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

Background: Exenatide 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.

Methods: Data 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.

Results: Baseline 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%).

Conclusion: Overall, 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.

Keywords: adverse events; exenatide; risk difference; safety.

Figure 1

Selection of trials for pooled analysis. Of the 61 clinical trials with available data, 19 placebo-controlled or comparator-controlled studies met the criteria for inclusion in the pooled analysis. Abbreviations: BID, twice daily; GAA-I, α-glucosidase inhibitor; INS, insulin; ITT, intent-to-treat; Met, metformin; SFU, sulfonylurea; TZD, thiazolidinedione; w/wout, with/without.

Figure 2

Mean treatment exposure. Cumulative duration of exposure (proportion of patients within each duration shown) and mean treatment exposure for the exenatide (166 days) and pooled comparator (171 days) groups. Abbreviation: BID, twice daily.

Figure 3

Incidence, recurrence, and duration of nausea and vomiting over time. Nausea and vomiting with exenatide twice daily 10 μg (4-week lead-in period with 5 μg exenatide twice daily, followed by dose increase to 10 μg twice daily for the duration of the trial; n = 2558), placebo (n = 1325), and insulin (n = 1008). (A) Occurrence and recurrence of nausea over time (grouped into 4-week intervals). (B) Occurrence and recurrence of vomiting over time. Each event is attributed to a defined period according to the event onset date, and recurrence of nausea/vomiting is defined as an event with onset during the defined period and any of the previous periods. Percentages are based on number of subjects who remained in the trial during the defined period. (C) Duration of nausea. (D) Duration of vomiting. The duration of the nausea/vomiting event is calculated as the resolution date (or the last participation date if event is ongoing at the time of study termination) minus the event onset date plus 1.

Figure 4

Incidence of hypoglycemia by treatment. Percentage of patients who experienced hypoglycemia (minor or major). Note: ^a95% confidence interval for the risk difference (exenatide incidence rate [%] minus pooled comparator incidence rate [%]). Abbreviations: RD, risk difference; Ex, exenatide; BID, twice daily; Ins, insulin; PBO, placebo; SFU, sulfonylurea. PBO + SFU or Ins refers to placebo with SFU or with background insulin.

Figure 5

Adverse events of interest. Exposure-adjusted incidence rate and risk difference of thyroid neoplasm, pancreatitis, and renal impairment (exenatide twice daily n = 3261, pooled comparator n = 2333) and major adverse cardiac events analysis (n = 2316, n = 1629, respectively). Thyroid neoplasm includes benign neoplasm of thyroid gland and malignant thyroid neoplasm. Pancreatitis includes acute pancreatitis and chronic pancreatitis. Renal impairment includes renal failure. Major adverse cardiac events include stroke, myocardial infarction, cardiac mortality, acute coronary syndrome, and revascularization procedures. Notes: ^a95% confidence interval for the risk difference (exenatide incidence rate [%] minus pooled comparator incidence rate [%]); ^bmajor adverse cardiac events analysis: risk ratio and 95% confidence interval for the risk ratio. Abbreviations: EAIR, exposure-adjusted incidence rate; BID, twice daily, MACE, major adverse cardiac events; PY, patient years.