Abstract
Background and aims: Hypoglycemic agents are the primary therapeutic approach for the treatment of diabetes and have been postulated to impact pancreatic cancer (PC) incidence in diabetic patients. We conducted a meta-analysis to further evaluate and establish the associations between four common types of hypoglycemic agents [metformin, sulfonylureas, thiazolidinediones (TZDs), and insulin] and PC incidence in individuals with diabetes mellitus (DM). Methods: A comprehensive literature search of PubMed, Web of Science, Embase, and the Cochrane Library identified studies that analyzed the relationship between hypoglycemic agents and PC published between January 2012 and September 2022. Randomized control trials (RCTs), cohorts, and case-control studies were included if there was clear and evaluated defined exposure to the involved hypoglycemic agents and reported PC outcomes in patients with DM. Furthermore, reported relative risks or odds ratios (ORs) or other provided data were required for the calculation of odds ratios. Summary odds ratio estimates with a 95% confidence interval (CI) were estimated using the random-effects model. Additionally, subgroup analysis was performed to figure out the source of heterogeneity. Sensitivity analysis and publication bias detection were also performed. Results: A total of 11 studies were identified that evaluated one or more of the hypoglycemic agents, including three case-control studies and eight cohort studies. Among these, nine focused on metformin, six on sulfonylureas, seven on TZDs, and seven on insulin. Meta-analysis of the 11 observational studies reported no significant association between metformin (OR = 1.04, 95% CI 0.73-1.46) or TZDs (OR = 1.13, 95% CI 0.73-1.75) and PC incidence, while the risk of PC increased by 79% and 185% with sulfonylureas (OR = 1.79, 95% CI 1.29-2.49) and insulin (OR = 2.85, 95% CI 1.75-4.64), respectively. Considerable heterogeneity was observed among the studies and could not be fully accounted for by study design, region, or adjustment for other hypoglycemic agents. Conclusion: Sulfonylureas and insulin may increase the incidence of pancreatic cancer in diabetic patients, with varying effects observed among different ethnicities (Asian and Western). Due to significant heterogeneity across studies, further interpretation of the relationship between hypoglycemic agents and pancreatic cancer incidence in diabetic patients requires well-adjusted data and better-organized clinical trials.