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    J Korean Med Sci. 2024 Jul 08;39:e199. Forthcoming. English.
    Published online Jun 11, 2024.
    https://doi.org/10.3346/jkms.2024.39.e199
    © 2024 The Korean Academy of Medical Sciences.
    Original Article

    Relationship Between Aspirin Use and Site-Specific Colorectal Cancer Risk Among Individuals With Metabolic Comorbidity

    Seokyung An,1 Madhawa Gunathilake,1 Jeonghee Lee,1 Minji Kim,1 Jae Hwan Oh,2 Hee Jin Chang,2 Dae Kyung Sohn,2 Aesun Shin,3 and Jeongseon Kim1
      • 1Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea.
      • 2Center for Colorectal Cancer, National Cancer Center Hospital, National Cancer Center, Goyang, Korea.
      • 3Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.
    • Address for Correspondence: Jeongseon Kim, PhD. Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 10408, Republic of Korea. Email: [email protected]
    Received December 15, 2023; Accepted May 22, 2024.

    This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

    Abstract

    Background

    The relationship between aspirin usage and the risk of colorectal cancer (CRC) among individuals with both hypertension (HTN) and diabetes mellitus (DM) remains unclear. This study aims to explore the impact of aspirin use on the site-specific CRC risk in patients with metabolic comorbidity.

    Methods

    A case-control study was conducted among 1,331 CRC patients and 2,771 controls recruited from the Nation Cancer Center in Korea. Multinomial logistic regression analyses were used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for the association between aspirin use, metabolic disease status, and site-specific CRC risk.

    Results

    Among the 4,102 participants, 1,191 individuals had neither HTN nor DM, 2,044 were diagnosed with HTN, 203 with DM, and 664 presented with HTN and DM comorbidity. An increasing number of HTN and DM was associated with an increased risk of overall CRC (HTN or DM: OR, 1.70; 95% CI, 1.39–2.07; HTN and DM: OR, 8.43; 95% CI, 6.37–11.16), while aspirin use was associated with a decreased risk of overall CRC (OR, 0.31; 95% CI, 0.21–0.46). These results remained consistent across anatomical sites. Among individuals with HTN and DM comorbidity, aspirin use notably associated with lower risk of overall CRC (OR, 0.39; 95% CI, 0.21–0.72), proximal colon (OR, 0.32; 95% CI, 0.13–0.71) and rectal cancer (OR, 0.27; 95% CI, 0.08–0.97), but not distal colon cancer (OR, 0.58; 95% CI, 0.27–1.24).

    Conclusion

    This study showed that aspirin use is negatively associated with overall and site-specific CRC, even among individuals with HTN and DM comorbidity.

    Graphical Abstract

    Keywords
    Aspirin; Hypertension; Diabetes Mellitus; Comorbidity; Colorectal Cancer

    INTRODUCTION

    Colorectal cancer (CRC) is a growing concern worldwide, with over 2 million new cases annually, and its incidence is increasing in Asia.1, 2, 3 While advances in screening and treatment have been made, preventive strategies, including chemoprevention and addressing metabolic disease, remain crucial for reducing CRC risk.4, 5, 6, 7, 8, 9, 10, 11 Aspirin, a commonly used nonsteroidal anti-inflammatory drug with both anti-inflammatory and anti-tumor effects, is regarded as an established agent for preventing CRC.12, 13, 14, 15 However, recent studies have suggested that aspirin has no significant effect on CRC, making the association between aspirin use and CRC risk controversial.16, 17

    Although several studies have explored the relationship between aspirin use and the risk of CRC, most of the research has been conducted in Western populations, and limited information is available on site-specific CRC risk.4, 14, 18, 19, 20 Additionally, it is well-established that cardiovascular disease (CVD) risk factors, including hypertension (HTN), type 2 diabetes mellitus (DM), obesity, and metabolic syndrome, contribute to an increased risk of developing CRC.6, 7, 8, 9, 10, 11, 21, 22, 23 Previous studies have identified HTN and DM as the most prevalent comorbidities among CRC patients.24 However, few studies have investigated the relationship between multiple metabolic comorbid conditions and the risk of CRC.25, 26, 27

