Risk of Pancreatitis and Pancreatic Carcinoma for Anti-diabetic Medications: Evidence Synthesis from Disproportionality Analysis

Background: Anti-diabetic drugs, particularly incretin mimetics and certain newer anti-diabetic medications, have been attributed to an increased risk of pancreatitis and pancreatic cancer in population-based case-control studies and animal studies. However, the topic remains debated due to the conflicting results published in recent systematic review and meta-analysis studies.

Objectives: To identify the safety signals of anti-diabetic medications related to pancreatitis and pancreatic carcinoma, which are not determined to date using post-marketing surveillance data.

Methods: We carried out a retrospective case/non-case study using spontaneous reports in the FDA Adverse Event Reporting System (FAERS) and Canada Vigilance of Adverse Reaction Online Database (CVAR) from the date of approval by the FDA to 1st June 2022. A disproportionality analysis was performed by calculating the Proportional Reporting Ratio (PRR), Reporting Odds Ratio (ROR), and the Information Component (IC) to identify pancreatitis and pancreatic carcinoma signal (if PRR ≥2, Lower Bound (LB) ROR>1 and IC025>0) for anti-diabetic drugs. We also performed a signal refinement analysis by eliminating the confounding co-prescribed medications to identify the robustness of the findings.

Results: Incretin mimetics produced stronger signals among all anti-diabetic drugs. Pancreatitis and pancreatic carcinoma signals were observed respectively for DPP-4 inhibitors like Sitagliptin [PRR=24.2, LB ROR=24.5, IC025=4.4];[PRR=16.5,LB ROR=16.0, IC025=3.9], Saxagliptin [PRR=14.0, LB ROR=12.2, IC025=3.5]; [PRR=3.4, LB ROR=2.4, IC025=1.2], and GLP-1 agonists like Liraglutide [PRR=20.6, LB ROR=20.5, IC025=4.2]; [PRR=9.1, LB ROR=8.4, IC025=3.0], Exenatide [PRR=12.3, LB ROR=12.0, IC025=3.5]; [PRR=4.1, LB ROR=3.8, IC025=1.9] followed by sulfonylureas (Repaglinide [PRR=2.7, LB ROR=1.7, IC025=0.7]; Mitiglinide [PRR=11.1, LB ROR=4.2, IC025=0.7]) were remarkable. A notable pancreatitis signals were observed for SGLT-2 inhibitors like Empagliflozin [PRR=4.0, LB ROR=3.4, IC025=1.7], Canagliflozin [PRR=3.7, LB ROR=3.2, IC025=1.6] and Dapagliflozin [PRR=3.2, LB ROR=2.6, IC025=1.3]. The analysis of global data through CVAR reiterated the findings of FAERS except for the signals identified from sulfonylurea derivatives.

Conclusions: Based on the up-to-date real-world post-marketing data analysis, we identified pancreatitis and pancreatic carcinoma signals for incretin mimetics, sulfonylurea derivatives, and pancreatitis signals among SGLT-2 inhibitors.