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

ABSTRACT

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 FDA Adverse Event Reporting System (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 randomized controlled trials (RCTs) on anti-diabetic drugs with pancreatic outcomes.

Results

The 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 sodium-glucose co-transporter-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 the 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.

Plain Language Summary

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. Also, conducted a 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 for 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 over the risk of pancreatitis and pancreatic carcinoma among the users of anti-diabetic medications, especially incretin mimetics.

KEYWORDS:

• Anti-diabetic medications
• disproportionality analysis
• pancreatic carcinoma
• pancreatitis
• pharmacovigilance
• signal detection

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contribution statement

K Undela and A Muhammed have planned, gathered, analyzed, and conducted the study. A Muhammed and C Thomas assisted with gathering information and manuscript writing. Proofreading and critical review of the content were provided by V Kalaiselvan and K Undela. The final manuscript was read and approved by all of the authors.

Acknowledgments

- The authors thank the providers of the FDA Adverse Event Reporting System (FAERS), VigiBase, and OpenVigil 2.1. Thanks to the authorities of the National Institute of Pharmaceutical Education and Research (NIPER) Guwahati and the Indian Pharmacopoeia Commission (IPC), National Coordination Centre-Pharmacovigilance Programme of India (PvPI) for their constant support while conducting this study.

- The work has previously been presented at ISPE’s 38^th International Conference on Pharmacoepidemiology (ICPE 2022), “Advancing Pharmacoepidemiology and Real-World Evidence for the Global Community” in Copenhagen, Denmark from 24^th to 28^th August 2022.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14740338.2023.2284992

Additional information

Funding

This paper was not funded.