Research Scholar National Institute of Pharmaceutical Education and Research Guwahati Guwahati, India
Background: Anti-diabetic drugs, particularly incretin mimetics and certain newer anti-diabetic medications, have been attributed to an increased risk of cholelithiasis and cholecystitis 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 cholelithiasis and cholecystitis, which are not determined to date using post-marketing surveillance data.
Methods: We carried out a retrospective case/non-case study for all the anti-diabetic medications using spontaneous reports in the FDA Adverse Event Reporting System (FAERS) from the date of approval by the FDA to 1st January 2023. A disproportionality analysis was performed by calculating the Proportional Reporting Ratio (PRR), Reporting Odds Ratio (ROR), and the Information Component (IC) to identify cholelithiasis and cholecystitis 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. Both cholelithiasis and cholecystitis signals were observed respectively in GLP-1 agonist Liraglutide [PRR=3.4, LB ROR=3.0, IC025 = 3.0];[PRR=2.4, LB ROR=1.8, IC025 = 0.8]. A considerable Cholelithiasis signals were identified for GLP-1 agonist like Exenatide [PRR=3.4, LB ROR=3.1, IC025=3.1], Lixisenatide [PRR=3.1,LB ROR=1.4, IC025 = 0.0], and DPP-4 inhibitors like Sitagliptin [PRR=2.5, LB ROR=2.2, IC025=2.2], and Saxagliptin [PRR=2.1, LB ROR=1.4, IC025=1.4], followed by sulfonylureas (Glimepiride [PRR=2.2, LB ROR=1.8, IC025 = 0.9], Nateglinide [PRR=2.5, LB ROR=1.4, IC025=0.2], Mitiglinide [PRR=4.8, LB ROR=1.8, IC025 = 0.0], and Chlorpropamide [PRR=9.5, LB ROR=3.1, IC025 = 0.0]). Other notable cholelithiasis signals were identified for Metformin [PRR=2.3, LB ROR=2.1, IC025 = 1.0], Voglibose [PRR=3.7, LB ROR=2.1, IC025 = 0.8], and Insulin Glulisine [PRR=2.3, LB ROR=1.4, IC025 = 0.4]. Mitiglinide showed considerable strength of signals for Cholecystitis [PRR=13.5, LB ROR=36.5, IC025 = 0.8].
Conclusions: Based on the up-to-date real-world post-marketing data analysis, we identified Cholelithiasis signals for incretin mimetics, sulfonylurea derivatives, and cholecystitis among GLP-1 agonists.
