Skip to main content
SpringerLink
Log in

Pancreatitis associated with the use of GLP-1 analogs and DPP-4 inhibitors: a case/non-case study from the French Pharmacovigilance Database

  • Original Article
  • Published:
Acta Diabetologica Aims and scope Submit manuscript

Abstract

In the recent past, concerns have raised regarding the potential risk of acute pancreatitis among type 2 diabetic patients using incretin-based drugs such as glucagon-like peptide 1 (GLP-1) analogs and dipeptidyl peptidase 4 (DPP-4) inhibitors. The aim of this study is to investigate the association between exposure to incretin-based drugs and the occurrence of pancreatitis reported in the French Pharmacovigilance Database. The case/non-case method was performed from serious adverse drug reactions (ADRs) involving antihyperglycemic agents (except insulin alone) reported to the French pharmacovigilance system between March 2008 (first marketing of an incretin-based drug in France) and March 2013. Cases were defined as reports of pancreatitis, and all other serious ADRs were considered non-cases. Disproportionality was assessed by calculating reporting odds ratios (ROR) adjusted for age, gender, history of pancreatitis, other antihyperglycemic drugs and other drugs associated with a higher risk of pancreatitis. Among 3,109 serious ADRs, 147 (4.7 %) reports of pancreatitis were identified as cases and 2,962 reports (95.3 %) of other ADRs as non-cases. Among the cases, 122 (83.0 %) involved incretin-based drugs. Disproportionality was found for all incretin-based drugs (adjusted ROR: 15.7 [95 % CI 9.8–24.9]), all GLP-1 analogs (29.4 [16.0–53.8]), exenatide (28.3 [12.8–62.3]), liraglutide (30.4 [15.4–60.0]), all DPP-4 inhibitors (12.1 [7.3–20.0]), sitagliptin (12.4 [7.3–21.0]), saxagliptin (15.1 [4.3–52.7]), and vildagliptin (7.4 [3.1–17.6]). Temporal analysis found disproportionality for incretin-based drugs since their first year of marketing in France. Compared with other antihyperglycemic agents, use of incretin-based drugs is associated with an increased risk of reported pancreatitis in France.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Information for Healthcare Professionals: Exenatide (marketed as Byetta)—8/2008 Update. Available from http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124713.htm, accessed 11 May 2012

  2. Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC (2011) Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology 141:150–156

    Article  CAS  PubMed  Google Scholar 

  3. Hawkes N (2011) Journal withdraws article after complaints from drug manufacturers. BMJ 342:d2335

    Article  PubMed  Google Scholar 

  4. Hauben M, Patadia V, Gerrits C, Walsh L, Reich L (2005) Data mining in pharmacovigilance: the need for a balanced perspective. Drug Saf 28:835–842

    Article  PubMed  Google Scholar 

  5. Raschi E, Piccinni C, Poluzzi E, Marchesini G, De Ponti F (2013) The association of pancreatitis with antidiabetic drug use: gaining insight through the FDA pharmacovigilance database. Acta Diabetol 50:569–577

    Article  CAS  PubMed  Google Scholar 

  6. Hauben M, Madigan D, Gerrits CM, Walsh L, Van Puijenbroek EP (2005) The role of data mining in pharmacovigilance. Expert Opin Drug Saf 4:929–948

    Article  CAS  PubMed  Google Scholar 

  7. Wilson AM, Thabane L, Holbrook A (2004) Application of data mining techniques in pharmacovigilance. Br J Clin Pharmacol 57:127–134

    Article  PubMed Central  PubMed  Google Scholar 

  8. Bate A, Evans SJ (2009) Quantitative signal detection using spontaneous ADR reporting. Pharmacoepidemiol Drug Saf 18:427–436

    Article  CAS  PubMed  Google Scholar 

  9. Moore N, Kreft-Jais C, Haramburu F et al (1997) Reports of hypoglycaemia associated with the use of ACE inhibitors and other drugs: a case/non-case study in the French pharmacovigilance system database. Br J Clin Pharmacol 44:513–518

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Balani AR, Grendell JH (2008) Drug-induced pancreatitis: incidence, management and prevention. Drug Saf 31:823–837

    Article  CAS  PubMed  Google Scholar 

  11. Pariente A, Gregoire F, Fourrier-Reglat A, Haramburu F, Moore N (2007) Impact of safety alerts on measures of disproportionality in spontaneous reporting databases: the notoriety bias. Drug Saf 30:891–898

