Review
The Association between Dyslipidemia and Pulmonary Diseases
2024 Volume 31 Issue 9 Pages 1249-1259
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2024 Volume 31 Issue 9 Pages 1249-1259
Dyslipidemia is one of the most common diseases worldwide. As a component of metabolic syndrome, the prevalence and mechanism by which dyslipidemia promotes cardiovascular diseases has been well studied, although the relationship between pulmonary diseases is not well understood. Because the lung is a respiratory organ with a large surface area and is exposed to the environment outside the body, it continuously inhales various substances. As a result, pulmonary diseases have a vast diversity, including chronic inflammatory diseases, allergic diseases, cancers, and infectious diseases. Recently, growing evidence has suggested that dyslipidemia plays a role in the pathogenesis and prognosis of various pulmonary diseases. We herein review the current understanding of the relationship between dyslipidemia and pulmonary diseases, including chronic obstructive pulmonary diseases, asthma, and lung cancer, and infectious pulmonary diseases, including community-acquired pneumonia, tuberculosis, nontuberculous mycobacterial pulmonary disease, and COVID-19. In addition, we focus on recent evidence of the utility of statins, specifically 3-hydroxy-3-methylglutaryl-coA reductase inhibitors, in the prevention and treatment of the various pulmonary diseases described above.
The lungs are major organs of the respiratory system that enable gas exchange between inhaled air and circulating blood. As they have a large surface area (approximately 70 m2 in adults) and are constantly exposed to the environment outside of the body1), various stimulations (pathogens, toxic substances, and allergens) cause pulmonary diseases, including infectious diseases, allergic diseases, chronic inflammatory diseases, and cancers.
Metabolic syndrome (MetS) is a cluster of risk factors, including hypertension, dyslipidemia, raised fasting glucose, and central obesity2). Patients with MetS are susceptible to cardiovascular disease and type 2 diabetes mellitus. Dyslipidemia is defined as an imbalance of plasma lipids and/or lipoproteins, such as triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). Dyslipidemia is the most notable risk factor for cardiovascular disease3), and its prevalence has increased worldwide over the past 30 years4). However, its relationship with pulmonary diseases is not well understood.
Statins, specifically 3-hydroxy-3-methylglutaryl-coA reductase inhibitors, are commonly used in the treatment of dyslipidemia because of their inhibitory effect on cholesterol synthesis5). Furthermore, statins have been reported to have anti-inflammatory and immunomodulatory effects (“pleiotropic” effects), mainly related to the inhibition of protein isoprenylation. As statins inhibit the synthesis of L-mevalonate, the production of downstream metabolites of L-mevalonate, including farnesyl pyrophosphate and geranylgeranyl pyrophosphate, is inhibited. These two molecules are essential for the activation of small GTPase proteins, including Ras, Rho, and Rac, via post-transcriptional isoprenylation. Because the activation of these cell signaling proteins is involved in cell differentiation, proliferation, and inflammation, statins are expected to contribute to the treatment of various diseases6).
In the present review, we explore the current understanding of the relationship between dyslipidemia and pulmonary diseases, including chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF), lung cancer, and infectious pulmonary diseases, as well as the clinical implications of statins for their prevention and treatment.
COPD is a heterogeneous lung condition characterized by chronic respiratory symptoms (dyspnea, cough, expectoration, and/or exacerbations) due to abnormalities of the airways and/or alveoli, which cause persistent, often progressive, airflow obstruction7). It is estimated that the global prevalence of COPD among people aged 30-79 years was 7.6% (391.9 million people) in 2019 8). Although primarily caused by cigarette smoking, the progression of COPD depends on numerous interacting environmental, genetic, and developmental factors7, 9).
COPD is also known to be a systemic inflammatory disease, and smoking-induced endothelial injury caused by oxidative stress is gaining attention as an additional contributor not only to the pathogenesis of COPD, but also to the pathogenesis of systemic comorbidities, including atherosclerosis, pulmonary hypertension, and chronic renal injury10).
Dyslipidemia, the most common risk factor for cardiovascular disease, is one of the most common comorbidities in COPD patients11). However, whether or not it affects COPD progression remains unknown. Recently, a nationwide population study cohort study in Taiwan, which enrolled more than 100,000 patients from the National Health Insurance Research Database, reported that patients with hyperlipidemia were more likely to develop subsequent COPD than those without hyperlipidemia12). Although this study had several limitations, including confounders, which are inevitable in registry-based studies, this evidence may support a link between the progression of COPD and dyslipidemia through endothelial injury10) (Fig.1).
