Exenatide once weekly: sustained improvement in glycemic control and cardiometabolic measures through 3 years

Abstract

Background: Type 2 diabetes mellitus is a progressive metabolic disease necessitating therapies with sustained efficacy and safety over time. Exenatide once weekly (ExQW), an extended-release formulation of the glucagon-like peptide-1 receptor agonist exenatide, has demonstrated improvements in glycemic and cardiometabolic measures from 30 weeks to 2 years of treatment. Here, the efficacy and safety of treatment with ExQW for 3 years are described.

Methods: Patients were initially randomized to receive either ExQW (2 mg) or exenatide twice daily for 30 weeks. Following the initial 30 weeks, all patients were treated with ExQW in an open-label extension. Analyses of primary glycemic endpoints, beta-cell function, and cardiometabolic measures were assessed for patients who completed 3 years of ExQW treatment and for the intention-to-treat population. Safety and tolerability analyses were provided for the intention-to-treat population.

Results: Sixty-six percent of the intention-to-treat population (n = 295) completed 3 years of treatment (n = 194). At 3 years, a significant reduction in hemoglobin A(1c) (least squares mean ± standard error) of -1.6% ± 0.08% was observed, with 55% and 33% of patients achieving hemoglobin A(1c) targets of <7% and ≤6.5%, respectively. Consistent with a sustained reduction in hemoglobin A(1c), improvements in beta-cell function were also observed. Body weight was significantly reduced by -2.3 ± 0.6 kg. Reductions in blood pressure, total cholesterol, low-density lipoprotein cholesterol, and triglycerides were also observed. Adverse events reported most frequently during both controlled and uncontrolled periods included diarrhea, nausea, and vomiting of mostly mild intensity. The incidence of these adverse events decreased over time. Incidence of minor hypoglycemia was low and no major hypoglycemia was observed.

Conclusion: ExQW produced clinically meaningful improvements in glycemic control that were durable through 3 years of treatment. Significant improvements in cardiometabolic measurements were also observed. ExQW was well-tolerated during long-term treatment and no new adverse events were noted.

Trial registration: ClinicalTrials.gov NCT00308139.

Keywords: DURATION-1; GLP-1 receptor agonist; diabetes; exenatide; hyperglycemia.

Figures

Figure 1

Enrollment, patient disposition, and baseline characteristics. Abbreviations: BID, twice daily; HbA1c, hemoglobin A1c; ITT, intention-to-treat; MET, metformin; QW, once weekly; SU, sulfonylurea; TZD, thiazolidinedione.

Figure 2

Glycemic control over 3 years. (A) The mean ± standard error HbA1c (%) over 3 years for the completer population. LS mean change from baseline to 3 years for the completer population. Dotted lines at 7% and 6.5% represent target HbA1c goals. (B) The proportion of patients reaching indicated HbA1c target goals in the completer population. 3.1% of the completer population was at HbA1c < 7% at baseline. (C) The mean ± standard error fasting plasma glucose over 3 years for the completer population. Notes: LS mean change from baseline to 3 years for the completer population are indicated. The dotted line at 7 mmol/L represents the threshold at which diabetes is diagnosed. Abbreviations: HbA1c, hemoglobin A1c; LS, least squares.

Figure 3

Change in body weight over 3 years. Notes: Scatter plot (individual subject data, n = 194) of change in HbA1c versus change in body weight in the completer population. Abbreviation: HbA1c, hemoglobin A1c.

Figure 4

Change in blood pressure and serum lipids. (A) LS mean ± standard error change from baseline in SBP and DBP after 3 years of treatment in the completer population (n = 194). Mean baseline values are indicated below the bars. (B) LS mean ± standard error change from baseline in serum lipids, and geometric LS mean change ± standard error from baseline in triglycerides in the completer population (n = 194). Notes: Mean baseline values are indicated; median is provided for triglycerides; *P < 0.05. Abbreviations: DBP, diastolic blood pressure; HDL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol; LS, least squares; SBP, systolic blood pressure.

Figure 5

Incidence of adverse events over time. From 0–30 weeks, only the incidence of AEs occurring in subjects in the ExQW group is included (n = 148). After week 30, all subjects remaining in the trial during a given period are included (n = 295). Events are attributed to a defined period according to the event onset date; periods are grouped into 30-week intervals. (A) Incidence of nausea, diarrhea, and vomiting through week 156. (B) Incidence of injection site pruritus and erythema through week 156. Abbreviations: AEs, adverse events; ExQW, exenatide once-weekly.