- Natural GLP-1 half-life: Only 1-2 minutes (rapidly degraded by DPP-4 enzyme)
- Semaglutide half-life: ~7 days (168 hours)
- The secret: Albumin binding extends duration dramatically
- Steady state: Takes 4-5 weeks to reach stable blood levels
- Flexibility: Long half-life allows timing flexibility
The Problem: Natural GLP-1 Is Too Short-Lived
Your body naturally produces GLP-1 after eating. But it's destroyed almost immediately:
This rapid degradation meant that simply injecting natural GLP-1 wouldn't work—you'd need continuous infusion. The breakthrough was engineering GLP-1 molecules that resist degradation.
The Evolution of GLP-1 Duration
| Generation | Drug | Half-Life | Dosing |
|---|---|---|---|
| Native GLP-1 | — | 1-2 minutes | Continuous infusion (research only) |
| 1st Gen | Exenatide (Byetta) | 2.4 hours | Twice daily |
| 2nd Gen | Liraglutide (Victoza/Saxenda) | 13 hours | Once daily |
| 3rd Gen | Semaglutide (Ozempic/Wegovy) | ~7 days | Once weekly |
| 3rd Gen | Tirzepatide (Mounjaro/Zepbound) | ~5 days | Once weekly |
| 3rd Gen | Dulaglutide (Trulicity) | ~5 days | Once weekly |
How Semaglutide Achieves a Week-Long Half-Life
Three key modifications transformed GLP-1 into a weekly medication:
1. DPP-4 Resistance: An amino acid substitution at position 8 (Ala→Aib) makes semaglutide resistant to the DPP-4 enzyme that normally destroys GLP-1 within minutes.
2. Fatty Acid Chain: A C18 fatty acid chain is attached via a linker. This chain binds strongly to albumin (a protein in blood).
3. Albumin Binding: When bound to albumin, semaglutide is protected from degradation and elimination. Only free (unbound) semaglutide is active, creating a slow-release effect.
The Albumin Reservoir Effect
Think of albumin as a storage reservoir:
- ~99% of semaglutide is bound to albumin at any time
- Only ~1% is free and active
- As free drug is used, more is released from albumin
- This creates sustained, stable drug levels
- Albumin's half-life (~19 days) extends drug duration
Steady State: Why It Takes Time to Work
Because of the long half-life, semaglutide builds up gradually:
- Week 1: First dose; blood levels rising but low
- Week 2: Second dose added to remaining first dose; levels higher
- Week 3: Accumulation continues
- Weeks 4-5: Steady state reached—what goes in equals what goes out
- Rule of thumb: Steady state takes ~5 half-lives (5 × 7 days = 35 days)
This explains why:
- Effects increase over the first month even at the same dose
- Side effects may emerge or worsen after 3-4 weeks
- Dose escalation should be gradual (typically monthly)
- Full effects of each dose aren't seen for 4-5 weeks
Practical Implications
Timing Flexibility
The long half-life means injection timing is flexible:
- Same day each week: The time of day doesn't matter
- Can shift days: If needed, move injection day (wait at least 48 hours between doses)
- Forgiveness: Blood levels won't drop dramatically if you're a few hours late
If You Miss a Dose
The long half-life provides a safety buffer:
- Within 5 days: Take it as soon as you remember, then resume normal schedule
- More than 5 days late: Skip that dose, take next scheduled dose
- Drug still present: Even after missing a dose, significant drug remains from previous weeks
How Long Until It's Out of Your System?
If you stop taking semaglutide:
| Time After Last Dose | Drug Remaining |
|---|---|
| 1 week | ~50% |
| 2 weeks | ~25% |
| 3 weeks | ~12.5% |
| 4 weeks | ~6% |
| 5 weeks | ~3% |
| ~10 weeks | Essentially eliminated |
This gradual elimination explains why:
- Appetite returns gradually after stopping
- Side effects take weeks to fully resolve
- Surgery timing: FDA recommends stopping 1 week before; some surgeons prefer longer
- Pregnancy planning: Stop at least 2 months before conception
Tirzepatide: Similar But Different
Tirzepatide (Mounjaro/Zepbound) also achieves weekly dosing but with slightly different pharmacokinetics:
- Half-life: ~5 days (vs. 7 for semaglutide)
- Also uses: Fatty acid chain for albumin binding
- Dual action: Activates both GLP-1 and GIP receptors
- Steady state: ~4 weeks (similar to semaglutide)
Oral vs. Injectable: Different Absorption
Oral semaglutide (Rybelsus) has the same molecule but different pharmacokinetics:
| Property | Injectable | Oral |
|---|---|---|
| Bioavailability | ~89% | ~1% |
| Peak levels | 1-3 days after injection | 1 hour after dose |
| Food effect | None | Must take fasting |
| Half-life | ~7 days | ~7 days (same once absorbed) |
- Lau J, et al. Discovery of the Once-Weekly GLP-1 Analogue Semaglutide. J Med Chem. 2015.
- Kapitza C, et al. Semaglutide Pharmacokinetics. Clin Pharmacokinet. 2015.
- Marbury TC, et al. Pharmacokinetics of Semaglutide in Renal Impairment. Clin Pharmacokinet. 2017.
- Drucker DJ. Mechanisms of Action of GLP-1. Cell Metab. 2018.
- Nauck MA, Meier JJ. The Incretin Effect. Diabetologia. 2018.
- FDA. Ozempic Prescribing Information - Clinical Pharmacology. 2017, updated 2024.
- FDA. Wegovy Prescribing Information. 2021, updated 2024.
- FDA. Mounjaro Prescribing Information. 2022.
- FDA. Zepbound Prescribing Information. 2023.
- Coskun T, et al. Tirzepatide Pharmacology. Mol Metab. 2022.