    Article  PubMed  Google Scholar 

  12. Hazell L, Shakir SA (2006) Under-reporting of adverse drug reactions: a systematic review. Drug Saf 29:385–396

    Article  PubMed  Google Scholar 

  13. Cohen D (2013) Reports of pancreatitis are 20–30 times more likely with GLP-1 drugs, analysis finds. BMJ 346:f2607

    Article  PubMed  Google Scholar 

  14. Institute for Safe Medication Practices (2013) Perspectives on GLP-1 agents for diabetes. Available from http://www.ismp.org/QuarterWatch/pdfs/2012Q3.pdf

  15. van der Heijden PG, van Puijenbroek EP, van Buuren S, van der Hofstede JW (2002) On the assessment of adverse drug reactions from spontaneous reporting systems: the influence of under-reporting on odds ratios. Stat Med 21:2027–2044

    Article  PubMed  Google Scholar 

  16. Galvus (vildagliptin) Summaries of Product Characteristics. EMA 2012. Available from http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000771/WC500020327.pdf

  17. Onglyza (liraglutide) Summaries of Product Characteristics. EMA 2012. Available from http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001026/WC500050017.pdf

  18. Byetta (exenatide) Summaries of Product Characteristics. EMA 2012. Available from http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000698/WC500051845.pdf

  19. Januvia (sitagliptin) Summaries of Product Characteristics. EMA 2012. Available from http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000722/WC500039054.pdf

  20. Onglyza (saxagliptin) Summaries of Product Characteristics. EMA 2012. Available from http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001039/WC500044316.pdf

  21. Gonzalez-Perez A, Schlienger RG, Rodriguez LA (2010) Acute pancreatitis in association with type 2 diabetes and antidiabetic drugs: a population-based cohort study. Diabetes Care 33:2580–2585

    Article  PubMed Central  PubMed  Google Scholar 

  22. Noel RA, Braun DK, Patterson RE, Bloomgren GL (2009) Increased risk of acute pancreatitis and biliary disease observed in patients with type 2 diabetes: a retrospective cohort study. Diabetes Care 32:834–838

    Article  PubMed Central  PubMed  Google Scholar 

  23. Girman CJ, Kou TD, Cai B et al (2010) Patients with type 2 diabetes mellitus have higher risk for acute pancreatitis compared with those without diabetes. Diabetes Obes Metab 12:766–771

    Article  CAS  PubMed  Google Scholar 

  24. Montastruc JL, Sommet A, Bagheri H, Lapeyre-Mestre M (2011) Benefits and strengths of the disproportionality analysis for identification of adverse drug reactions in a pharmacovigilance database. Br J Clin Pharmacol 72:905–908

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Sommet A, Grolleau S, Bagheri H, Lapeyre-Mestre M, Montastruc JL (2008) Was the thrombotic risk of rofecoxib predictable from the French Pharmacovigilance Database before 30 September 2004? Eur J Clin Pharmacol 64:829–834

    Article  CAS  PubMed  Google Scholar 

  26. Matveyenko AV, Dry S, Cox HI et al (2009) Beneficial endocrine but adverse exocrine effects of sitagliptin in the human islet amyloid polypeptide transgenic rat model of type 2 diabetes: interactions with metformin. Diabetes 58:1604–1615

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Butler PC, Elashoff M, Elashoff R, Gale EA (2013) A critical analysis of the clinical use of incretin-based therapies: are the GLP-1 therapies safe? Diabetes Care 36:2118–2125

    Article  PubMed  Google Scholar 

  28. Butler AE, Campbell-Thompson M, Gurlo T, Dawson DW, Atkinson M, Butler PC (2013) Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors. Diabetes 62:2595–2604

    Google Scholar 

  29. Nauck MA (2013) A critical analysis of the clinical use of incretin-based therapies: the benefits by far outweigh the potential risks. Diabetes Care 36:2126–2132

    Article  PubMed  Google Scholar 

  30. Kahn SE (2013) Incretin therapy and islet pathology: a time for caution. Diabetes 62:2178–2180

    Article  CAS  PubMed  Google Scholar 

  31. Drucker DJ (2013) Incretin action in the pancreas: potential promise, possible perils, and pathological pitfalls. Diabetes 62:3316–3323

    Google Scholar 

  32. Alves C, Batel-Marques F, Macedo AF (2012) A meta-analysis of serious adverse events reported with exenatide and liraglutide: acute pancreatitis and cancer. Diabetes Res Clin Pract 98:271–284

