Physicians and patients may be interested to know when novel long-acting therapies, such as the GLP-1RA exenatide QW, become effective and when maximum efficacy is achieved. This post hoc analysis demonstrated that glycemic control from exenatide QW begins before steady state concentrations are achieved, with near-maximal FPG reductions and clinically relevant HbA1c reductions within 4 weeks and near-maximal HbA1c reductions by 14 weeks.
In this study, measured plasma exenatide concentrations progressively increased to steady state at week 8. Similarly, reports on the PK and pharmacodynamics of exenatide QW among patients with T2D in the United States, China, and Japan showed exenatide concentrations reaching steady state after 6–8 weeks of weekly dosing [7–10].
Consistent with multiple mechanisms of action for exenatide, multiple relationships of exenatide exposure with clinical responses were demonstrated. FPG reduction was observed most rapidly (at week 4—the earliest time point measured), as the PK threshold for FPG lowering (~50 pg/mL) [12] is typically reached at 2 weeks [9]. A recent post hoc analysis of pooled data from 12 clinical trials reported significant reductions in FPG, HbA1c, body weight, and blood pressure as early as 2 weeks after initiating treatment with exenatide QW, further supporting an early onset of action [13]. In this study, the time course of HbA1c change, which is more gradual than FPG because it depends on red blood cell turnover, was near maximal 14 weeks after initiation of exenatide QW. Changes in weight also occurred more slowly than effects on FPG, as the physiology of weight loss is more gradual than that of FPG reductions.
It is important for physicians and patients to understand the time course of AEs associated with a long-acting medication. As shown in this study, the majority of gastrointestinal AEs with exenatide QW occurred early in therapy, after the efficacy threshold but before steady state was reached, and declined over time as tolerance developed. A gradual increase in exenatide concentrations, as occurs with exenatide QW during microsphere dissolution, has been associated with improved gastrointestinal tolerability compared with rapid dose escalation [14]. Similarly, pooled analyses of randomized controlled trials found that gastrointestinal AEs occurred less frequently with exenatide QW (providing continuous exenatide exposure) compared with exenatide BID (providing intermittent exenatide exposure), and decreased over time [15, 16]. These analyses further support the notion that the gradual increase in exenatide concentration through the microspheres enhances gastrointestinal tolerability.
While some physicians and patients seek to avoid gastrointestinal AEs, others may believe that nausea indicates response to therapy. Our subanalysis results counter this belief, showing that improvements in glycemic control were similar in patients with or without nausea although weight loss may be slightly greater in patients with nausea.
Limitations of this study include the small number of patients and the post hoc nature of the analysis; in particular, there were a small number of patients with nausea in the subanalysis and it was not powered to analyze differences between patients with and without nausea. In addition, the time course of clinical responses and PK of exenatide QW were evaluated in different although well-matched, patient populations. This study also lacked glycemic efficacy measures at earlier (1 or 2 week) time points because they were not indicated in the protocol.