Pancreatic cancer (PC) stands as one of the most lethal cancers globally, ranking 12th in prevalence and sixth in cancer-related deaths. Its aggressive nature and often late diagnosis contribute to a dismal 5-year survival rate of merely 12%. While surgical resection offers the only potential cure, most patients are diagnosed at advanced stages, rendering surgery ineffective. Currently, effective and cost-efficient screening tools for the general population are lacking, and recommended screening strategies, like cross-sectional imaging and endoscopic ultrasonography, are limited to high-risk individuals.

• Notably, type 2 diabetes mellitus (T2DM) is a significant risk factor for PC. The relationship between T2DM and PC is complex and bidirectional; chronic diabetes can promote pancreatic carcinogenesis through systemic inflammation, hyperglycemia, insulin resistance, and hyperinsulinemia. Conversely, new-onset diabetes can be an early sign of PC, with nearly 25% of PC patients presenting with diabetes at diagnosis. Despite this link, routine PC screening for T2DM patients isn’t recommended due to the absence of effective screening methods.

• Aspirin, a widely-used antiplatelet agent, has shown chemopreventive effects against several digestive cancers, including colorectal cancer. Its mechanisms involve inhibiting cyclooxygenase enzymes, reducing prostaglandin synthesis, and modulating tumorigenesis, apoptosis, and angiogenesis. However, aspirin’s protective role against pancreatic cancer, especially in T2DM patients, remains unclear. Recently, the team of Professor Ka-Shing Cheung and Professor Wai-Keung Leung from The University of Hong Kong, China, published a study in the Gut (IF=23.1). This study delves into aspirin’s potential protective effect on the development and mortality of pancreatic cancer in newly diagnosed T2DM patients.

• Using the Clinical Data Analysis and Reporting System (CDARS) of the Hong Kong Hospital Authority, a comprehensive electronic health record database, we conducted a retrospective cohort study. We focused on adults aged 18 and older newly diagnosed with T2DM between January 1, 2001, and December 31, 2015. T2DM diagnosis was established through lab results, medication use, or diagnostic codes aligned with American Diabetes Association criteria.

• We excluded patients with a history of pancreatic cancer, pancreatic cysts, IgG4-related disease, or pancreatectomy. To avoid reverse causality, where undiagnosed pancreatic cancer might manifest as new-onset diabetes, we excluded patients diagnosed with pancreatic cancer within one year of T2DM diagnosis and those with less than one year of follow-up. The follow-up period lasted until pancreatic cancer occurrence, death, pancreatectomy, or the study’s end on December 31, 2020.

• Our primary outcome was pancreatic cancer incidence, identified through ICD-9 codes or histological confirmation. Secondary outcomes included pancreatic cancer-related mortality and all-cause mortality. Aspirin use was considered a time-varying variable, defined as continuous use for at least 180 days within each one-year interval, to address immortal-time bias.

• We employed multivariable Cox proportional hazards models to calculate adjusted hazard ratios (aHRs) for pancreatic cancer development, PC-related mortality, and all-cause mortality. Covariates included age, sex, body mass index (BMI), smoking status, alcohol use, comorbidities (e.g., hypertension, dyslipidemia, cardiovascular diseases), and concurrent medication use. As a secondary analysis, we used propensity score (PS) matching to balance baseline characteristics between aspirin users and non-users. Sensitivity analyses further validated our findings.

• Our study cohort comprised 343,966 newly diagnosed T2DM patients, with a median follow-up of 10.5 years. The average age was 58.8 years, and 52.2% were men. Aspirin users were typically older and had higher rates of cardiovascular comorbidities compared to non-users.

• Aspirin use was significantly linked to a 42% reduction in pancreatic cancer risk (aHR: 0.58; 95% CI: 0.49–0.69) in time-dependent analysis. Propensity score-matched analysis confirmed a 39% reduced risk (aHR: 0.61; 95% CI: 0.48–0.77). Pancreatic cancer incidence rates were 3.1 and 4.1 per 10,000 person-years among aspirin users and non-users, respectively.

• Furthermore, aspirin use was associated with a 57% lower risk of PC-related mortality (aHR: 0.43; 95% CI: 0.34–0.53) and a 22% reduction in all-cause mortality (aHR: 0.78; 95% CI: 0.76–0.80). A significant dose-response and duration-response relationship was observed. Patients using aspirin for over 10 years had a 69% lower pancreatic cancer risk (aHR: 0.31; 95% CI: 0.23–0.40). Higher aspirin doses (>100 mg) were linked to greater risk reduction compared to lower doses (≤100 mg).

• The protective effect of aspirin was consistent across subgroups, including age, sex, BMI, smoking status, and glycemic control. However, the benefit was less evident among patients with alcohol use disorder or new-onset diabetes, possibly due to underlying undiagnosed pancreatic cancer.

• Our large-scale, population-based study reveals that aspirin use is significantly associated with reduced pancreatic cancer risk and related mortality in T2DM patients. This protective effect is consistent across multiple subgroups and more pronounced with longer duration and higher doses of aspirin use.

• Aspirin’s chemopreventive effects may stem from inhibiting inflammation through cyclooxygenase suppression, modulating tumor microenvironments, and interfering with tumor cell proliferation and metastasis. These findings align with aspirin’s established role in preventing other digestive cancers but highlight its previously underexplored benefit in pancreatic cancer prevention among T2DM patients.

• Despite our robust findings, some limitations exist. The retrospective design introduces potential residual confounding. Over-the-counter aspirin use and adherence couldn’t be confirmed, although this is unlikely to significantly impact results in Hong Kong, where aspirin is typically prescribed. Additionally, our study’s population was predominantly Chinese, potentially limiting generalizability to other ethnicities.

In conclusion, our comprehensive study provides strong evidence that aspirin use is associated with a significant reduction in pancreatic cancer incidence and mortality among newly diagnosed T2DM patients. The dose-response and duration-response relationships further bolster aspirin’s potential as a chemopreventive agent. Future randomized controlled trials are needed to validate these findings and inform clinical guidelines on using aspirin for pancreatic cancer prevention in high-risk populations.