The pathogenesis of COPD and dyslipidemia
Among the many comorbidities accompanied by COPD, cardiovascular diseases frequently coexist with COPD13) and are associated with increasing mortality, which accounts for 16%-39% of death in COPD patients14). Interestingly, in the Hokkaido COPD Cohort study in Japan, cardiovascular diseases accounted for only 11% of deaths in COPD patients, which is significantly lower than that in Western countries15). Adiponectin has gained attention for explaining this difference. Adiponectin is an adipocytokine released from adipose tissue. Adiponectin has anti-inflammatory and antioxidative properties and is known to be higher in underweight populations than obese populations16). Tomoda et. al reported that plasma adiponectin levels are four times higher in COPD patients than in controls and two times higher even in normal weight COPD patients in Japan17). In addition, serum adiponectin has been reported to be inversely associated with cardiovascular events in patients18). As the underweight and non-obese phenotype of COPD is dominant in Japan19), it is estimated that Japanese patients with COPD have relatively high levels of serum adiponectin, which might explain their lower rate of cardiovascular events than patients in Western countries.
Regarding whether or not the use of statins to treat dyslipidemia and anti-inflammatory therapy would improve the outcomes of COPD, many observational studies have reported conflicting results, possibly due to the influence of major biases20). Of the two randomized control studies that have been conducted, one reported that simvastatin had no effect on COPD exacerbation21), while the other reported that simvastatin prolonged the time to first COPD exacerbation and reduced exacerbation frequency22). Further studies are required to elucidate the precise effects of statins on COPD treatment.
2.2 AsthmaAsthma is one of the most common chronic, non-communicable diseases, affecting 4.3% of adults worldwide23) and accounting for 1 in every 250 deaths worldwide24). Asthma is a heterogeneous and multifactorial disease characterized by variable respiratory symptoms (cough, chest tightness, shortness of breath, and wheezing) and airflow limitation. These symptoms are typically caused by chronic airway inflammation, hypersensitivity, and remodeling. Pathologically, eosinophilic, type 2-high airway inflammation accounts for approximately 50% of adult asthma cases, although some asthma cases exhibit type 2-low airway inflammation, represented by neutrophilic inflammation23). Various types of cells are involved in asthma inflammation, including T cells, macrophages, granulocytes, B cells, and lipid mediators, such as leukotrienes, prostaglandins, and fatty acids, regulate cell signaling between these cells25). Among lipid mediators, leukotrienes play an important role in the pathogenesis of asthma26), and leukotriene receptor antagonists, such as montelukast, play an important role in the pharmacological treatment of asthma23).
Although inhaled corticosteroids significantly improved the treatment of asthma in the 20th century, whether or not certain types of asthma patients, particularly obese patients, respond to traditional corticosteroid therapy remains unclear27). In addition, the prevalence of asthma in the obese population is twice as high as that in the normal-weight population28). Hence, the relationship between obesity and asthma has been extensively studied. Many explanations have been proposed for the complex interactions between asthma and obesity, including developmental factors, genetic factors, mechanical factors, systemic inflammation, metabolic inflammation, and oxidative stress29). Among these, MetS has recently become the focus of research. A small study reported that adult-onset asthma is associated with MetS independent of the body mass index (BMI)30). In addition, an explorative study reported that elevated serum TGs levels were independently associated with asthma in obese patients, suggesting the role of dyslipidemia in the pathogenesis of asthma31). More recently, a retrospective cohort study reported that elevated triglyceride-glucose index, a biomarker of metabolic dysfunction calculated from fasting TG and fasting glucose, was an independent predictor of severe asthma exacerbation32). Accumulating evidence suggests a link between asthma and dyslipidemia, especially high TG levels, although the mechanism by which elevated TG levels affect the pathogenesis of asthma remains unknown.
Considering their anti-inflammatory and immune-modulating effects, statins appear to be a promising pharmacological treatment for severe asthma. Indeed, a study in an animal model of obesity-related asthma revealed that pravastatin exerts anti-asthmatic effects by suppressing the Th2 and Th17 signaling pathways33). Many RCTs focusing on statin effects on asthma have been conducted, and recently, a meta-analysis of 12 RCTs reported that statins did not alter the lung function in patients with asthma but did improve asthma symptoms and inflammatory indexes in blood and sputum34).
