Dose-Escalation Regimens for Incretin Mimetics in Type 2 Diabetes Are Associated With Tolerance for Nausea and Vomiting.

AIMS/HYPOTHESIS: Initial dose-escalation has been shown to mitigate gastrointestinal adverse events in people treated with incretin-based medications. We aimed to analyse dose-response relationships for the proportion of study participants reporting nausea and vomiting among those exposed to incretin mimetics approved for Type 2 diabetes (GLP-1 receptor agonists and the dual GIP/GLP-1 receptor agonist tirzepatide) in Phase 1 (no or short dose escalation) and Phase 3 (with dose escalation) trials.

METHODS: Non-linear regression analysis (curve fitting) was used to estimate the dose that would elicit nausea or vomiting in 50% of exposed subjects (ED50). We used the ratio of ED50ies determined for Phase 1 and Phase 3 trials as an indicator of developing tolerance.

RESULTS: The development of tolerance for nausea and vomiting (indicated by a ratio of ED50ies Phase 3/Phase 1) for semaglutide (both s.c. and oral) and for tirzepatide was significantly higher than 1. Comparing all approved incretin-based medications, a higher ratio, indicating the development of more tolerance, was associated with (a) a longer drug escalation period and (b) a greater number of dose-escalation steps. This ED50 ratio (Phase 3/Phase 1) was also significantly associated with effect sizes for intended therapeutic actions of incretin mimetics (reductions in HbA1c and body weight).

CONCLUSIONS/INTERPRETATION: Taken together, optimised dose-escalation regimens may lead to greater tolerance for nausea and vomiting, which allows to use of higher doses, which are associated with greater therapeutic effectiveness.