Longer Acting GLP-1 Receptor Agonists and the Potential for Improved Cardiovascular Outcomes

A Review of Current Literature

Courtney Aavang Tibble; Tricia Santos Cavaiola; Robert R Henry


Expert Rev Endocrinol Metab. 2013;8(3):247-259. 

In This Article

LA-GLP1 RA Effects on the Risk of Pancreatitis

GLP1-based medications have been shown to cause pancreatitis in animal models, potentially due to amplification and induction of acinar to ductal metaplasia and/or cell proliferation of the exocrine pancreas. Although reports of pancreatitis have also been seen in humans using GLP1-based therapies, a causal relationship has not been established.[63] Similar findings have arisen with the LA GLP1-RA. The DURATION trials showed mixed results. No cases of pancreatitis were seen in DURATION-1 (EQW vs exenantide b.i.d).[12] In DURATION-2 (EQW vs sitagliptin or pioglitazone as add-on therapy to metformin) no pancreatitis was seen with either GLP1-based therapy (EQW or sitagliptin), but two cases (1%) were seen in the pioglitazone group.[14] Pancreatic enzyme concentrations were measured during the DURATION-3 trial (EQW vs glargine). A small number of patients had concentrations greater than three-times the upper limit of normal at end point (five EQW vs zero glargine); however, this compares with similar numbers seen at baseline (two EQW vs three glargine). There was one case of symptomatic edematous pancreatitis diagnosed in the EQW group, but peak enzyme levels were less than three-times the upper limit of normal, which resolved after 1 day and did not require hospitalization.[15] There were no clinically significant changes in pancreatic enzymes in the DURATION-4 trial (EQW vs metformin, pioglitazone or sitagliptin as monotherapy). However, one patient in the sitagliptin arm, who had an elevated lipase at study entry, developed moderate chronic pancreatitis 8 days after treatment that was subsequently discontinued.[16] Variable concentrations of pancreatic enzymes were seen throughout DURATION-5 (EQW vs exenatide b.i.d.) and DURATION-6 (EQW vs liraglutide), and one case of pancreatitis was seen in the EQW groups in both studies.[17,24] No episodes of pancreatitis were seen with varying doses of albiglutide,[34] while dulaglutide was associated with two episodes of pancreatitis compared with placebo when studied in T2D.[36]