Skip to main content
SpringerLink
Log in

Incretin-based therapies and acute pancreatitis risk: a systematic review and meta-analysis of observational studies

  • Meta-Analysis
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Concerns raised by several animal studies, case reports, and pharmacovigilance warnings over incretin-based therapy potentially exposing type two diabetes patients to an elevated risk of pancreatitis have cast a shadow on the overall safety of this class of drugs. This systematic review evaluates the data from observational studies that compared treatment with or without incretins and the risk of pancreatitis. We searched PubMed for publications with the key terms incretins or GLP-1 receptor agonists or DPP-4 inhibitors or sitagliptin or vildagliptin or saxagliptin or linagliptin or alogliptin or exenatide or liraglutide AND pancreatitis in the title or abstract. Studies were evaluated against the following criteria: design (either cohort or case–control); outcome definition (incidence of pancreatitis); exposure definition (new or current or past incretins users); and comparison between patients receiving incretins or not for type 2 diabetes. Two authors independently selected the studies and extracted the data. Six studies meeting the inclusion criteria were reviewed. No difference was found in the overall risk of pancreatitis between incretin users and non-users (odds ratio 1.08; 95 % CI [0.84–1.40]). A risk increase lower than 35 % cannot be excluded according to the power calculation. This systematic review and meta-analysis suggests that type 2 diabetes patients receiving incretin-based therapy are not exposed to an elevated risk of pancreatitis. Limitations of this analysis are the low prevalence of incretin users and the lack of a clear distinction by the studies between therapy with DPP-4 inhibitors or with GLP-1 receptor agonists.

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
Fig. 3

Similar content being viewed by others

References

  1. C.F. Deacon, E. Mannucci, B. Ahre´n, Glycaemic efficacy of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors as add-on therapy to metformin in subjects with type 2 diabetes-a review and meta analysis. Diabetes. Obes. Metab. 14, 762–767 (2012)

    Article  CAS  PubMed  Google Scholar 

  2. B. Gallwitz, Extra-pancreatic effects of incretin-based therapies. Endocrine (2014). doi:10.1007/s12020-014-0223-0

  3. N. Mikhail, Effects of incretin-based therapy in patients with heart failure and myocardial infarction. Endocrine 47(1), 21–28 (2014). doi:10.1007/s12020-014-0175-4

  4. J.A. Koehler, L.L. Baggio, B.J. Lamont, S.D. Ali, D.J. Drucker, Glucagon-like peptide-1 receptor activation modulates pancreatitis-associated gene expression but does not modify the susceptibility to experimental pancreatitis in mice. Diabetes. 58, 2148–2161 (2009)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. J.S. Nachnani, D.G. Bulchandani, A. Nookala, B. Herndon, A. Molteni, P. Pandya, R. Taylor, T. Quinn, L. Weide, L.M. Alba, Biochemical and histological effects of exendin-4 (exenatide) on the rat pancreas. Diabetologia. 53, 153–159 (2010)

    Article  CAS  PubMed  Google Scholar 

  6. K. Tatarkiewicz, P.A. Smith, E.J. Sablan, C.J. Polizzi, D.E. Aumann, C. Villescaz, D.M. Hargrove, B.R. Gedulin, M.G.W. Lu, L. Adams, T. Whisenant, D. Roy, D.G. Parkes, Exenatide does not evoke pancreatitis and attenuates chemically induced pancreatitis in normal and diabetic rodents. Am. J. Physiol. Endocrinol. Metab. 299, E1076–E1086 (2010)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. S.N. Iyer, A.J. Drake, R.I. West, C.E. Mendez, R.J. Tanenberg, Case report of acute necrotizing pancreatitis associated with combination treatment of sitagliptin and exenatide. Endocr. Pract. 18, 10–13 (2012)

    Article  Google Scholar 

  8. A.S. Franks, P.H. Lee, C.M. George, Pancreatitis: a potential complication of liraglutide? Ann. Pharmacother. 46, 1547–1553 (2012)

    Article  PubMed  Google Scholar 

  9. M. Sue, A. Yoshihara, K. Kuboki, N. Hiroi, G. Yoshino, A case of severe acute necrotizing pancreatitis after administration of sitagliptin. Clin. Med. Insights. Case. Rep. 6, 23 (2013)

    Article  PubMed Central  PubMed  Google Scholar 

  10. M. Elashoff, A.V. Matveyenko, B. Gier, R. Elashoff, P.C. Butler, Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology. 141, 150–156 (2011)

    Article  CAS  PubMed  Google Scholar 

  11. J.L. Faillie, S. Babai, S. Crépin, V. Bres, M.L. Laroche, H. Le Louet, P. Petit, J.L. Montastruc, D. Hillaire-Buys, The French Pharmacovigilance Centers Network. 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(3), 491–497 (2014)

