Safety and tolerability of exenatide twice daily in patients with type 2 diabetes: integrated analysis of 5594 patients from 19 placebo-controlled and comparator-controlled clinical trials

Abstract

BackgroundExenatide twice daily is a first-in-class glucagon-like peptide receptor agonist approved for the treatment of type 2 diabetes. The objective of this analysis was to evaluate the safety profile of exenatide twice daily and to compare its profile with that of a pooled comparator (placebo and insulin) in patients with type 2 diabetes.MethodsData from 19 completed, randomized, controlled clinical trials of exenatide twice daily (5 μg and 10 μg) were pooled and analyzed; the pooled data included 5594 intent-to-treat patients who were followed for 12–52 weeks. Incidence rates, exposure-adjusted incidence rates, and 95% confidence intervals around risk differences between groups were calculated.ResultsBaseline demographics and exposure time were comparable between groups (exenatide, N = 3261; pooled comparator, N = 2333; mean exposure time 166–171 days). Transient, mild- to-moderate nausea was the most frequent adverse event with exenatide (36.9% versus 8.3% in the pooled comparator). The incidence of hypoglycemia (minor or major) with concomitant sulfonylurea (exenatide 26.5%, pooled comparator 20.7%) was higher than that without sulfonylurea (exenatide 3.1%, pooled comparator 2.7%) in all groups. Serious adverse events, discontinuations due to serious adverse events, and deaths were reported with similar frequency in the exenatide and pooled comparator groups. Composite exposure-adjusted incidence rates were not statistically different between groups for pancreatitis, renal impairment, or major adverse cardiac events; there was a difference in incidence rates for benign thyroid neoplasm (0.3% versus 0%).ConclusionOverall, this analysis, representing over 1500 patient-years of exposure, demonstrated that exenatide twice daily was safe and generally well tolerated in patients with type 2 diabetes. The incidence of most adverse events, including serious adverse events, was similar in both exenatide-treated and comparator-treated patients. The most distinct differences between groups were in gastrointestinal-related adverse events, which is consistent with other therapies within the glucagon-like peptide class.

Efficacy and Tolerability of Exenatide Once Weekly Over 6 Years in Patients with Type 2 Diabetes: An Uncontrolled Open-Label Extension of the DURATION-1 Study

“…14,15 No incremental safety findings were observed with up to 6 years of exenatide QW treatment in the current study of a self-selected population. The exposure-adjusted event rates of nausea and injection-site reactions with exenatide QW were lower during the extension period than during the 30-week controlled period.…”

Evolution of Exenatide as a Diabetes Therapeutic

“…ExBID was approved for human use in 2005 by the U.S. Food and Drug Administration and there is a large clinical trial database of safety events available for analysis [137]. The most common side effects are gastrointestinal in nature, mild, and transient.…”

Comparison of extended release GLP-1 receptor agonist therapy versus sitagliptin in the management of type 2 diabetes

“…Different results were obtained in an analysis of a large health insurance transaction database, which found that the absolute risk of acute pancreatitis among exenatide and sitagliptin initiators was 0.13% (37 cases among 27,996 patients) and 0.12% (19 cases among 16,267 patients), respectively; these rates were equivalent to the absolute risk in a propensity score-matched cohort of metformin/glyburide initiators 48. Furthermore, in a recent integrated safety analysis of pooled data from 19 completed randomized controlled trials, composite exposure-adjusted incidence rates for pancreatitis among EBID users (n=3,261) and the pooled comparator group (n=2,333) were not statistically different 40. The current package insert recommends that EQW be discontinued immediately if pancreatitis is suspected and that other antidiabetic therapies may be considered in patients with a history of pancreatitis 18…”