    Furthermore, the association between aspirin use and CRC risk among individuals with HTN and DM comorbidity remains unclear. Previous studies have been limited in scope, focusing solely on DM patients.28, 29 Therefore, the purpose of this study is to investigate the impact of aspirin use on site-specific CRC risk in high-risk individuals with metabolic comorbid conditions within the Korean population.

    METHODS

    Study participants

    The study comprised 1,780 newly diagnosed CRC patients collected by the Center for Colorectal Cancer of the National Cancer Center (NCC) in Korea from August 2010 to September 2020. Additionally, 18,471 controls who were previously not diagnosed with CRC and underwent the health screening at the NCC, provided by the National Health Insurance Service between October 2007 and December 2022, were selected. Among 20,251 individuals, 7,270 subjects without a completed lifestyle questionnaire were excluded. Among them, we conducted individual matching in a 1:2 ratio (cases:controls) based on age and sex for the 497 cases. For the 923 cases that could not be individually matched with controls, we performed frequency matching using 5-year age intervals, resulting in the selection of 1,420 cases and 2,840 controls for analysis. We excluded 158 subjects lacking information on blood pressure, fasting glucose level, their history of HTN and DM, aspirin use and duration, and anatomical site. Finally, a total of 4,102 participants including 1,331 CRC cases and 2,771 controls were eligible for final analysis (Fig. 1).

    Fig. 1
    Flow chart for selection of study population.

    Key variables

    The baseline characteristics, including age, socioeconomic status, lifestyle factors, body mass index (BMI), and family history of CRC, were collected. HTN was defined as having a history of HTN or systolic blood pressure above 130 mmHg or diastolic blood pressure above 80 mmHg.23, 30, 31 DM was defined as having a history of DM or a fasting glucose level higher than 120 mg/dL.23 Participants were categorized into five groups based on their baseline HTN and DM status: 1) None, 2) HTN only, 3) DM only, 4) HTN or DM, and 5) both HTN and DM.

    Aspirin usage was defined as self-reported aspirin use, along with its duration. The duration of aspirin use was classified into three categories: no use (zero years), less than 5 years, and 5 years or more.

    Statistical analysis

    The study compared the general characteristics of cases and controls using χ2 test and Fisher’s exact test for categorical variables whereas Student’s t-test was used to compared continuous variables. The primary outcome was a newly diagnosed CRC, defined as hospitalization for cancer diagnosis or surgery. Logistic regression analyses were conducted to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for assessing the relationship between aspirin use, its duration, and the risk of CRC among patients with metabolic conditions. Adjusted ORs and 95% CIs for CRC were calculated while adjusting for the potential covariates including enrollment age (< 50, 50–69, and ≥ 60 year), sex, education level (middle school or less, high school, and college or more), income level, marital status (married and single), BMI (< 18.5, 18.5–24.9, ≥ 25.0 kg/m2), cigarette smoking status (non-smoker, ex-smoker, and current smoker), drinking status (non-drinker, ex-drinker, and current drinker), regular exercise (no and yes), history of dyslipidemia (no and yes), history of heart disease (no and yes), and family history of CRC (no and yes).

    For subgroup analysis, CRC was divided into three parts: proximal colon (comprising cecum, ascending colon, hepatic flexure, transverse colon, and splenic flexure), distal colon (including descending colon, sigmoid-descending colon junction, and sigmoid colon), and the rectum (encompassing the rectosigmoid colon).32 Multinomial logistic regression was conducted for the subgroup analysis, investigating the association between the aspirin use and the risk of anatomical sites of CRC stratified combination of HTN and DM. All statistical analyses were performed using SAS 9.4 software (SAS Institute, Cary, NC, USA) and R (version 4.0.5; R Foundation for Statistical Computing, Vienna, Austria).

