Risk of acute pancreatitis with incretin-based therapy: a systematic review and updated meta-analysis of cardiovascular outcomes trials

ABSTRACT

Background

The link of acute pancreatitis (AP) with Incretin based therapies (IBTs) in type 2 diabetes has existed since United States Food and Drug Administration alert in 2010. This issue still remains unresolved due to conflicting results among studies.

Research design and methods

We performed a systematic search of the PubMed, Embase, and Cochrane Library databases until 31 July 2019, and retrieved all cardiovascular outcome trials (CVOTs) of IBTs conducted for ≥12 months that reported the pre-specified and or pre-adjudicated pancreatitis outcomes. Subsequently, we conducted a meta-analysis to study the risk of AP observed with IBT in CVOTs.

Results

A meta-analysis of seven CVOTs of GLP-1 receptor agonists (GLP-1RAs) compared with placebo (N = 55,932) found no significant increase in AP (odds ratio [OR], 1.05; 95% confidence interval [CI], 0.77–1.42; p = 0.77). In contrast, meta-analysis of five CVOTs comparing DPP-4 inhibitors with placebo (N = 47,714) and six CVOTs comparing DPP-4 inhibitors with placebo or active comparator (N = 53,747), found a significant increase (OR, 1.81; 95% CI, 1.21–2.70; p = 0.04 and OR, 1.54; 95% CI, 1.08–2.18; p = 0.02, respectively) in AP without any significant heterogeneity.

Conclusions

This meta-analysis revealed a significant association between pancreatitis and DPP-4 inhibitors; however, no such association was observed for GLP-1RAs.

KEYWORDS:

• Type 2 diabetes
• acute pancreatitis
• DPP-4 inhibitors
• GLP-1 receptor agonists
• cardiovascular outcome trials

Article highlights

• Acute pancreatitis (AP) associated with the use of incretin-based therapy, including GLP-1 receptor agonists (GLP-1RAs) and DPP-4 inhibitors (DPP-4is) in patients with type 2 diabetes has been of concern since the relevant US Food and Drug Administration alert in 2010. Subsequently, several reports, including case reports, the Food and Drug Administration adverse reporting system, and case-control studies, have supported this finding; however, many other cohorts, observational, and randomized controlled trials did not find such an association; thus, this issue remains unresolved.

• Although meta-analyses of both observational studies and randomized controlled trials of GLP-1RAs did not show a significant increase in AP, this did not appear to be the case with DPP-4is. Some meta-analyses have suggested no association, whereas others found a significant increase in AP with DPP-4is.

• None of the individual cardiovascular outcome trials (CVOTs) comparing either of these classes of antidiabetic drugs that studied AP (as a predefined and pre-adjudicated endpoint, adjudicated by an independent and blinded adjudication committee) demonstrated any statistically significant increase.

• However, the pooled meta-analyses of these CVOTs assessing GLP-1RAs and DPP-4is yielded varying results. Although there was no significant increase in AP with GLP-1RAs in a pooled meta-analysis of seven CVOTs, a significant increase in AP was noted with DPP-4is from a pooled meta-analysis of five CVOTs conducted either against placebo or against placebo or active comparator (six CVOTs).

• Although no causal association has been established, pharmacovigilance is clearly required with the use of DPP-4is to detect and avoid AP.

Acknowledgments

We would like to thank Dr. J.J. Mukherjee for giving his valuable inputs while preparing this manuscript.

Author contributions

All authors were involved in the conception and design, or analysis and interpretation of the data; the drafting of the paper or revising it critically for intellectual content; and the final approval of the version to be published; and that all authors agree to be accountable for all aspects of the work.

Declaration of interest

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.

Supplemental material

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Additional information

Funding

This paper was not funded.