Effectiveness of Progressive Dose-Escalation of Exenatide (Exendin-4) in Reducing Dose-Limiting Side Effects in Subjects with Type 2 Diabetes

Fineman MS, Shen LZ, Taylor K, Kim DD, Baron AD. Diabetes Metab Res Rev. 2004;20:411-417.

Nausea and vomiting are 2 dose-limiting adverse events associated with exenatide, an incretin mimetic. The purpose of this placebo-controlled, randomized, triple-blind study was to determine if tolerance to nausea and vomiting associated with exenatide could be induced using dose escalation in patients with type 2 diabetes.

In total, 123 participants were randomized to 1 of 2 treatment arms: an exenatide-primed arm and an exenatide-naive arm. Participants in the exenatide-primed arm received a dose-escalation regimen of exenatide starting at 0.02 µg/kg TID and increasing by increments of 0.02 µg/kg every 3 days to a maximum dose of 0.24 µg/kg TID on Day 35 for 3 days. Participants in the exenatide-naive arm received placebo TID for 35 days followed by 0.24 µg/kg exenatide TID for 3 days. Primary outcome measurements were the number of participants experiencing vomiting, severe nausea, or withdrawal due to nausea.

Of the 123 participants enrolled, 99 (80.5%) completed the study. Thirteen participants (10.6%) withdrew due to an adverse event; 6 (4.9%) in the exenatide-naive arm and 7 (5.7%) in the exenatide-primed arm. Most participants in the exenatide-naive and exenatide-primed arms experienced an adverse event (93.4% [n=57] and 82.3% [n=51], respectively). In terms of primary outcome measures, fewer participants experienced vomiting, severe nausea, or withdrew due to nausea in the exenatide-primed arm compared with the exenatide-naive arm (27.4% vs 55.7%, P = .0018), and cumulative incidence of these measures was 0.28 in the exenatide-primed arm and 0.68 in the exenatide-naive arm (P≤0.001). Compared with participants in the exenatide-primed arm, more participants in the exenatide-naive arm reported severe vomiting (9.7% vs 31.1%) and severe nausea (29.0% vs 47.5%).

Although previous short-term studies have suggested that increasing the duration of exenatide treatment is associated with a decrease in the incidence of nausea and vomiting, this is the first published study to suggest that dose escalation of exenatide can be used to lower the proportion of patients experiencing dosing-limiting nausea and vomiting.