The goal of this observational study is to learn if a specific diabetes medicine can lower the risk of lung cancer in people with type 2 diabetes and chronic obstructive pulmonary disease (COPD).

The main question it aims to answer is:

- Does taking medicines called SGLT2 inhibitors lower the chance of getting lung cancer compared to medicines called sulfonylureas?

Researchers will compare the medical records of people taking SGLT2 inhibitors to those taking sulfonylureas to see if the SGLT2 group has fewer cases of lung cancer.

Participants will not need to visit a doctor or take new medicines for this study. Researchers will use information from existing medical records to answer the research question.

Study Design: This is a comparative effectiveness research study utilizing large-scale, population-based Real-World Data (RWD). By analyzing longitudinal data from existing medical records, researchers will emulate a target trial to minimize bias and provide robust estimates of the treatment effect.

Statistical Analysis Plan: The study employs a rigorous analytic framework consisting of a primary analysis and multiple sensitivity analyses to ensure the validity of the findings:

Primary Analysis: A comparison of SGLT2 inhibitors versus sulfonylureas using an Intention-To-Treat (ITT) framework, with follow-up censored upon treatment switching to estimate the effect of the initial treatment choice.

Sensitivity Analysis 1 (Active Comparator): A comparison of DPP-4 inhibitors versus SGLT2 inhibitors using the same ITT framework (censoring on switching) to assess the consistency of the results against an alternative second-line antidiabetic class.

Sensitivity Analysis 2 (As-Treated): A comparison of SGLT2 inhibitors versus sulfonylureas using an As-Treated approach, defining continuous use with a permissible gap (grace period) of 60 days between prescriptions to account for adherence patterns.

Significance and Impact Current guidelines for diabetes management prioritize cardiovascular and renal protection. This study aims to expand the clinical evidence base by:

• Providing actionable Real-World Evidence (RWE) on the long-term cancer-related outcomes of diabetes medications.
• Evaluating whether the choice of antidiabetic agents can serve as a strategy for lung cancer prevention in high-risk groups (COPD-T2DM).
• Contributing to the development of comprehensive treatment guidelines that consider cancer prevention alongside metabolic, cardiac, and renal health.

Abbreviation:

COPD, Chronic Obstructive Pulmonary Disease; DPP-4, Dipeptidyl Peptidase-4; ICD-10, International Classification of Diseases, 10th Revision; ICS, Inhaled Corticosteroids; ITT, Intention-To-Treat; LABA, Long-Acting Beta-2 Agonists; LAMA, Long-Acting Muscarinic Antagonists; RWD, Real-World Data; RWE, Real-World Evidence; SABA, Short-Acting Beta-2 Agonists; SAMA, Short-Acting Muscarinic Antagonists; SGLT2, Sodium-Glucose Cotransporter-2; SU, Sulfonylurea; T2DM, Type 2 Diabetes Mellitus;

Inclusion Criteria:

• Adults aged ≥40 years with prior COPD (from 2009) and newly diagnosed diabetes who initiated SU or SGLT2i between January 1, 2014 and December 31, 2023

Exclusion Criteria:

• Pre-existing
• ESRD
• Cancer
• Concurrent prescribing of the study drugs at the index date
• Exposure to the drugs of interest during the year preceding the index date
• Death or cancer incidence within a month

In the sensitivity analysis, we are planning to substitute sulfonylurea to DPP4 inhibitors.

The study included adults aged ≥40 years with a prior history of COPD (screened from 2009) and newly diagnosed type 2 diabetes who initiated treatment with either sulfonylureas or SGLT2 inhibitors between January 1, 2014, and December 31, 2023. Type 2 diabetes was defined as having two or more diagnosis records within one year using ICD-10 codes E10-E14. COPD was defined by the presence of ICD-10 codes J43 or J44 (excluding J43.0) concurrent with the prescription of COPD medications at least twice within a year; these medications included long-acting muscarinic antagonists (LAMA), long-acting beta-2 agonists (LABA), ICS plus LABA, short-acting muscarinic antagonists (SAMA), short-acting beta-2 agonists (SABA), SAMA plus SABA, methylxanthines, and systemic beta agonists.

In the sensitivity analysis, we are planning to substitute sulfonylurea to DPP4 inhibitors.