    Ethics statement

    The study was conducted following the guidelines approved by the Institutional Review Board (IRB) of the National Cancer Center (IRB No. NCCNCS-10-350 and NCC 2015-0202), and informed consent was obtained from all participants.

    RESULTS

    A total of 4,102 participants, including 1,331 cases and 2,771 controls, were included in this study. Of the cases, 415 were proximal colon, 448 were distal colon, and 468 were identified as rectal cancer. Table 1 presents the descriptive characteristics of the CRC cases and age- and sex-matched controls. The mean age (standard deviation) for cases and controls was 58.3 ± 10.3 and 57.6 ± 9.4 years, respectively (P = 0.880). In comparison to the controls, CRC patients had lower education and income levels, were more likely to be current drinkers, engaged in less regular exercise, and had a higher prevalence of family history of CRC (Table 1).

    Table 1
    General characteristics of stie-specific colorectal cancer cases versus controls

    Among the 4,102 participants, 1,191 individuals had neither HTN nor DM, 2,044 were diagnosed with HTN only, 203 with DM only, and 664 presented both HTN and DM. After adjusting for factors including enrollment age, sex, education level, income level, marital status, BMI, cigarette smoking status, drinking status, regular exercise, history of dyslipidemia, history of heart disease, and family history of CRC, having HTN or/and DM was associated with overall and site-specific CRC (Table 2). The adjusted ORs for overall CRC were 1.41 (95% CI, 1.15–1.73) for those with HTN only, 6.92 (95% CI, 4.67–10.26) for those with DM only, and 8.43 (95% CI, 6.37–11.16) for those with both HTN and DM (Table 2). Regarding anatomical location, HTN was significantly associated with an increased risk of distal colon cancer (OR, 1.96; 95% CI, 1.43–2.68). Individuals with DM only had a positive association with proximal colon (OR, 7.27; 95% CI, 4.25–12.45), distal colon (OR, 7.75; 95% CI, 4.46–13.49), and rectal cancers (OR, 7.03; 95% CI, 4.24–11.68). Additionally, we found that the increasing number of HTN and DM is positively associated with overall and site-specific CRC. In comparison to individuals without HTN and DM, the adjusted ORs for overall CRC were 1.70 (95% CI, 1.39–2.07) among individuals with HTN or DM and 8.43 (95% CI, 6.37–11.16) in those with HTN and DM. Moreover, this association was more pronounced in the proximal colon (OR, 10.46; 95% CI, 7.05–15.53) and distal colon regions (OR, 12.15; 95% CI, 8.20–18.00) than in the rectum (OR, 5.00; 95% CI, 3.36–7.42) (Table 2).

    Table 2
    Combination of hypertension and diabetes mellitus and the risk of colorectal cancer according to anatomic site

    In the total population, the use of aspirin was negatively associated with overall CRC, with an adjusted OR of 0.31 (95% CI, 0.21–0.46). These results remained consistent across anatomical sites of the CRC, with ORs of 0.24 (95% CI, 0.13–0.45) for proximal colon, 0.36 (95% CI, 0.21–0.62) for distal colon, and 0.33 (95% CI, 0.17–0.61) for rectal cancer (Table 3). Individuals who had regularly used aspirin for 5 or more years and those who had used it for less than 5 years were both negatively associated with overall CRC risk, with adjusted ORs of 0.30 (95% CI, 0.17–0.52) and 0.36 (95% CI, 0.21–0.63), respectively (Table 3). A similar association was observed in site-specific CRC (Table 3).

