology Plan (grant No. 2023ZL394); and Research Project of Zhejiang Chinese Medical University (grant No. 2022FSYYZY04). The study sponsors had no role in the study design; in the collection, analysis and interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1-2794/coif). The authors have no conflicts of interest to declare.
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