The particulars: dizziness · orforglipron.
I can predict the outcome but I cannot explain it, which means I will get the next case wrong.
I would like to know how confident the field actually is about this.
What is actually going on here, physically?
Answer first: the titration schedule exists to let tolerance to the gastrointestinal effects develop between steps, and every step in it is a tolerability decision rather than an efficacy one.
For an agent with a one-week half-life, steady state after a dose change is reached in about four to five weeks. Escalating at two weeks means escalating from a position you have not yet reached, and the resulting exposure is higher than the schedule intends.
| Week | Fraction of steady state | Trough as × dose |
|---|---|---|
| 1 | 50 % | 0.50 |
| 2 | 75 % | 0.75 |
| 3 | 88 % | 0.88 |
| 4 | 94 % | 0.94 |
| 5 | 97 % | 0.97 |
| 6 | 98 % | 0.98 |
This is why a four-week step interval is approximately, but not exactly, steady state.
The published tirzepatide schedule steps 2.5, 5, 7.5, 10, 12.5 and 15 mg at four-week intervals, with 2.5 mg as the initiation step rather than a therapeutic one.
Faster titration does not reach the destination sooner in any way that matters; it reaches the symptoms sooner.
Four half-lives between steps, minimum. Work it out for your agent.
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Browse resultsStart with the half-life, because the interval between steps should be at least four half-lives or you are escalating before the previous step has expressed itself.
Liraglutide titrates weekly rather than four-weekly because its half-life is about thirteen hours, so steady state is reached within days. The interval follows the pharmacokinetics in both cases.
The dose that produces an acceptable result with acceptable tolerability is the endpoint, not the top of the schedule. A substantial fraction of trial participants did well below the maximum.
Hold rather than escalate while symptoms are active. Always.
The underlying point is that escalating while symptomatic resets the tolerance process and is the mechanism behind most miserable titrations.
Titrating downward is available too. Stepping back and holding is a normal adjustment rather than a failure.
In practice, the published semaglutide weight-management schedule steps 0.25, 0.5, 1.0, 1.7 and 2.4 mg at four-week intervals, with 0.25 mg as an initiation step rather than a therapeutic one.
Trial data show gastrointestinal adverse events concentrated in the escalation phase and declining at stable doses.
A schedule described here is a published schedule for a licensed product and is not a recommendation.
Stepping back is a normal adjustment, not a failure.
edited 22 Mar 2026 by cake_intact — reworded for clarity after a comment
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