    Table 3
    Aspirin use and risk of colorectal cancer according to anatomic site

    The association between aspirin use and the risk of CRC, stratified by the number of HTN and DM, was presented in Table 4. In comparison to nonusers, the adjusted ORs for overall CRC were 0.17 (95% CI, 0.02–1.34) among aspirin users without HTN and DM, 0.31 (95% CI, 0.18–0.54) for those with HTN or DM, and 0.39 (95% CI, 0.21–0.72) for those with both HTN and DM (Table 4). Similar associations were observed for different anatomical sites. Among individuals with both HTN and DM, aspirin use was significantly associated with a decreased risk of proximal colon (OR, 0.32; 95% CI, 0.13–0.71), and rectal cancer (OR, 0.27; 95% CI, 0.08–0.97), but not distal colon cancer (OR, 0.58; 95% CI, 0.27–1.24) (Table 4, Supplementary Table 1).

    Table 4
    Association between regular aspirin use and risk of colorectal cancer stratified by number of HTN and DM

    DISCUSSION

    In this study, we found that having both HTN and DM was positively associated with CRC. On the other hand, an inverse association was shown between aspirin use and the risk of CRC. These results remained consistent across anatomical sites. Among individuals with HTN and DM comorbidity, aspirin use notably associated with lower risk of overall, proximal colon, and rectal cancer, but not distal colon cancer. These results underscored the potential benefits of aspirin use in mitigating site-specific CRC risk, especially among individuals with comorbid conditions.

    This study contributes additional evidence that reinforces the association between multiple metabolic conditions and an increased risk of CRC. Well-recognized CVD risk factors, such as HTN and DM, have been consistently associated with an elevated likelihood of overall6, 7, 8, 9, 10, 11 and site-specific CRC.4, 33 Previous research has also indicated metabolic syndrome is linked to a higher risk of early-onset CRC, particularly in proximal and distal colon cancer cases.25 Moreover, a nationwide study conducted in Korea has demonstrated the association between metabolic syndrome and obesity with an elevated risk of early-onset CRC.27 Nevertheless, the impact of the combination of HTN and DM on site-specific CRC risk, particularly within an Asian population, has been underexplored. The findings of this study highlighted the potential mechanisms linking HTN and DM comorbidity to the increased risk of CRC. The presence of chronic inflammation and oxidative stress in individuals with both HTN and DM comorbidity may create a favorable environment for tumor growth, thereby contributing to the heightened CRC risk.31, 34, 35, 36, 37

    Aspirin is believed to reduce the risk of CRC by inhibiting the production of prostaglandins, which are involved in processes such as inflammation and cell growth and have been linked to an increased risk of cancer.12, 13, 38 Aspirin blocks the activity of cyclooxygenase,39 an enzyme responsible for the production, and has been found to have anti-tumor properties, including inhibition of angiogenesis and apoptosis.40, 41 Previous studies consistently demonstrate that aspirin use is associated with a decreased risk of CRC,4, 14, 18, 19, 20 while no significant association has been shown in recent randomized clinical trials 16and Mendelian randomization study.17 Therefore, there is controversy regarding the association between aspirin use and the risk of CRC. Moreover, the majority of previous studies were focused on Western populations. In this study, we investigated the association between aspirin use and the risk of site-specific CRC in the Korean population. We found that using aspirin for more than 5 years was inversely associated with overall, proximal colon, and distal colon cancer risk. However, no significant association was found with the risk of rectal cancer. Similarly, in a cohort study, regular aspirin use (≥ 650 mg per week) for over 10 years was associated with a lower risk of CRC, excluding rectal cancer, compared to nonregular users.12 Another study, which included five randomized trials, reported that taking at least 75 mg of aspirin daily resulted in a reduced incidence of CRC, particularly in the case of proximal colon cancer.42 In both our study and previous research, aspirin use has been found to be strongly associated with colon cancer than rectal cancer, regardless of baseline disease condition. When stratifying by disease status, previous study showed that aspirin had preventive effects on both colon and rectal cancer among patients with DM.43 We also found a similar association with the risk of proximal, distal colon, and rectal cancer among the individuals with HTN or DM. However, among individuals with both HTN and DM, there is a significant association with proximal colon and rectal cancer, not distal colon cancer.

