Treatment intensity-dependent association between the number of oral hypoglycemic agents and insulin use and lung cancer risk in patients with type 2 diabetes

Introduction

Diabetes mellitus is considered a major public health problem, increasing with aging, Western diet, obesity, urbanization, and sedentary lifestyles (1). In 2020, approximately 6.05 million Korean adults aged ≥30 years were estimated to have diabetes mellitus, with an estimated prevalence of 16.7% (19.2% in men and 14.3% in women) (2). Diabetes mellitus is associated with increased incidence and mortality of overall cancers (3,4), including lung cancer (5-7). Of note, lung cancer is one of the most common cancers and is regarded as a major cause of cancer-related death (8,9). In Korea, the prevalence of lung cancer was as high as 11.6% (26,985 patients) in 2017, making it the third most common cancer (9).

Although some cohort studies reported no significant association between diabetes and lung cancer risk (3,4,10), a meta-analysis of observational studies, including 34 studies from 24 manuscripts (10 case-control studies and 24 cohort studies), revealed an association between diabetes mellitus and an increased risk of lung cancer compared with non-diabetic controls, even after adjustment for smoking status [risk ratio: 1.11, 95% confidence interval (CI): 1.02–1.20, sample sizes ranged from approximately 600 to nearly 91,000 in case-control studies and from approximately 20,000 to nearly 2 million in cohort studies] (6). This association becomes prominent with insulin treatment [insulin users vs. never-users, adjusted hazard ratio (aHR): 1.56, 95% CI: 1.48–1.61] (11), which may be related to insulin resistance, hyperinsulinemia, and promotion of an inflammatory microenvironment and cancer growth (11-14). While previous studies have investigated the association between oral hypoglycemic agents (OHAs) and insulin and lung cancer risk, they have provided inconsistent results and have limitations in their study design, including limited covariates in the multivariable model (e.g., age, sex) (5), a lack of smoking status (5,11), and investigating insulin users only or each OHA separately (5,11,15).

In clinical practice, treatment for diabetes mellitus is usually started with one type of OHA during the early stage. With progression of this disease, other types of OHAs are subsequently added, and insulin is eventually required for the management of diabetes mellitus. In this context, an increasing number of OHAs and subsequent insulin use can serve as a proxy for diabetes mellitus severity in a treatment-intensity-dependent association (16). Many patients with diabetes mellitus receive combinations of more than two types of OHAs. Nonetheless, to the best of our knowledge, no previous study has yet investigated the collective effects of the number of OHAs on lung cancer risk. Therefore, the current study aimed to investigate whether the number of OHAs and insulin use are associated with lung cancer risk in a treatment-intensity-dependent manner using a Korean nationwide database. This approach and analysis model (the number of OHAs and insulin use) would be consistent with the usual clinical practice, which intensifies diabetes mellitus medication as the severity and duration. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-680/rc).

Methods

Data source

The Korean National Health Information Database is a public database established by the Korean National Health Insurance Service (NHIS, https://nhiss.nhis.or.kr), which has provided data on the sociodemographic characteristics, insurance claims, national health examination, and mortality of the entire Korean people (approximately 50 million) (17,18). The NHIS is a single public health insurer covering 97% of the Korean people, while the remaining 3%—those with the lowest income—are covered by the Medical Aid, a public assistance program. However, the NHIS also manages all administrative processes for Medical Aid beneficiaries.

The NHIS has offered national health screening programs since 1995 (19). Until 2018, all employees aged ≥19 years or adults aged ≥40 years with health insurance were required to undergo a national health screening program every 2 years (annually for manual workers), including laboratory tests, simple chest radiography, and self-report questionnaires about lifestyle behaviors and medical history (18,20).

Ethics statement

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was granted exemption from review by the Institutional Review Board of Asan Medical Center, Seoul, Republic of Korea as it utilized publicly available databases. The need for informed consent was waived because this was a retrospective study that used anonymized data.