  12. E.A. Gale, GLP-1 based agents and acute pancreatitis: drug safety falls victim to the three monkey paradigm. BMJ. 346, f1263 (2013)

    Article  PubMed  Google Scholar 

  13. C.J. Girman, T.D. Kou, B. Cai, C.M. Alexander, E.A. O’Neill, D.E. Williams-Herman, L. Katz, Patients with type 2 diabetes mellitus have higher risk for acute pancreatitis compared with those without diabetes. Diabetes. Obes. Metab. 12, 766–771 (2010)

    Article  CAS  PubMed  Google Scholar 

  14. R.A. Noel, D.K. Braun, R.E. Patterson, G.L. Bloomgren, Increased risk of acute pancreatitis and biliary disease observed in patients with type 2 diabetes: a retrospective cohort study. Diabetes. Care. 32, 834–838 (2009)

    Article  PubMed Central  PubMed  Google Scholar 

  15. A. Gonzalez-Perez, R.G. Schlienger, L.A. Rodríguez, Acute pancreatitis in association with type 2 diabetes and antidiabetic drugs: a population-based cohort study. Diabetes. Care. 33(12), 2580–2585 (2010)

    Article  PubMed Central  PubMed  Google Scholar 

  16. S.-W. Lai, C.-H. Muo, K.-F. Liao, F.-C. Sung, P.-C. Chen, Risk of acute pancreatitis in type 2 diabetes and risk reduction on anti-diabetic drugs: A population-based cohort study in Taiwan. Am. J. Gastroenterol. 106, 1697–1704 (2011)

  17. K.B. Blomgren, A. Sundstrom, G. Steineck, B.E. Wiholm, Obesity and treatment of diabetes with glyburide may both be risk factors for acute pancreatitis. Diabetes. Care. 25, 298–302 (2002)

    Article  CAS  PubMed  Google Scholar 

  18. F.L. Fimognari, A. Corsonello, R. Pastorell, R. Antonelli-Incalzi, Metformin-induced pancreatitis: a possible adverse drug effect during acute renal failure. Diabetes. Care. 29, 1183 (2006)

    Article  PubMed  Google Scholar 

  19. S. Mallick, Metformin-induced acute pancreatitis precipitated by renal failure. Postgrad. Med. J. 80, 239–240 (2004)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. C.B. Giorda, E. Nada, B. Tartaglino, Pharmacokinetics, safety, and efficacy of DPP-4 inhibitors and GLP-1 receptor agonists in patients with type 2 diabetes mellitus and renal or hepatic impairment. A systematic review of the literature. Endocrine 46(3), 406–419 (2014)

    Article  CAS  PubMed  Google Scholar 

  21. M. Monami, I. Dicembrini, E. Mannucci, Dipeptidyl peptidase-4 inhibitors and pancreatitis risk: a meta-analysis of randomized clinical trials. Diabetes. Obes. Metab. 16(1), 48–56 (2014)

    Article  CAS  PubMed  Google Scholar 

  22. B.M. Scirica, D.L. Bhatt, E. Braunwald, P.G. Steg, J. Davidson, P. Hirshberg, R. Frederich, S.D. Wiviott, E.B. Hoffman, M.A. Cavender, J.A. Udell, N.R. Desai, O. Mosenzon, D.K. McGuire, K.K. Ray, L.A. Leiter, I. Raz, the SAVOR-TIMI 53 Steering Committee and Investigators, Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N. Engl. J. Med. 369(14), 1317–1326 (2013)

    Article  CAS  PubMed  Google Scholar 

  23. W.B. White, C.P. Cannon, S.R. Heller, S.E. Nissen, R.M. Bergenstal, G.L. Bakris, A.T. Perez, P.R. Fleck, C.R. Mehta, S. Kupfer, C. Wilson, W.C. Cushman, F. Zannad, the EXAMINE Investigators, Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N. Engl. J. Med. 369(14), 1327–1335 (2013)

    Article  CAS  PubMed  Google Scholar 

  24. L.V. Hedges, T.D. Pigott, The power of statistical test in meta-analysis. Psychol. Methods. 6, 203–217 (2001)

    Article  CAS  PubMed  Google Scholar 

  25. D.D. Dore, M. Hussein, C. Hoffman, E.M. Pelletier, D.B. Smith, J.D. Seeger, A pooled analysis of exenatide use and risk of acute pancreatitis. Curr. Med. Res. Opin. 29(12), 1577–1586 (2013)

    Article  CAS  PubMed  Google Scholar 

  26. D.D. Dore, G.L. Blomgren, M. Wenten et al., A cohort study of acute pancreatitis in relation to exenatide use. Diabetes. Obes. Metab. 13(6), 559–566 (2011)