    In this study, we found that aspirin use significantly decreased the risk of overall and site-specific CRC, even in individuals with HTN and DM comorbidity. While there is an established association between metabolic disease, aspirin, and CRC, there are few studies examining the relationship between aspirin and CRC in individuals with metabolic comorbidities. Although some research has examined the significant association between aspirin and CRC risk among patients with DM,29, 43 there is still a limited number of studies conducted for patients with both HTN and DM, which are the most prevalent comorbidities among CRC patients.24 Therefore, our findings carry potential implications for cancer prevention and management in individuals with comorbidity. Despite aspirin use being inversely associated with CRC risk, aspirin has significant side effects such as gastrointestinal bleeding.15 Further research targeting these high-risk individuals, while considering these side effects, will be valuable for informing clinical practice and formulating effective preventive strategies.

    This study has several strengths. First, this study focused on site-specific CRC risk, providing valuable insights into the association between aspirin use and various anatomical sites of CRC within the Asian population. Second, this study examined the association between aspirin use and CRC risk, specifically among patients with comorbid HTN and DM. As these individuals are already at a higher risk for developing CRC, investigating the impact of aspirin in this high-risk subgroup can help identify potential preventive measures for decreasing CRC incidence in these patients.

    This study has several limitations that should be taken into consideration. Firstly, the case-control study design may introduce recall bias and selection bias, where the cases and controls selected may not fully represent the population of interest. Secondly, the information on aspirin uses and medical history relied on self-reported questionnaires, which may result in measurement bias and inaccuracies. Thirdly, due to the lack of hemoglobin A1C data, only fasting glucose levels and self-reported DM were used to define DM in this study. It might underestimate the prevalence of DM in this study population. Lastly, due to the absence of information regarding the dosage of aspirin intake and cancer stage, we only suggested an association between aspirin duration and CRC risk. Further studies are needed to investigate the relationship between the dose of aspirin use and stage-specific risk of CRC according to the baseline disease status. Despite these limitations, this study highlights the importance of investigating the potential benefits of aspirin use among individuals with metabolic comorbidity and its potential implications for CRC prevention and management. Further research with a larger and more representative sample, as well as a prospective design and dose-response association, will be needed to validate these mechanisms and clinical implications of aspirin use in this high-risk subgroup.

    In conclusion, this study provides evidence that aspirin use is associated with a decreased risk of overall, proximal, and rectal cancer, even in individuals with HTN and DM comorbidity. These findings could have important implications for the development of effective strategies aimed at preventing CRC within high-risk groups.

    SUPPLEMENTARY MATERIAL

    Supplementary Table 1

    Association between regular aspirin use and risk of colorectal cancer stratified by combination of metabolic diseases

    Click here to view.(42K, doc)

    Notes

    Funding:This research was supported by National Research Foundation grant funded by the Ministry of Science and IST (2021R1A2C2008439), and by a research grant from the National Cancer Center in Korea (2310470).

    Disclosure:The authors have no potential conflicts of interest to disclose.

    Author Contribution:

    • Conceptualization: An S, Kim J.

    • Data curation: An S, Gunathilake M, Lee J, Kim M.

    • Formal analysis: An S.

    • Funding acquisition: Kim J.

    • Investigation: An S, Gunathilake M.

    • Methodology: An S, Gunathilake M, Lee J.

    • Project administration: Lee J, Kim J.

    • Resources: An S, Lee J, Kim M.

    • Supervision: Kim J.

    • Validation: An S, Gunathilake M, Lee J, Oh JH, Chang HJ, Sohn DK, Shin A, Kim J.

    • Visualization: An S.

    • Writing - original draft: An S, Kim J.

    • Writing - review & editing: An S, Gunathilake M, Lee J, Kim M, Oh JH, Chang HJ, Sohn DK, Shin A, Kim J.

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