Distinct prognostic impact of diabetes subtypes, metformin use, and glycemic control in pancreatic cancer: a systematic review and meta-analysis of cohort studies.

BACKGROUND: The prognostic significance of glycemic status in pancreatic ductal adenocarcinoma (PDAC) remains controversial, largely due to heterogeneity in the exposure definitions (new-onset vs. long-standing diabetes, metformin use, and single fasting glucose measurement). This meta-analysis aimed to clarify the association of four distinct glycemic exposures with overall survival (OS) in patients with PDAC. METHODS: We systematically searched Web of Science, PubMed, and EMBASE from 1 January 2010 to 1 June 2026. Cohort studies reporting hazard ratios (HRs) for OS were included and categorized into four subgroups: 1) new-onset diabetes (NOD) vs. non-diabetes; 2) long-standing diabetes (LSD) vs. non-diabetes; 3) metformin use vs. non-use; and 4) hyperglycemia (elevated preoperative fasting glucose or poor glycemic control) vs. normoglycemia. Random-effects meta-analyses were performed. Heterogeneity was assessed using I 2, and publication bias was evaluated via funnel plots and the trim-and-fill method. RESULTS: A total of 21 studies (six for NOD, four for LSD, six for metformin, and eight for hyperglycemia) were included. NOD was significantly associated with worse OS (pooled HR = 1.33, 95%CI = 1.13-1.57, I 2 = 72.5%). LSD showed no significant association (HR = 1.21, 95%CI = 0.98-1.49, I 2 = 70.1%). Metformin use was associated with a 33% reduction in mortality (HR = 0.67, 95%CI = 0.53-0.84, I 2 = 70.5%). Preoperative hyperglycemia or poor glycemic control consistently predicted worse OS (HR = 1.45, 95%CI = 1.29-1.62, I 2 = 25.7%). No substantial publication bias was detected (trim-and-fill added zero studies for all subgroups). CONCLUSIONS: NOD and preoperative hyperglycemia are independent negative prognostic factors in PDAC, whereas LSD did not show a statistically significant association. An indirect comparison between NOD and LSD yielded a null result, suggesting that diabetes duration may not be the key determinant of prognosis. The potential mediating role of hyperglycemia requires further investigation. Metformin use was associated with a marked survival benefit, particularly in patients with resectable tumors. These findings highlight the need to differentiate diabetes subtypes and optimize glycemic control, while clinical decisions regarding antidiabetic agents should be made with caution. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=261415381, identifier CRD420261415381.