2.3 IPFIPF is the most common idiopathic interstitial pneumonia with a poor prognosis. The prevalence of IPF ranges from 10 to 60 cases per 100,000 35) and is 10.0 in Japan36). IPF is characterized by severe, chronic, progressive, and irreversible pulmonary fibrosis that occurs in the lung parenchyma. The median survival time of patients with IPF is less than five years. Despite extensive research, the precise pathogenesis of IPF remains obscure, but according to our current understanding, the fibrosis of IPF is generated by recurrent of chronic epithelial-cell injury, which leads to aberrant wound healing37). Aside from lung transplantation, there is no fundamental treatment for IPF. However, in the last decade, two antifibrotic agents, pirfenidone and nintedanib, have been shown to mitigate the progression of fibrosis and have been approved38, 39).
Although the exact causes of IPF remain unknown, several potential risk factors have been identified, including cigarette smoking, occupational and environmental inhalation of particles (chemical fumes, dust, etc.), viral infections, and comorbidities, such as gastroesophageal reflux, diabetes mellitus, and obstructive sleep apnea37). As both IPF and dyslipidemia frequently occur in elderly patients, whether or not dyslipidemia affects IPF progression is unclear. In a systematic review, the prevalence of hyperlipidemia in IPF patients ranged from 6% to 53%40). A recent nationwide cohort study in South Korea reported that the prevalence of dyslipidemia in IPF patients was 50.49% at the diagnosis, second only to gastroesophageal reflux disease41). However, to our knowledge, no relationship has been identified between IPF pathogenesis and dyslipidemia.
Statins are expected to mitigate the progression of pulmonary fibrosis through pleiotropic effects. Many observational clinical studies and basic research have been conducted to date; however, they have shown inconclusive results42). Recently, two studies based on South Korea’s database of the National Health Insurance Service reported that the use of statins had beneficial effects on IPF, including lowering the risk of IPF and improving mortality in IPF patients43, 44). However, a large-scale prospective study is needed to elucidate the precise effects of statins on IPF.
2.4 Lung CancerLung cancer is now the most frequently diagnosed cancer and the leading cause of cancer-related deaths worldwide45). Despite recent advances in treatment, including oncogenic alteration-specific molecular-targeted agents and immunotherapies using immune checkpoint inhibitors (ICIs)46), the 5-year survival from lung cancer tends to be below 20% in most countries45).
Although cigarette smoking is the strongest risk factor for lung cancer, a small proportion of the population develops lung cancer despite no history of smoking47). In addition, despite a decrease in the size of the smoking population, the incidence of lung cancer is increasing, suggesting the potential presence of other as-yet-unidentified risk factors.
Recently, the association between lung cancer and MetS, including dyslipidemia, has been extensively studied, and several cohort studies have reported that high levels of TG and low levels of HDL-C are associated with the risk of lung cancer48-50). Some hypotheses have been proposed to explain this, including the suggestion that oxidative stress and reactive oxygen species caused by high TG levels promote carcinogenesis, while low HDL-C levels abolish the anti-inflammatory, antioxidant, and anti-proliferative effects of HDL-C50).
More recently, a prospective cohort study on the UK biobank, which enrolled 331,877 people, reported that the hazard ratio of MetS was 1.21 (95% confidence interval [CI], 1.09-1.33) for the overall risk of lung cancer, and a positive association with lung cancer was observed for low levels of HDL-C, an increased waist circumference, and hyperglycemia51). Previous studies have demonstrated that an excessive BMI acts as a protective factor against lung cancer52), as in Japan53), although its biological mechanism remains unknown. However, even with a careful analysis, the confounding effect of smoking was unavoidable in these studies52, 53). In the present study, the same association between lung cancer and the BMI was observed; however, after controlling for the BMI, an increased waist circumference was still identified as a risk factor for lung cancer. The authors speculated that abdominal adiposity may be an important risk factor for promoting carcinogenesis through hyperinsulinemia, altered levels of sex hormones, and proinflammatory adipokines51). Although further studies are needed, the perspective of abdominal adiposity may contribute to the understanding of the relationship between MetS and lung cancer (Fig.2).
Lung cancer and metabolic syndrome
Similar to other cardiovascular/anti-inflammatory drugs, the effect of statins for treating or preventing cancers is also of interest, although a meta-analysis could not validate the beneficial effects54). In lung cancer, one observational study reported that statin use was positively correlated with the prognosis of patients receiving immunotherapy by ICIs, which the authors speculated on the synergy of the immunomodulatory effects of statins and ICIs55). Another study of South Korea’s National Health Insurance Service database suggested that statins have an independent protective association with lung cancer development in patients with IPF43). Further studies are expected to reveal the effective use of statins in the clinical management, prevention, and treatment of lung cancer.
