Risk of pancreatitis and pancreatic carcinoma for anti-diabetic medications: findings from real-world safety data analysis and systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The existing evidence from pre- and post-marketing studies is conflicting on the risk of pancreatic events for anti-diabetic medications.

RESEARCH DESIGN AND METHODS: A retrospective case/non-case study was conducted by using spontaneous reports on pancreatic events for anti-diabetic medications from the FAERS and VigiBase. Proportional Reporting Ratio (PRR), Reporting Odds Ratio (ROR), and Information Component (IC) were calculated by a disproportionality analysis. Furthermore, PubMed, Google Scholar, Scopus, and ClinicalTrials.gov were systematically searched for RCTs on anti-diabetic drugs with pancreatic outcomes.

RESULTS: FAERS data analysis found strong signals on incretin mimetics causing pancreatic events, with sitagliptin having the highest risk [PRR = 24.2, lower bound (LB) ROR = 24.4, IC025  = 4.4 for pancreatitis, and PRR = 15.4, LB ROR = 14.9, IC025  = 3.8 for pancreatic carcinoma]. Empagliflozin was the most pancreatitis-risk SGLT-2 inhibitor [PRR = 4.0, LB ROR = 3.5, IC025  = 1.8]. VigiBase reiterated these findings and identified some new signals for novel anti-diabetics. Meta-analysis revealed that the incidence of pancreatitis and pancreatic carcinoma with anti-diabetic medications was insignificant. However, compared to placebo/active comparator, gliptins had a higher risk of acute pancreatitis (OR 1.44; 95% CI 1.03, 2.01; P  = 0.03).

CONCLUSION: Evidence from the post-marketing safety data analysis identified a strong association between incretin mimetics and pancreatic events. Fewer events in RCTs may justify insignificant meta-analysis results.