    Article  CAS  PubMed  Google Scholar 

  27. M. Wenten, J.A. Gaebler, M. Hussein, E.M. Pelletier, D.B. Smith, P. Girase, R.A. Noel, D.K. Braun, G.L. Bloomgren, Relative risk of acute pancreatitis in initiators of exenatide twice daily compared with other anti-diabetic medication: a follow-up study. Diabet. Med. 29(11), 1412–1418 (2012)

    Article  CAS  PubMed  Google Scholar 

  28. D.D. Dore, D. John, J.D. Seeger, Arnold Chan K. 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(4), 1019–1027 (2009)

    Article  CAS  PubMed  Google Scholar 

  29. R. Garg, W. Chen, M. Pendergrass, Acute pancreatitis in type 2 diabetes treated with exenatide or sitagliptin: a retrospective observational pharmacy claims analysis. Diabetes. Care. 33(11), 2349–2354 (2010)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. J.A. Romley, D.P. Goldman, M. Solomon, D. McFadden, A.L. Peters, Exenatide therapy and the risk of pancreatitis and pancreatic cancer in a privately insured population. Diabetes. Technol. Ther. 14(10), 904–911 (2012)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. S. Singh, H.Y. Chang, T.M. Richards, J.P. Weiner, J.M. Clark, J.B. Segal, Glucagon-like 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(7), 534–539 (2013)

    Article  CAS  PubMed  Google Scholar 

  32. C.B. Giorda, R. Picariello, E. Nada, B. Tartaglino, L. Marafetti, G. Costa, R. Gnavi, Incretin therapies and risk of hospital admission for acute pancreatitis in an unselected population of European patients with type 2 diabetes: a case-control study. www.thelancet.com/diabetes-endocrinology. Accessed 12 Nov 2013. doi:10.1016/S2213-8587(13)70147-5

  33. M. Monami, I. Iacomelli, N. Marchionni, E. Mannucci, Dipeptidyl peptidase-4 inhibitors in type 2 diabetes: a meta-analysis of randomized clinical trials. Nutr. Metab. Cardiovasc. Dis. 20, 224–235 (2010)

    Article  CAS  PubMed  Google Scholar 

  34. E. Raschi, C. Piccinni, E. Poluzzi, G. Marchesini, F. De Ponti, The association of pancreatitis with antidiabetic drug use: gaining insight through the FDA. Acta Diabetol. 50(4), 569–577 (2013)

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed Central  PubMed  Google Scholar 

  36. M.A. Nauck, J.J. Meier, Pancreatitis and incretin-based drugs: clarity or confusion? Comment. www.thelancet.com/diabetes-endocrinology. Accessed 12 Nov 2013. doi:10.1016/S2213-8587(13)70186-4

  37. L. Frulloni, C. Lunardi, R. Simone et al., Identification of a novel antibody associated with autoimmune pancreatitis. N. Engl. J. Med. 361, 2135–2142 (2009)

    Article  CAS  PubMed  Google Scholar 

  38. H.M. Lando, M. Alattar, A.P. Dua, Elevated amylase and lipase levels in patients using glucagon-like peptide-1 receptor agonists or dipeptidyful-peptidase-4 inhibitors in the outpatient setting. Endocr. Pract. 18, 472–477 (2012)

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by Chaira Medica Association (non-profit organization for the study of endocrine and metabolic disorders), Chieri, Italy; EN is employed with the Association.

Conflict of interest

CBG discloses teaching and speaking fees from Merck, Novo Nordisk, BMS/AZ Alliance, and BI/Lilly Alliance. All the other authors declare no conflicts of interest.

Author information

Authors and Affiliations

  1. Metabolism and Diabetes Unit, ASL TO5, Regione Piemonte, Chieri, Italy

    Carlo B. Giorda & Lisa Marafetti

  2. Unit of Cancer Epidemiology, University of Turin, Turin, Italy

    Carlotta Sacerdote

  3. Chaira Medica Association, Chieri, Italy

    Elisa Nada

  4. Unit of Biostatistics, Epidemiology and Public Health, University of Padua, Padua, Italy

    Ileana Baldi

  5. Epidemiology Unit, ASL TO3, Regione Piemonte, Grugliasco, Italy

    Roberto Gnavi

Authors
  1. Carlo B. Giorda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carlotta Sacerdote
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elisa Nada
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lisa Marafetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ileana Baldi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Roberto Gnavi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Carlo B. Giorda.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Giorda, C.B., Sacerdote, C., Nada, E. et al. Incretin-based therapies and acute pancreatitis risk: a systematic review and meta-analysis of observational studies. Endocrine 48, 461–471 (2015). https://doi.org/10.1007/s12020-014-0386-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-014-0386-8

Keywords

Search

Navigation