2.5 Infectious Diseases 2.5.1 Community-Acquired Pneumonia (CAP)CAP is defined as pneumonia acquired outside a hospital. It is usually caused by a bacterial infection, represented by Streptococcus pneumoniae56), although viruses or fungi can be responsible for this57). Despite advances in antimicrobial agents, lower respiratory tract infections, including pneumonia (excluding COVID-19), remain the fifth leading cause of death as of 2021 58). In Japan, the estimated incidence rates of adult CAP, hospitalization, and in-hospital death are 16.9, 5.3, and 0.7 per 1,000 person-years, respectively59).
Many risk factors for CAP have been identified, including age, sex, lifestyle, and comorbidities. Dyslipidemia has not yet been identified as a risk factor for CAP60). However, in the study of sepsis, growing evidence has highlighted the importance of plasma cholesterol in severe bacterial infections. A meta-analysis reported hypocholesterolemia, including total cholesterol, HDL-C, and LDL-C to be associated with a poor prognosis in sepsis61), and another meta-analysis found that hypocholesterolemia, especially low HDL-C levels, is associated with increased mortality due to sepsis62), although the mechanism is not well understood.
Regarding the relevance of plasma cholesterol levels to severe CAP, a small study reported that hypocholesterolemia was associated with increased mortality from severe CAP63). Although not limited to CAP, a large cohort study from the Mayo Clinic reported that, among patients hospitalized with pneumonia, those diagnosed with hyperlipidemia showed lower short- and long-term mortality than those not diagnosed with hyperlipidemia, and LDL-C levels were inversely associated with mortality64). These findings suggest that the plasma cholesterol level is a promising prognostic factor for CAP (Fig.3A).
A: Dyslipidemia and community-acquired pneumonia. B: Dyslipidemia and tuberculosis. C: Dyslipidemia and COVID-19.
Numerous observational studies have been conducted to clarify whether or not statins have beneficial effects in the prevention or treatment of CAP, but the results have been inconsistent and conflicting65, 66). Considering that the utility of statins in sepsis has not been established61), more studies are needed to elucidate the role of statins in CAP treatment.
2.5.2 TuberculosisTuberculosis is an airborne infectious disease caused by Mycobacterium tuberculosis infection, which mainly targets the lungs and is transmitted through the air67). Although tuberculosis is now a preventable and usually curable disease, it remained the world’s second leading cause of death from a single infectious agent, after coronavirus disease 2019 (COVID-19), in 2022, and it is estimated that more than 10 million people will become ill and 1.30 million people will die from tuberculosis every year67). Furthermore, with the emergence of multidrug-resistant tuberculosis, which is resistant to current tuberculosis drugs68), it remains a public health threat in most parts of the world.
After inhalation, M. tuberculosis is phagocytosed by the alveolar macrophages. While it evades the antimicrobial activity of macrophages by inhibiting phagosome-lysosome fusion, host immunity contains infected macrophages within granulomas and limits bacterial growth69).
The risk of tuberculosis in immunocompromised hosts, such as patients with AIDS or solid organ transplantation, has been well recognized and studied70). However, the relationship between tuberculosis and dyslipidemia is poorly understood. Ngo et al. summarized the current understanding of the association between dyslipidemia and tuberculosis71). Interestingly, observational studies have shown that susceptibility to tuberculosis, unlike other inflammatory pulmonary diseases, low total cholesterol is associated with an increased risk of tuberculosis72), and low total cholesterol, low HDL-C, and low LDL-C levels are associated with extensive lung lesions of pulmonary tuberculosis infection73, 74). In addition, another study reported that elevated levels of cholesterol are associated with reduced systemic inflammation and mortality in pulmonary tuberculosis, independent of the BMI75). These studies strongly suggest that serum cholesterol levels are protective against tuberculosis infection. The mechanism by which serum cholesterol affects tuberculosis infection is elusive, although several studies have suggested that cholesterol plays an essential role in the phagocytosis of macrophages76, 77) (Fig.3B).
If low cholesterol levels affect the course of pulmonary tuberculosis, does a high-cholesterol diet or treatment for dyslipidemia affect the course as well? A high-cholesterol diet has shown adverse results so far, as a large cohort study in Singapore reported a dose-dependent relationship between a high-cholesterol diet and active tuberculosis78), while a small RCT study reported that a cholesterol-rich diet accelerated the sterilization rate of sputum cultures in patients with pulmonary tuberculosis79). Regarding statin treatment, a study on the South Korean nationwide database reported no protective effect of statins against tuberculosis80), while a study on Taiwan’s national database reported a positive relationship between statin use and lower risk of tuberculosis81). Further studies are required to confirm these findings.
