Pancreatic cancer is among the most lethal malignancies worldwide, with rising mortality trends driven by aging populations and increasing prevalence of key risk factors.

This study investigated the effects of potential risk factors on global pancreatic cancer mortality. We conducted a longitudinal analysis of pancreatic cancer mortality rates from 1990 to 2021 across 204 countries using the Global Burden of Disease data. Potential determinants—including HDI, life expectancy at birth, tobacco, alcohol, and diabetes prevalence—were incorporated into a series of Generalized Estimating Equation (GEE) models. To account for between country heterogeneity, we applied longitudinal k means clustering. The GEE models were then fitted to estimate subgroup specific effects of covariates.

Overall, between 1990 and 2021, the mean pancreatic cancer mortality rate increased from 4.22 to 7.58 per 100,000 population. In the unadjusted GEE model, mortality rose by 0.571 deaths per 100,000 every five years (p < 0.001), but this time effect attenuated to 0.068 (p = 0.370) after full adjustment. HDI (β = 0.122, p < 0.001) and diabetes prevalence (β ≈ 0.30, p < 0.001) were positively associated with mortality, whereas life expectancy at birth and alcohol consumption exhibited non‑significant effects. Longitudinal k‑means clustering approach classified countries into five subgroups. Pancreatic cancer mortality has increased globally, but the magnitude and drivers vary substantially by country subgroup. Elevated HDI and diabetes prevalence emerge as key determinants, especially in high income regions.

Tailored prevention and early detection strategies accounting for regional socioeconomic and demographic contexts—are urgently needed to curb the rising pancreatic cancer burden.