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

Faillie, Jean‐Luc; Babai, Samy; Crépin, Sabrina; Brès, Virginie; Laroche, Marie‐Laure; Louët, Hervé Le; Petit, Pierre; Montastruc, Jean‐Louis; Hillaire‐Buys, Dominique

doi:10.1007/s00592-013-0544-0

Cited by 42 publications

(36 citation statements)

References 35 publications

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“…In contrast to the above results, several recent studies and meta-analyses failed to show increased risk of pancreatitis with the use of GLP-1 receptor agonists [72][73][74][75][76][77][78][79][80][81][82]. A meta-analysis of 55 randomized controlled trials (n = 33,350) showed no increased risk of pancreatitis with GLP-1 agonists compared with controls (OR: 1.05, 95% CI: 0.37-2.94) [83].…”

Section: Pancreasmentioning

confidence: 77%

Adverse Effects of GLP-1 Receptor Agonists

2014

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■ AbstractGlucagon-like peptide-1 (GLP-1) receptor agonists are a class of injective anti-diabetic drugs that improve glycemic control and many other atherosclerosis-related parameters in patients with type 2 diabetes (T2D). However, the use of this relatively new class of drugs may be associated with certain adverse effects. Concerns have been expressed regarding the effects of these drugs on pancreatic and thyroid tissue, since animal studies and analyses of drug databases indicate an association of GLP-1 receptor agonists with pancreatitis, pancreatic cancer, and thyroid cancer. However, several meta-analyses failed to confirm a cause-effect relation between GLP-1 receptor agonists and the development of these adverse effects. One benefit of GLP-1 receptor agonists is that they do not cause hypoglycemia when combined with metformin or thiazolidinediones, but the dose of concomitant sulphonylurea or insulin may have to be decreased to reduce the risk of hypoglycemic episodes. On the other hand, several case reports have linked the use of these drugs, mainly exenatide, with the occurrence of acute kidney injury, primarily through hemodynamic derangement due to nausea, vomiting, and diarrhea. The most common symptoms associated with the use of GLP-1 receptor agonists are gastrointestinal symptoms, mainly nausea. Other common adverse effects include injection site reactions, headache, and nasopharyngitis, but these effects do not usually result in discontinuation of the drug. Current evidence shows that GLP-1 receptor agonists have no negative effects on the cardiovascular risk of patients with T2D. Thus, GLP-1 receptor agonists appear to have a favorable safety profile, but ongoing trials will further assess their cardiovascular effects. The aim of this review is to analyze critically the available data regarding adverse events of GLP-1 receptor agonists in different anatomic systems published in Pubmed and Scopus. Whenever possible, certain differences between GLP-1 receptor agonists are described. The review also provides the reader with structured data that compare the rates of the most common adverse effects for each of the various GLP-1 receptor agonists.

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Section: Pancreasmentioning

confidence: 77%

Adverse Effects of GLP-1 Receptor Agonists

2014

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“…Much of the controversy has focused on concerns that these drugs may cause proliferative changes in pancreatic duct cells that lead to acute pancreatitis and possibly pancreatic cancer (3). These concerns have been corroborated by reports from adverse event databases (4,5), although such analyses have well-known limitations. In contrast, the observational studies conducted to date have been conflicting and inconclusive (6)(7)(8)(9)(10)(11)(12)(13)(14)(15).…”

Section: Dwilliam T Cefalu Editor In Chief Diabetes Carementioning

confidence: 95%

Incretin-Based Drugs and Adverse Pancreatic Events: Almost a Decade Later and Uncertainty Remains

Azoulay

2015

Diabetes Care

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Over the past few years, substantial clinical data have been presented showing that incretin-based therapies are effective glucose-lowering agents. Specifically, glucagon-like peptide 1 receptor agonists demonstrate an efficacy comparable to insulin treatment with minimal hypoglycemia and have favorable effects on body weight. Thus, many of the unmet clinical needs noted from prior therapies are addressed by these agents. However, even after many years of use, many continue to raise concerns about the long-term safety of these agents and, in particular, the concern with pancreatitis. This clearly remains a complicated topic. Thus, in this issue of Diabetes Care, we continue to update our readers on this very important issue by presenting two studies evaluating incretin-based medications and risk of pancreatitis. Both have undergone significant revisions based on peer review that provided significant clarification of the data. We applaud both author groups for being extremely responsive in providing the additional data and revisions requested by the editorial team. As such, because of the critical peer review, we feel both articles achieve the high level we require for Diabetes Care and are pleased to now present them to our readers. In keeping with our aim to comprehensively evaluate this topic, we asked for additional commentaries to be prepared. In the narrative outlined below, Dr. Laurent Azoulay provides a commentary about the remaining uncertainty in this area and also discusses the results from a nationwide population-based case-control study. In the narrative preceding Dr. Azoulay’s contribution, Prof. Edwin A.M. Gale provides a commentary on the report that focuses on clinical trials of liraglutide in the treatment of diabetes. From the journal’s perspective, both of the articles on pancreatitis and incretin-based therapies reported in this issue have been well vetted, and we feel both of the commentaries are insightful. —William T. Cefalu Editor in Chief, Diabetes Care

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“…The authors found the usage of all investigated incretin-based drugs (exenatide, liraglutide, sitagliptin, saxagliptin and vildagliptin) to be associated with an elevated risk of pancreatitis. 187 In a recent case report, vildagliptin was reported to induce acute pancreatitis after 5 weeks of therapy, of note, again in a type 2 diabetic woman with per se elevated risk of pancreatitis. 183 The inconsistent results may be explained -as already discussed elsewhere 138,188 -by limited statistical power, short duration of follow-up or inadequate adjustment for confounders, such as diabetes severity.…”

Section: Dppiv Inhibitorsmentioning

confidence: 97%

Antihyperglycaemic therapies and cancer risk

Lutz

Staiger

Fritsche

et al. 2014

Diabetes and Vascular Disease Research

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Aims: This review is aimed at highlighting the potential mitogenic/tumour growth-promoting or antimitogenic/tumour growth-inhibiting effects of the main antihyperglycaemic drug classes. Methods: We review and discuss the most current studies evaluating the association between antidiabetic medications used in clinical practice and malignancies as described so far. Results: Metformin seems to be the only antidiabetic drug to exert protective effects both on monotherapy and also when combined with other oral antidiabetic drugs or insulins in several site-specific cancers. In contrast, several other drug classes may increase cancer risk. Some reason for concern remains regarding sulphonylureas and also the incretinbased therapies regarding pancreas and thyroid cancers and the sodium glucose cotransporter-2 inhibitors as well as pioglitazone regarding bladder cancer. The majority of meta-analyses suggest that there is no evidence for a causal relationship between insulin glargine and elevated cancer risk, although the studies have been controversially discussed. For α-glucosidase inhibitors and glinides, neutral or only few data upon cancer risk exist. Conclusion: Although the molecular mechanisms are not fully understood, a potential risk of mitogenicity and tumour growth promotion cannot be excluded in case of several antidiabetic drug classes. However, more large-scale, randomized, well-designed clinical studies with especially long follow-up time periods are needed to get reliable answers to these safety issues.

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

Cited by 42 publications

References 35 publications

Adverse Effects of GLP-1 Receptor Agonists

Adverse Effects of GLP-1 Receptor Agonists

Incretin-Based Drugs and Adverse Pancreatic Events: Almost a Decade Later and Uncertainty Remains

Antihyperglycaemic therapies and cancer risk

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