Is There a Link Between Liraglutide and Pancreatitis?
Is There a Link Between Liraglutide and Pancreatitis?
Objective To report the incidence of pancreatitis in type 2 diabetes trials of liraglutide and details of all pancreatitis cases.
Research Design and Methods Data 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.
Results Total exposure to liraglutide and active comparators was 5,021 and 1,354 patient-years, 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.
Conclusions Based 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. This update was based on six acute pancreatitis cases in patients receiving exenatide twice daily in clinical trials together with several postmarketing case reports; similar observations were made with liraglutide. Today, GLP-1 receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors carry warning text for acute pancreatitis on their labels.
A number of studies investigated the association between incretin-based therapies and pancreatitis, with varied conclusions. A systematic review and meta-analysis of 55 randomized clinical trials (33,350 patients) indicated an odds ratio (95% CI) for pancreatitis of 1.11 (0.57, 2.17) with incretin-based therapies versus control; estimates calculated by incretin therapy class (GLP-1 receptor agonists or DPP-4 inhibitors) showed similar results. In the same study, the authors described results of five observational studies without pooled analysis due to variation in outcome measures and data forms. Four of these observational studies showed no increased risk of pancreatitis associated with incretin exposure, but one linked exenatide or sitagliptin use with a significantly increased odds of acute pancreatitis (use within 2 years vs. no use 2.07 [1.36, 3.13]).
Since its initial approval for clinical use in 2009, mixed conclusions have been drawn in publications related to liraglutide and pancreatitis. At least 11 case reports suggested a relationship between liraglutide and pancreatitis, highlighting pancreatitis as a potential complication of therapy and suggesting caution when prescribing liraglutide. Meanwhile, a meta-analysis of 25 longitudinal studies (22 randomized controlled trials, 3 retrospective cohort analyses, 775,602 patients) concluded that liraglutide was not associated with an increased risk of acute pancreatitis (odds ratio [95% CI] 0.97 [0.21, 4.39]). More recently, a liraglutide audit conducted by the Association of British Clinical Diabetologists reported that after 3,720 years of exposure to liraglutide across 6,010 patients, four cases of possible pancreatitis were documented. Likely causes were identified in three patients, and one patient had no etiological cause. The authors concluded that "people with type 2 diabetes are at greater risk of acute pancreatitis (hazard ratio between 1.5 and 2.8). Thus, the possibility of liraglutide-associated pancreatitis in 'real-world' clinical practice (0.027/100 patient-years) represents a very small risk".
Based on a report showing pancreatic pathology in human tissue and a claims database study indicating increased hospitalization for acute pancreatitis with sitagliptin or exenatide treatment, which were subsequently re-evaluated and criticized, both the European Medicines Agency (EMA) and the FDA initiated investigations regarding the pancreatic safety of incretin-based therapies. In February 2014, the EMA and FDA concluded that based on available data, the "assertions concerning a causal association between incretin-based drugs and pancreatitis or pancreatic cancer, as expressed recently in the scientific literature and in the media, are inconsistent with the current data". Until further information becomes available, pancreatitis will continue to be considered a risk associated with these therapies, and both agencies continue to monitor the safety signals. At the time of this writing, the EMA and FDA believed that "current knowledge is adequately reflected in the product information or labeling". The current article reviews all cases of pancreatitis reported during Novo Nordisk–sponsored, randomized clinical trials of liraglutide as the primary investigational product for type 2 diabetes (Novo Nordisk trial identifiers prefixed with NN2211 only) completed by 19 April 2013.
Abstract and Introduction
Abstract
Objective To report the incidence of pancreatitis in type 2 diabetes trials of liraglutide and details of all pancreatitis cases.
Research Design and Methods Data 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.
Results Total exposure to liraglutide and active comparators was 5,021 and 1,354 patient-years, 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.
Conclusions Based 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.
Introduction
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. This update was based on six acute pancreatitis cases in patients receiving exenatide twice daily in clinical trials together with several postmarketing case reports; similar observations were made with liraglutide. Today, GLP-1 receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors carry warning text for acute pancreatitis on their labels.
A number of studies investigated the association between incretin-based therapies and pancreatitis, with varied conclusions. A systematic review and meta-analysis of 55 randomized clinical trials (33,350 patients) indicated an odds ratio (95% CI) for pancreatitis of 1.11 (0.57, 2.17) with incretin-based therapies versus control; estimates calculated by incretin therapy class (GLP-1 receptor agonists or DPP-4 inhibitors) showed similar results. In the same study, the authors described results of five observational studies without pooled analysis due to variation in outcome measures and data forms. Four of these observational studies showed no increased risk of pancreatitis associated with incretin exposure, but one linked exenatide or sitagliptin use with a significantly increased odds of acute pancreatitis (use within 2 years vs. no use 2.07 [1.36, 3.13]).
Since its initial approval for clinical use in 2009, mixed conclusions have been drawn in publications related to liraglutide and pancreatitis. At least 11 case reports suggested a relationship between liraglutide and pancreatitis, highlighting pancreatitis as a potential complication of therapy and suggesting caution when prescribing liraglutide. Meanwhile, a meta-analysis of 25 longitudinal studies (22 randomized controlled trials, 3 retrospective cohort analyses, 775,602 patients) concluded that liraglutide was not associated with an increased risk of acute pancreatitis (odds ratio [95% CI] 0.97 [0.21, 4.39]). More recently, a liraglutide audit conducted by the Association of British Clinical Diabetologists reported that after 3,720 years of exposure to liraglutide across 6,010 patients, four cases of possible pancreatitis were documented. Likely causes were identified in three patients, and one patient had no etiological cause. The authors concluded that "people with type 2 diabetes are at greater risk of acute pancreatitis (hazard ratio between 1.5 and 2.8). Thus, the possibility of liraglutide-associated pancreatitis in 'real-world' clinical practice (0.027/100 patient-years) represents a very small risk".
Based on a report showing pancreatic pathology in human tissue and a claims database study indicating increased hospitalization for acute pancreatitis with sitagliptin or exenatide treatment, which were subsequently re-evaluated and criticized, both the European Medicines Agency (EMA) and the FDA initiated investigations regarding the pancreatic safety of incretin-based therapies. In February 2014, the EMA and FDA concluded that based on available data, the "assertions concerning a causal association between incretin-based drugs and pancreatitis or pancreatic cancer, as expressed recently in the scientific literature and in the media, are inconsistent with the current data". Until further information becomes available, pancreatitis will continue to be considered a risk associated with these therapies, and both agencies continue to monitor the safety signals. At the time of this writing, the EMA and FDA believed that "current knowledge is adequately reflected in the product information or labeling". The current article reviews all cases of pancreatitis reported during Novo Nordisk–sponsored, randomized clinical trials of liraglutide as the primary investigational product for type 2 diabetes (Novo Nordisk trial identifiers prefixed with NN2211 only) completed by 19 April 2013.
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