Is There a Link Between Liraglutide and Pancreatitis? A Post Hoc Review of Pooled and Patient-Level Data From Completed Liraglutide Type 2 Diabetes Clinical Trials

Abstract

OBJECTIVETo report the incidence of pancreatitis in type 2 diabetes trials of liraglutide and details of all pancreatitis cases. RESEARCH DESIGN AND METHODSData from Novo Nordisk-sponsored trials with liraglutide (phase 2 and 3; NN2211 identifiers) completed by 19 April 2013 were pooled. All pancreatitis cases were reviewed. RESULTSTotal exposure to liraglutide and active comparators was 5,021 and 1,354 patientyears, respectively (n = 6,345 and 1,846, respectively). Eight cases of acute pancreatitis (AP) with liraglutide and one with any comparator (glimepiride) were found. The incidence of AP was 1.6 cases/1,000 patient-years exposure (PYE) for liraglutide vs. 0.7 cases/1,000 PYE for total active comparators. One of the eight AP cases reported with liraglutide did not meet diagnostic criteria for AP. In six of these eight cases, recognized risk factors for AP were present and/or the onset of AP occurred >6 months after liraglutide initiation. All patients were receiving multiple medications. Four cases of chronic pancreatitis (CP) with liraglutide and none with comparators were found. One of these four cases fulfilled diagnostic criteria for CP; these criteria were not met or information was missing in the remaining three. CONCLUSIONSBased on the small number of cases observed, the incidences of reported AP and CP were numerically greater with liraglutide than with comparators. Not all cases fulfilled diagnostic criteria, and confounding variables were present in 75% of the AP cases with liraglutide therapy, precluding firm conclusions.In 2007, the U.S. Food and Drug Administration (FDA) prompted an update of the exenatide twice daily label to include a warning for acute pancreatitis (1). This update was based on six acute pancreatitis cases in patients receiving exenatide twice daily in clinical trials together with several postmarketing case reports (1); 1 UK Medical Affairs, Novo Nordisk Ltd., Gatwick, U.K. A slide set summarizing this article is available online.

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

“…There has been considerable interest in a potential association between the use of GLP-1-receptor agonists and pancreatitis and pancreatic cancer, although there is no consistent preclinical, pharmacovigilance, or epidemiologic evidence to date. [23][24][25] Higher levels of lipase and amylase were observed in the liraglutide group, a finding that is similar to results in other studies. 24 Blinded medications were to be stopped only in relation to confirmed pancreatitis as evaluated by the investigator.…”

“…[23][24][25] Higher levels of lipase and amylase were observed in the liraglutide group, a finding that is similar to results in other studies. 24 Blinded medications were to be stopped only in relation to confirmed pancreatitis as evaluated by the investigator. There were 1.5 episodes of pancreatitis per 1000 patient-years of observation in both regimens combined, and there were numerically fewer acute or chronic pancreatitis events with liraglutide than with placebo.…”

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

“…In the other study in this issue, Jensen et al (20) pooled data from 18 randomized controlled trials (RCTs) conducted by the manufacturer of the glucagonlike peptide 1 analog liraglutide. The authors report eight events of acute pancreatitis in the liraglutide group versus one event in the comparator group, generating incidence rates of 1.6 and 0.7 per 1,000 patient-years, respectively (relative risk 2.1 [95% CI 0.3-16.0]).…”

Pancreatic safety in Japanese patients with type 2 diabetes treated with once weekly dulaglutide 0.75 mg up to 52 weeks in phase 3 clinical trials

“…Rates of acute pancreatitis reported in observational studies in patients with T2D in other countries include the following: Taiwan: 2.77 patients/1,000 patient-years [28]; Canada, United States, and the United Kingdom: 1.49 patients/1,000 patient-years [29]. The exposure-adjusted incidence rates of acute pancreatitis in patients treated with liraglutide or exenatide have been reported as 1.6 cases and 5.7 cases/1,000 patient-years, respectively [5,7]. In global phase 3 studies of incretin-based therapies, including dulaglutide, amylase and lipase have been assessed together, and increases in both have been observed with GLP-1 receptor agonists (dulaglutide, liraglutide, and exenatide) and DPP-4 inhibitors (sitagliptin) [15,17,23].…”

“…Pooled analyses of studies of GLP-1 receptor agonists exenatide, liraglutide, and lixisenatide suggested a numerically increased incidence of pancreatitis with these drugs, but there were few cases [7,8]. After comprehensive review of data from study drugs in the incretin class from many sponsors, the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have stated that available evidence does not support concern about pancreatic safety with incretin-based thera-…”