Understanding GLP-1 Half-Life

Native GLP-1 has a half-life of just 1–2 minutes — it is rapidly degraded by the enzyme DPP-4. Every successful GLP-1 therapy is, at its core, an exercise in extending that half-life.

The degradation problem

Without intervention, GLP-1 can’t be a drug. Three strategies have succeeded:

1. DPP-4 inhibitors (e.g., sitagliptin) prolong the life of your endogenous GLP-1.
2. Short-acting analogs (e.g., exenatide IR) resist DPP-4 but are still cleared within hours — requiring twice-daily dosing.
3. Long-acting analogs (e.g., Semaglutide Injection (Ozempic/Wegovy), Tirzepatide (Mounjaro)) add structural modifications plus an albumin-binding moiety, extending half-life to roughly a week.

Half-life → steady state

A drug reaches steady state after about 4–5 half-lives. For a week-long half-life, that’s roughly a month. This is why GLP-1 titration schedules advance monthly — each new dose level needs ~4 weeks to equilibrate.

Why longer isn’t always better

Very long half-lives (e.g., mazdutide, ~18 days) mean slower washout if side effects become intolerable. There’s a pharmacokinetic sweet spot, and most approved agents cluster around 5–7 days.