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

ABSTRACT 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 (ED 50 ). We used the ratio of ED 50 ies 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 ED 50 ies 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 ED 50 ratio (Phase 3/Phase 1) was also significantly associated with effect sizes for intended therapeutic actions of incretin mimetics (reductions in HbA 1c 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.