Study population

Individuals who participated in the 2015–2016 national health examination were screened. Among them, a total of 2,616,828 individuals with type 2 diabetes mellitus were identified according to the following definition: (I) fasting blood glucose (FBG) level ≥126 mg/dL at the time of health screening; or (II) insurance claims for type 2 diabetes mellitus [International Classification of Diseases 10th Revision (ICD-10) codes E11–E14] accompanied by at least one prescription of OHAs or insulin within the same year (January to December) of their health screening (21-23). The following individuals were excluded: 323 individuals under the age of 20; 133,735 individuals with any insurance claim for cancer (ICD-10 codes C00–97) and critical illness registration for cancer (code V193) before their health screening (wash-out of all cancer); 83,846 individuals lacking sufficient medical data; and 60,754 individuals who were diagnosed with cancer (ICD-10 codes C00–97 and special code V193) within 1 year following the index date (1-year lag period). This 1-year lag was implemented to reduce the risk of surveillance bias due to over-detection of cancer shortly after their health examination. After these exclusions, 2,338,170 eligible individuals with type 2 diabetes mellitus were included and started follow-up at 1 year after the index date. The follow-up continued until December 2022 and ended at the occurrence of lung cancer (study outcome), censor (e.g., out-migration), or death. Consequently, 25,198 individuals with newly developed lung cancer were identified (Figure 1).

Figure 1 Study flowchart.

Study outcome: lung cancer

The primary outcome was the occurrence of lung cancer, which was determined by identifying insurance claims for ICD-10 codes C33 and C34, and cross-referencing them with data from the critical illness registry (code V193). In Korea, the NHIS offers a 95% copayment deduction for individuals diagnosed with cancer. To grant this benefit, the NHIS requires the diagnosis certificates from attending physicians, which are verified and registered in the critical illness registry. Insurance claims and registry-matched data ensure highly accurate cancer diagnosis in Korea (24,25).

Main exposure: number of OHAs or insulin use

OHAs were classified into (I) metformin; (II) sulfonylurea; (III) alpha-glucosidase inhibitor; (IV) thiazolidinedione; (V) dipeptidyl peptidase-4 inhibitor; (VI) meglitinide; and (VII) sodium-glucose cotransporter-2 inhibitor. Glucagon-like peptide-1 receptor agonist was not included in this study because it was prescribed in a negligible number of cases owing to health insurance coverage (2). Drug exposure was defined as any prescription of OHAs or insulin within 1 year after the date of health examination.

The number of OHAs was defined as the largest number of OHA categories at once without insulin use. Insulin users were defined as individuals who had any prescription of insulin, irrespective of OHA. During the study period, metformin, dipeptidyl peptidase-4 inhibitor, sulfonylurea, and thiazolidinedione were the most frequently prescribed OHAs in Korea; thus, we further analyzed the effect of the combination of these OHAs on lung cancer risk (2).

Covariates

Anthropometric data—including body weight, height, and blood pressure—along with information on lifestyle behaviors, such as tobacco smoking, alcohol consumption, and physical activity, were collected during the national health examination. Body mass index (BMI) was calculated by dividing body weight by height squared (kg/m²). Smoking status was categorized into never, former, and current smokers. Alcohol intake was divided into three categories: nondrinkers, mild drinkers (1–29.9 g/day), and heavy drinkers (≥30 g/day). Regular physical activity was defined as engaging in moderate-intensity exercise for over 30 minutes at least five times weekly or vigorous-intensity exercise for more than 20 minutes at least three times per week (26). Income level was stratified into quartiles, with Q1 being the lowest and Q4 being the highest; medical aid beneficiaries were grouped into Q1 category.

Comorbidities were determined using data from the NHIS and national health screening records within 1 year before the index date, based on the following criteria: (I) hypertension: either an insurance claim for ICD-10 codes I10–13 and I15 accompanied by antihypertensive prescriptions or measured systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg during the health screening; (II) dyslipidemia: either an insurance claim for ICD-10 code E78 with corresponding lipid-lowering treatment, or total serum cholesterol level ≥240 mg/dL during the health screening; (III) chronic kidney disease: either the critical illness registration program code V003 or an estimated glomerular filtration rate of <60 mL/min/1.73 m² by the Modification of Diet in Renal Disease Study equation during the health screening. Complications of type 2 diabetes were defined using NHIS data within 3 years before the index date, according to the following criteria: (I) cardiovascular diseases, defined as either an insurance claim for ICD-10 codes I21–22 (myocardial infarction) or I63–64 (stroke); and (II) diabetic retinopathy, defined as either more than two insurance claims or a hospitalization with ICD-10 code H36.0.

