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
The existing evidence from pre- and post-marketing studies is conflicting on the risk of pancreatic events for anti-diabetic medications.
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.
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).
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.
We conducted this research to identify the risk of pancreatitis and pancreatic carcinoma among anti-diabetic medications from pre-and post-marketing evidence available from clinical trials data and pharmacovigilance databases ;(FAERS, VigiBase). A disproportionality analysis of pharmacovigilance data was done to statistically check whether the selected drug-event pairs were frequently reported from the database (known as a ‘signal’). We performed further signal refinement analysis using OpenVigil 2.1 on the generated signals to check whether the signal sustains even after removing co-prescribed medications possessing the same risk and then followed by the systematic review of randomized controlled trials for evidence generation regarding the pancreatic safety of the medications. The findings from real-world data indicated that, among all anti-diabetics, incretin mimetics and sulfonylurea compounds produced signals for both pancreatitis and pancreatic carcinoma. Notable pancreatitis risk was also identified from newer anti-diabetics like SGLT-2 inhibitors. The findings from the meta-analysis of clinical trials indicated a 44% risk of DPP-4 inhibitors in causing acute pancreatitis and a 60% risk of GLP-1 agonists in elevating the lipase level, compared to placebo/active comparator. Thus, the study raises concerns about reducing or preventing the risk.