    Article  CAS  PubMed  Google Scholar 

  33. Engel SS, Round E, Golm GT, Kaufman KD, Goldstein BJ (2013) Safety and tolerability of sitagliptin in type 2 diabetes: pooled analysis of 25 clinical studies. Diabetes Ther 4:119–145

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Scirica BM, Bhatt DL, Braunwald E et al (2013) Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 369:1317–1326

    Article  CAS  PubMed  Google Scholar 

  35. White WB, Cannon CP, Heller SR et al (2013) Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 369:1327–1335

    Article  CAS  PubMed  Google Scholar 

  36. Dore DD, Bloomgren GL, Wenten M et al (2011) A cohort study of acute pancreatitis in relation to exenatide use. Diabetes Obes Metab 13:559–566

    Article  CAS  PubMed  Google Scholar 

  37. Dore DD, Seeger JD, Arnold Chan K (2009) Use of a claims-based active drug safety surveillance system to assess the risk of acute pancreatitis with exenatide or sitagliptin compared to metformin or glyburide. Curr Med Res Opin 25:1019–1027

    Article  CAS  PubMed  Google Scholar 

  38. Garg R, Chen W, Pendergrass M (2010) Acute pancreatitis in type 2 diabetes treated with exenatide or sitagliptin: a retrospective observational pharmacy claims analysis. Diabetes Care 33:2349–2354

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Romley JA, Goldman DP, Solomon M, McFadden D, Peters AL (2012) Exenatide therapy and the risk of pancreatitis and pancreatic cancer in a privately insured population. Diabetes Technol Ther 14:904–911

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Wenten M, Gaebler JA, Hussein M et al (2012) Relative risk of acute pancreatitis in initiators of exenatide twice daily compared with other anti-diabetic medication: a follow-up study. Diabet Med 29:1412–1418

    Article  CAS  PubMed  Google Scholar 

  41. Singh S, Chang HY, Richards TM, Weiner JP, Clark JM, Segal JB (2013) Glucagonlike peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: a population-based matched case–control study. JAMA Intern Med 173:534–539

    Article  CAS  PubMed  Google Scholar 

  42. Eurich DT, Simpson S, Senthilselvan A, Asche CV, Sandhu-Minhas JK, McAlister FA (2013) Comparative safety and effectiveness of sitagliptin in patients with type 2 diabetes: retrospective population based cohort study. BMJ 346:f2267

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank the French Network of Pharmacovigilance Centres and Pascal Auriche (ANSM) for access and extraction of data from the French Pharmacovigilance Database. The authors assume responsibility for the content and conclusions of this article.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Medical Pharmacology and Toxicology, Pharmacovigilance Regional Center, CHRU Montpellier, 371 Avenue du Doyen Gaston Giraud, 34295, Montpellier, France

    Jean-Luc Faillie, Virginie Bres, Pierre Petit & Dominique Hillaire-Buys

  2. Pharmacovigilance Regional Center, CHU Créteil, Créteil, France

    Samy Babai & Hervé Le Louet

  3. Department of Pharmacology and Toxicology, Pharmacovigilance Regional Center, CHU Limoges, Limoges, France

    Sabrina Crépin & Marie-Laure Laroche

  4. Department of Medical and Clinical Pharmacology, Pharmacovigilance Regional Center, CHU Toulouse, Toulouse, France

    Jean-Louis Montastruc

  5. Department of Pharmacoepidemiology, Faculty of Medicine, INSERM U1027, Toulouse, France

    Jean-Luc Faillie & Jean-Louis Montastruc

  6. Faculty of Medicine, INSERM U1058, Montpellier, France

    Dominique Hillaire-Buys

Authors
  1. Jean-Luc Faillie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Samy Babai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sabrina Crépin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Virginie Bres
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marie-Laure Laroche
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hervé Le Louet
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Pierre Petit
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jean-Louis Montastruc
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Dominique Hillaire-Buys
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

The French Pharmacovigilance Centers Network

Corresponding author

Correspondence to Jean-Luc Faillie.

Additional information

Communicated by Massimo Porta.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Faillie, JL., Babai, S., Crépin, S. et al. Pancreatitis associated with the use of GLP-1 analogs and DPP-4 inhibitors: a case/non-case study from the French Pharmacovigilance Database. Acta Diabetol 51, 491–497 (2014). https://doi.org/10.1007/s00592-013-0544-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00592-013-0544-0

Keywords

Search

Navigation