Cardiovascular-Kidney-Metabolic Syndrome Severity and Risk of Pancreatic Cancer in a Large Prospective Cohort

Pancreatic cancer remains one of the most lethal malignancies due to late diagnosis and limited opportunities for prevention. Cardiovascular-kidney-metabolic (CKM) syndrome reflects the cumulative burden of metabolic, renal, and cardiovascular dysfunction, but its association with pancreatic cancer risk has not been well established. We investigated this relationship in a large prospective cohort from the UK Biobank.

Participants without pancreatic cancer at baseline (2006-2010) were followed through national cancer and mortality registries until 31 December 2022. CKM syndrome was categorised into five stages (0-4) according to American Heart Association criteria. Incident pancreatic cancer was identified using ICD-9 and ICD-10 codes. Fine-Gray subdistribution hazard models accounting for death were used to estimate subdistribution hazard ratios (SHRs) and 95% confidence intervals (CIs), with prespecified subgroup analyses performed.

Among 326,148 participants, 1234 incident pancreatic cancer cases were identified over a mean follow-up of 13.5 years (SD 2.0). Incidence rates increased progressively from 9.0 to 48.6 per 100,000 person-years across CKM stages. Compared with CKM stage 0, multivariable-adjusted SHRs for pancreatic cancer were 1.97 (95% CI 1.28-3.02) for stage 1, 2.02 (1.42-2.87) for stage 2, and 2.08 (1.42-3.04) for stages 3-4 (p for trend < 0.001). Associations were generally consistent across subgroup analyses according to age, sex, smoking status, and alcohol consumption, without statistically significant interaction effects.

Advanced CKM syndrome was independently associated with higher pancreatic cancer risk, supporting its potential role in risk stratification and early detection strategies.