The interactions among factors associated with the risk of lung cancer among diabetes patients: a survival tree analysis

The present study revealed that despite tobacco smoking being a well-established risk factor for lung cancer, age, smoking, and COPD may interact to differentiate the risk of lung cancer in diabetes. The tree model identified age at 64 years as optimal age cutoff to primarily differentiate the risk of lung cancer among the study diabetes population. Among old ever smokers characterized by a longer history of diabetes (median: 6–8 years), the presence of COPD emerged as key risk factor for lung cancer. Young never smokers, old never smokers, young ever smokers, old ever smokers without metformin use/COPD, and old ever smokers with metformin use and COPD demonstrated a gradient of increasing lung cancer risk.

In the current study, age, smoking, and COPD exhibited an interaction pattern on the risk of lung cancer under diabetes condition. Aging, smoking, diabetes, and COPD are intricately linked and may collectively influence the risk of lung cancer among diabetes patients. Diabetes¹⁸ and COPD^19,20 are both age-related diseases^18,19,20, and characterized by chronic low-grade inflammation^18,20 and cellular senescence^18,19,21. Prior research has shown that COPD, but not asthma, is associated with an elevated risk of diabetes, potentially due to the shared oxidative stress, systematic inflammation mechanism, and cytokine profile between two diseases²². Elevated levels of proinflammatory factors in COPD may promote insulin resistance over time^22,23. On the other hand, while smoking exposure is a major risk factor for COPD, it is estimated that one-third of patients with COPD are never smokers²⁴. Previous research has demonstrated that COPD is a risk factor for lung cancer regardless of smoking status²⁵. Nevertheless, smoking exposure may induce additional damage to the lungs by intensifying oxidative stress and triggering systematic inflammation¹⁰. Moreover, the repairing process of injured lungs may cause scar formation¹⁰. Smoking and COPD may both accelerate lung functioning decline faster than the normal physiological aging process¹¹. In addition, cumulative exposure to carcinogens in tobacco smoke may increase with age. Furthermore, under chronic hyperglcemia, the lungs may suffer from further injury due to microangiopathy in diabetes⁷. As a result, in addition to direct exposure to carcinogens in tobacco smoke, the co-existence of accelerated decline in lung functioning and systematic inflammation under smoking exposure, chronic lung disease, and diabetes^10,22, may collectively accelerate carcinogenesis of the lungs.

There are some potential public health implications of the present study. While the overall association between diabetes and lung cancer remains controversial in the literature^2,3,4,5,6, biological aging, smoking, and COPD may collectively promote chronic inflammation and accelerate decline in lung functioning faster than normal aging in diabetes¹¹. Prior research suggests that improved metabolic health may potentially delay progression of chronic lung diseases such as COPD²³. In addition to preventing tobacco use, improved metabolic health may slow down deterioration of lung functioning in the presence of chronic lung diseases²³, potentially lowering the risk of developing lung cancer under diabetes condition.

Some limitations are potentially present in the current study. First, information on cumulative exposure to active smoking was not available in this study. Dose-response effects of smoking were not evaluated. Second, smoking information was self-reported and prone to social desirability bias. Third, information on COPD severity was not available in this study. Fourth, glycemic levels were measured at baseline in this study. The subsequent change in glycemic levels was not captured. Fifth, dosage and duration of medication use was not evaluated in the present study. Sixth, information on occupational and environmental exposures to potential carcinogenic agents was not available in this study. Seventh, histological subtypes of lung cancer were not differentiated in the study. Lastly, the dominant factors and optimal cutoff for age may vary across different populations. Further studies are warranted to verify generalizability of the findings in other populations.