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

Abstract

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

Incretin based drugs and the risk of pancreatic cancer: international multicentre cohort study

“…Overall, these analyses yielded findings that were consistent with those of the primary analysis (see supplementary figures [18][19][20][21][22][23]. The pooled adjusted hazard ratio in the fixed effects model was identical to that generated with the random effects model for the primary analysis (1.02, 0.80 to 1.23).…”

“…[12][13][14][15][16][17] These studies have, however, provided conflicting results and several had methodological shortcomings. 18 Given this controversy, regulatory agencies have called for additional studies of this potential association. 19 To this end, the Canadian Network for Observational Drug Effect Studies (CNODES) 20 designed a large, international, multicentre study to determine whether the use of incretin based drugs is associated with an increased risk of pancreatic cancer in people with type 2 diabetes.…”

Use of incretin agents and risk of acute and chronic pancreatitis: A population‐based cohort study

“…Recent literature shows limited and conflicting evidence for an association between incretin‐based therapy and risk of acute pancreatitis . Spontaneous adverse event reporting systems have detected cases of pancreatitis in incretin users .…”

Emerging opportunities for the treatment of metabolic diseases: Glucagon-like peptide-1 based multi-agonists

“…Nevertheless, the controversy is not going away and thus must still be addressed (Azoulay, 2015), particularly with GLP-1 based multi-agonists with integrated activities that have their own proliferative concerns in the exocrine pancreas, notably estrogen and gastrin. Additionally, pre-clinical studies in rodents revealed elevated levels of circulating calcitonin and an increased incidence of thyroid C-cell tumors after GLP-1R agonist treatment (Bjerre Knudsen et al, 2010), instigating a concern of an elevated risk for medullary thyroid cancer in humans.…”