Statistical analysis

Continuous variables were presented as means ± standard deviations and were compared across groups using analysis of variance. Categorical variables were summarized as numbers (percentages) and were compared using the χ² test. The incidence rate of lung cancer was calculated by dividing the number of newly diagnosed lung cancer cases by the total person-years at risk, and expressed per 1,000 person-years. The cumulative lung cancer incidence was demonstrated through a Kaplan-Meier survival analysis. A multivariable Cox proportional hazards model was used to assess the association between risk factors and the time to lung cancer development. Model 1 was non-adjusted. Model 2 was adjusted for age and sex. Model 3 (the main analysis model) was adjusted for the covariates included in Model 2, as well as BMI, income level, smoking status, alcohol consumption, regular exercise, hypertension, dyslipidemia, chronic kidney disease, FBG level, diabetes mellitus duration, cardiovascular disease, and diabetic retinopathy. A subgroup analysis stratified by age, sex, smoking status, and alcohol consumption was conducted using Model 3. All P values were two-tailed, and statistical significance was set at P<0.05. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA).

Results

Baseline characteristics

Our study cohort was followed up for a mean duration of 5.77±0.98 years, with the maximum follow-up duration after the health examination being 8.00 years. Table 1 summarizes the baseline characteristics of the study population according to the number of OHAs and insulin use. The mean participant age was 59.2±12.0 years, with men accounting for 60.5%. Individuals without prescription of OHAs and insulin were predominantly young (mean age: 53.5±12.5 years), males (70.0%), current smokers (31.3%), and alcohol drinkers (58.3%). Compared with individuals without prescription of OHAs and insulin, those with prescription of any OHA or insulin were generally older, never smokers, and non-alcohol drinkers across all categories.

Lung cancer risk according to the number of OHAs and insulin use

Table 2 and Figure 2 show the association between the number of OHAs and insulin use and lung cancer development. Individuals without prescription of OHAs and insulin exhibited the lowest lung cancer incidence rate (1.25 per 1,000 person-years), whereas individuals with prescription of any OHA had an increased lung cancer incidence rate (2.02–2.07 per 1,000 person-years). The lung cancer risk gradually increased with the number of OHAs, resulting in the highest risk among individuals with ≥3 OHAs (aHR: 1.21, 95% CI: 1.15–1.28) compared with individuals without prescription of OHAs or insulin. Insulin users exhibited the highest lung cancer incidence rate (2.51 per 1,000 person-years) and the highest lung cancer risk (aHR: 1.35, 95% CI: 1.27–1.43) in a treatment-intensity-dependent manner across all categories. Stratified analyses revealed that this trend for the lung cancer risk according to the number of OHAs and insulin use was more prominent among individuals aged <65 years, males, current smokers, and heavy alcohol drinkers (Table 3).

Figure 2 Cumulative incidence of lung cancer according to diabetes medication and insulin.

Subsequently, further analysis considering the combination of OHAs was performed. Although we did not observe notable differences between separate OHA and OHA combinations in each number of the OHA category, an increasing tendency for lung cancer risk with the overall number of OHAs and insulin use was noted (Table 4).

Discussion

The current study investigated the association between the number of OHAs and insulin use and lung cancer risk in individuals with type 2 diabetes mellitus. The lung cancer risk increased with the number of OHAs, resulting in the highest risk among individuals with ≥3 OHAs compared with individuals without prescription of OHAs or insulin. Furthermore, insulin users showed the highest lung cancer incidence rate and lung cancer risk (higher than ≥3 OHAs). Stratified analyses revealed that the lung cancer risk according to the number of OHAs and insulin use was more prominent among individuals aged <65 years, males, current smokers, and heavy alcohol drinkers. To our knowledge, this is the first study to demonstrate an association between the number of OHAs and insulin use and lung cancer risk in a treatment-intensity-dependent manner.

We propose that the number of OHAs and insulin use is associated with the diabetes severity, poor glycemic control, or insulin resistance in a treatment-intensity-dependent association (27). Our findings indicated that the lung cancer risk increased with the number of OHAs, with the highest lung cancer risk being observed in insulin users. A previous study reported that serum insulin concentration or insulin resistance was positively correlated with lung cancer risk, which supports our findings (13,28). Insulin resistance commonly occurs in individuals with diabetes mellitus, which is linked to an increased cancer risk (14,29,30). In the case of type 2 diabetes mellitus, the pancreas increases insulin production in an attempt to overcome insulin resistance and maintain euglycemic status, resulting in hyperinsulinemia (29). Hyperinsulinemia (the hallmark of insulin resistance) and an increase in insulin-like growth factor I enhance cell proliferation and affect cell metabolism, promoting cancer neogenesis (14,29,30).

