Accepted answer
Week 4 is day 28: on a four-week ladder that is week 4 of dose step 1, and — at the seven-day half-life this class runs on — 4 half-lives in. Steady state is about five half-lives, so day 35 is where the concentration stops climbing on its own. Day 28 is 1 weeks short of it, so the level is still rising even though the dose has not changed. That distinction is most of the question: at week 4 of a step, an effect that is still accumulating is indistinguishable from one that is not resolving unless you know which side of day 35 you are on. Nausea in this class tracks the rate of change more than the level: the trial programmes report it clustered in the fortnight after each step and decaying across the weeks that follow, which is why the week number is worth locating on the ladder before anything else. Dose decisions are made under supervision, and nothing here is medical advice.
Stated carefully, this is the most common adverse effect in the class and the one with the most consistent management advice.
Tolerance develops through receptor desensitisation over one to two weeks at a stable dose. Escalating before that has happened resets the process, which is the mechanism behind most miserable titrations.
Gastrointestinal adverse events, indicative pooled rates
| Event | Active arm | Placebo arm | Timing |
|---|
| Nausea | 40–45 % | 15–20 % | Peaks 1–2 wk after each step |
| Vomiting | 15–25 % | 5–8 % | Follows nausea |
| Diarrhoea | 20–30 % | 10–15 % | Early, variable |
| Constipation | 20–25 % | 8–12 % | Later onset, persistent |
| Discontinuation for GI events | 4–7 % | 1–2 % | Mostly during escalation |
Ranges span agents and doses; read the specific prescribing information for a specific figure.
Concretely, trial incidence for nausea in this class runs to roughly a quarter to a half of participants depending on agent and dose, concentrated in the escalation phase, with discontinuation for it in low single-figure percentages.
Area postrema involvement in nausea from GLP-1 receptor agonism is supported by lesion studies in animals and by the anatomy of the circumventricular organs.
Nothing here is medical advice; I am describing a pattern, not managing anybody.
Smaller meals, less fat, stop at first fullness, fluids between meals.