2.5.3 Nontuberculous Mycobacterial Pulmonary Disease (NTM PD)NTM PD is a non-communicable, chronic infectious pulmonary disease caused by nontuberculous mycobacterial infection, representing over 190 species and subspecies from ubiquitous environment82). The prevalence of NTM PD is increasing worldwide, especially in Asia83). As biological agents are widely used in the treatment of immune-mediated inflammatory diseases, the rise in NTM infection as a severe adverse event is a concern84). Importantly, as the clinical course of NTM PD varies widely depending on the species of NTM and the immune system of hosts, the treatment of NTM PD has not yet been established82). Therefore, precise identification of risk factors and improved treatment of NTM are required.
There are several known risk factors for NTM PD, including the environment (e.g. isolation of NTM in showerheads, humidity), structural lung disease, genetic disorders, and impaired immunity85). Clinically, it has been documented that thin, older women are predisposed to NTM PD, which is referred as “Lady Windermere Syndrome”86). Regarding dyslipidemia, a case-control, retrospective study first reported the relationship between NTM PD and the level of serum total cholesterol, which was significantly lower in patients with NTM PD than in those without it87). In addition, in patients with disease progression, which is defined by radiological exacerbation and positive sputum culture, the total cholesterol level tended to decrease as the disease progressed, suggesting the usefulness of total cholesterol level as a predictor of disease progression87). The mechanism underlying the relationship between the level of total cholesterol and NTM PD is uncertain, but one possible explanation is that a low total cholesterol level reflects the host’s malnutrition, as other studies have suggested that a low BMI88), low visceral fat, and low nutrient intake89) are associated with NTM PD.
The treatment of NTM PD varies depending on the species, but in general, regimens include a combination of several kinds of antibiotics82). To our knowledge, the utility of statins has not been confirmed in any clinical studies so far; however, basic evidence suggests the effectiveness of statins in NTM PD treatment via a mechanism common with tuberculosis90).
2.5.4 COVID-19Since the emergence of SARS-CoV-2 in 2019, COVID-19 has rapidly spread worldwide, evolving into a pandemic, and remains a significant international threat to public health. As the pandemic has been on a downward trend, the World Health Organization declared COVID-19 no longer a global health emergency in 2023 91). However, the risk of the emergence of new variants remains.
In the early stage of the pandemic, the risk of severe acute respiratory syndrome and mortality in patients with COVID-19 was quite high, so the risk factors correlated with the severity and mortality of COVID-19 have been extensively researched. Among the identified risk factors, MetS has been associated with adverse COVID-19 outcomes92, 93). As for dyslipidemia, a meta-analysis reported that the prevalence of dyslipidemia increased the mortality and severity of COVID-19 94), and an umbrella review reported that a history of dyslipidemia was likely associated with the severity of COVID-19. They also warned about the ambiguity of the definition of dyslipidemia in previous studies95).
The precise mechanism by which dyslipidemia affects the COVID-19 prognosis remains unknown. One possible explanation for this is that viruses, including SARS-CoV-2, use lipid membranes not only as entry points for host cells but also as viral membranes; therefore, the level of cholesterol may affect the efficiency of viral replication96) (Fig.3C).
During the pandemic, vigorous research was poured into identifying widely available and inexpensive drugs that might improve the outcome of COVID-19. Among them, statins were found to be particularly promising, owing to their anti-inflammatory effects. Many favorable relationships aligned with these data have been reported from multiple observational studies, and a meta-analysis reported that statin use improved mortality, intensive-care unit admission, and mechanical ventilation rates97). This effect on mortality was preserved in a meta-analysis of propensity-matched cohorts98). Recently, the results of an international multicenter RCT that administered simvastatin to critically ill COVID-19 patients from October 2020 to January 2023 were reported. The primary outcome was organ support-free days, and although it did not meet the prespecified criteria, initiation of simvastatin was superior to the control at a probability of 95.9%99). Despite the promising results of this study, however, verification of the effectiveness of statins in COVID-19 treatment might no longer be possible, as the number of severe COVID-19 cases has already dramatically decreased. However, these data may be able to be utilized in future pandemics of infectious pulmonary diseases.
This review summarizes the latest understanding of the relationship between dyslipidemia and pulmonary diseases and the current knowledge of the effects of statins on pulmonary diseases. Growing evidence from clinical studies as well as basic research suggests the importance of lipidomics in pulmonary diseases and the potential effectiveness of statins. Although further studies are needed, lipidomic approaches appear to be promising for the prevention and treatment of pulmonary disease.
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