Age is strongly and positively associated with lung cancer incidence, as shown by an observational study performed in England (31). Because age is one of the most potent risk factors for cancer, the association with the number of OHAs and insulin use may become more prominent in younger individuals. Furthermore, individuals with type 2 diabetes mellitus diagnosed at an earlier age have a higher risk of all-cause and cancer-related mortality, as well as a shorter life expectancy than individuals without type 2 diabetes mellitus (32). Therefore, to optimize the management of type 2 diabetes mellitus and delay disease progression, insulin therapy should be initiated as clinically indicated among young adults with type 2 diabetes mellitus.

With respect to lifestyle behavior, we found that the lung cancer risk was prominent among current smokers and heavy alcohol drinkers. Smoking and alcohol consumption are established risk factors for lung cancer and may have synergistic effects on lung cancer development (8). Additionally, smoking and alcohol consumption are associated with the risk of type 2 diabetes mellitus and poor glycemic control, which may aggravate insulin resistance and increase the risk of lung cancer (33,34). Furthermore, current smoking or heavy drinking is associated with an unhealthy diet, including higher fast-food consumption, higher energy intake, and less vegetable, fruit, or dairy product consumption, which could also be linked to cancer risk (35,36). Regarding sexual difference, smoking and drinking are predominant among men in Korea, and this association may contribute to an increased lung cancer risk in men (37,38).

Growing evidence suggests that compared to the general population, individuals with diabetes mellitus carry an increased risk of several common cancers, including lung cancer (5-7). A previous study has also suggested the association between diabetes mellitus and significantly inferior overall survival in lung cancer (39). Unfortunately, there are no official guidelines for lung cancer screening strategies in individuals with diabetes mellitus. Since 2019, Korea has implemented a nationwide lung cancer screening program for individuals aged 54–74 years with a smoking history of ≥30 pack-years. This program has led to an overall decrease in 1-year mortality, particularly lung cancer-related mortality (40). In this context, lung cancer screening strategies for selected high-risk individuals with type 2 diabetes mellitus, such as insulin users and current smokers, may be beneficial for national healthcare policy.

This study has some limitations. First, because the national health examination is a screening test for the general population, only FBG levels were available, and information on long-term glycemic control, such as hemoglobin A1c (HbA1c), was lacking. Second, drug exposure was defined as any prescription of OHAs or insulin within 1 year after the date of health examination, which may have led to an overestimation of prescription history. Furthermore, because the ICD-10 system does not differentiate lung cancer by histological subtype, it is not possible to distinguish these subtypes using claims data. Third, voluntary participation and the use of a self-reported questionnaire in the national health examination might have resulted in a selection bias or recall bias. Finally, the current investigation was a retrospective observational study conducted in Korea; thus, our findings should be cautiously interpreted, particularly in the case of other ethnicities. Nevertheless, our results underscore that some individuals with type 2 diabetes mellitus, such as insulin users and current smokers, are at increased risk of lung cancer.

Conclusions

In conclusion, the lung cancer risk increased with the number of OHAs, with insulin users exhibiting the highest risk in a treatment-intensity-dependent manner. Stratified analyses revealed that the lung cancer risk was more prominent among individuals aged <65 years, males, current smokers, and heavy alcohol drinkers. Additional analysis indicated complex interactive effects of OHA combinations on lung cancer risk. These findings suggest that lung cancer screening strategies should be considered for selected high-risk individuals with type 2 diabetes mellitus, such as insulin users and current smokers.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-680/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-680/prf

Funding: This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. RS-2023-NR077159, to S.W.L.), the Bio&Medical Technology Development Program of the NRF funded by the MSIT (Nos. RS-2022-NR067421 and RS-2023-00222687, to S.W.L.), and the National Institute of Health research project (No. 2024ER080601, to S.W.L.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-680/coif). S.W.L. received the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. RS-2023-NR077159), the Bio&Medical Technology Development Program of the NRF funded by the MSIT (Nos. RS-2022-NR067421 and RS-2023-00222687), and the National Institute of Health research project (No. 2024ER080601). The other authors have no conflicts of interest to declare.

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. The study was granted exemption from review by the Institutional Review Board of Asan Medical Center, Seoul, Republic of Korea as it utilized publicly available databases. The need for informed consent was waived because this was a retrospective study that used anonymized data.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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