Also known as: Ozempic · Wegovy · Rybelsus · NNC0113-0217
| Parameter | SC (Ozempic / Wegovy) | Oral (Rybelsus) |
|---|---|---|
| Half-life (t½) | ~7 days (168 h) | ~1 hour |
| Tmax | 1–3 days | ~1 hour |
| Bioavailability | ~89% | ~1% (fasted, water only) |
| Steady-state | 4–5 weeks (once-weekly) | ~5 days (daily) |
| Protein binding | >99% (albumin) | >99% (albumin) |
| Clearance | Proteolysis + minor renal | Proteolysis + hepatic |
| 5 half-lives (SC) | ~35 days | ~5 hours (oral) |
| Dosing frequency | Once weekly | Once daily |
| Data Quality | Human RCT — FDA NDA 209637, NDA 213051, NDA 213182 | |
Semaglutide is a GLP-1 (glucagon-like peptide-1) receptor agonist that shares 94% amino acid sequence homology with endogenous human GLP-1 1–37.[1] It was engineered by Novo Nordisk from liraglutide's backbone through three key structural changes: (1) substitution of alanine with α-aminoisobutyric acid (Aib) at position 8 to resist DPP-4 cleavage, (2) attachment of a C18 fatty diacid side chain at lysine-26 via a two-unit miniPEG spacer enabling high-affinity, reversible albumin binding, and (3) substitution of arginine-34 with lysine to allow site-specific acylation.[1]
These structural modifications collectively extend the plasma half-life from GLP-1's native ~2 minutes to approximately 7 days in SC-administered semaglutide — long enough for once-weekly injection. Oral semaglutide (Rybelsus) contains the same peptide formulated with the absorption enhancer SNAC, but the different delivery mechanism and hepatic first-pass effect yield a much shorter effective plasma half-life of approximately 1 hour.[3]
FDA approved Ozempic (SC, type 2 diabetes) in December 2017 (NDA 209637), Wegovy (SC, obesity) in June 2021 (NDA 213051), and Rybelsus (oral, type 2 diabetes) in September 2019 (NDA 213182).[1][2][3]
Semaglutide binds and activates the GLP-1 receptor (GLP-1R), a class B G-protein coupled receptor expressed on pancreatic beta cells, hypothalamic neurons, gastric parietal cells, and cardiac myocytes. Receptor activation stimulates cyclic AMP production, leading to glucose-dependent insulin secretion, suppression of glucagon, delayed gastric emptying, and activation of hypothalamic satiety centers via the vagus nerve.[1]
The C18 fatty diacid chain at Lys-26 binds non-covalently to serum albumin in the plasma compartment. Albumin has a plasma half-life of approximately 19 days partly through FcRn (neonatal Fc receptor) recycling — semaglutide hijacks this mechanism to achieve its ~7-day half-life. The miniPEG linker separates the fatty acid from the peptide backbone, preserving GLP-1R binding affinity while maximizing albumin association.[1]
Unmodified GLP-1 is rapidly cleaved at position 2 (Ala→Pro) by dipeptidyl peptidase-4 (DPP-4), giving a native half-life of ~2 minutes. The Aib8 substitution in semaglutide creates steric hindrance that prevents DPP-4 binding, eliminating this primary clearance pathway. Semaglutide is instead eliminated predominantly through proteolytic degradation distributed across multiple tissues (no single organ dominates clearance), with minor renal excretion of metabolite fragments. This distributed clearance mechanism contributes to the absence of clinically meaningful renal or hepatic dose adjustment requirements at approved doses.[1]
Log semaglutide doses, visualize plasma concentration curves based on the 7-day half-life, and track clinical endpoints — all in one place. Built for weekly injectables.
Download Free — iOSMost sources report only plasma half-life. Understanding the full PK picture requires separating three distinct timescales — this is Halflife Labs' core differentiator:
| Layer | Metric | Value (SC) | Source |
|---|---|---|---|
| Layer 1 | Plasma half-life | ~7 days (168 h) | FDA NDA 209637 |
| Layer 2 | Time to near-complete clearance | ~35 days (5 × t½) | Derived from NDA PK data |
| Layer 3 | Biological effect duration | GI effects may persist beyond plasma levels; appetite suppression correlates with receptor occupancy, not just plasma concentration | FDA NDA 209637; clinical observation |
Plasma half-life ≠ effect duration. GLP-1R in the enteric nervous system and hypothalamus may maintain functional responses at lower plasma concentrations than peak. This is why dose reduction (not cessation) is often the first step when GI side effects occur — partial receptor occupancy may provide benefit with reduced GI burden.
| Parameter | SC Semaglutide (Ozempic/Wegovy) | Oral Semaglutide (Rybelsus) |
|---|---|---|
| Half-life | ~7 days | ~1 hour |
| Bioavailability | ~89% | ~1% (fasted) |
| Tmax | 1–3 days | ~1 hour |
| Dosing frequency | Once weekly | Once daily |
| Absorption mechanism | Direct SC absorption → lymphatics → systemic | SNAC raises local gastric pH; transcellular absorption across gastric epithelium |
| Effect of food | Not significant | Food markedly reduces absorption; water volume >4 oz reduces absorption |
| Maximum approved dose | 2.4 mg/week (Wegovy obesity) | 14 mg/day (Rybelsus T2D) |
| FDA indications | T2D (Ozempic), obesity (Wegovy) | T2D only (Rybelsus) |
The SNAC mechanism (sodium N-[8-(2-hydroxybenzoyl)amino] caprylate) works by two actions: it transiently elevates gastric pH immediately around the tablet, protecting semaglutide from acid degradation, and it acts as a permeation enhancer facilitating transcellular absorption through gastric epithelial cells. This is why the tablet must dissolve in a small volume of water — sufficient SNAC concentration at the gastric wall is required for absorption enhancement to occur.[3]
After the last subcutaneous dose, plasma concentration declines logarithmically. Using a half-life of 7 days:
| Time After Last Dose | Half-lives Elapsed | Approx. % Remaining | Clinical Note |
|---|---|---|---|
| 7 days | 1 | ~50% | Missed-week level |
| 14 days | 2 | ~25% | Significant drop; GI effects typically diminishing |
| 21 days | 3 | ~12.5% | Appetite suppression weakening in most patients |
| 28 days | 4 | ~6% | Near-baseline hunger returning for many |
| 35 days | 5 | ~3% | Pharmacologically negligible; near-complete clearance |
| Route | Bioavailability | Published Human Data? |
|---|---|---|
| Subcutaneous injection (abdomen, thigh, upper arm) | ~89% | Yes — FDA NDA 209637, NDA 213051 |
| Oral tablet (Rybelsus) | ~1% (fasted) | Yes — FDA NDA 213182 |
| Intramuscular | No published data | No |
| Intravenous (investigational only) | 100% by definition; not approved route | Pharmacokinetic studies only; not for clinical use |
With once-weekly SC dosing, semaglutide accumulates approximately 3-fold before reaching steady-state concentrations at weeks 4–5. This accumulation ratio is predictable from the 7-day half-life and 7-day dosing interval. The accumulation factor = 1 / (1 − e−0.693 × τ/t½) ≈ 3.07, where τ is the dosing interval (7 days) and t½ is 7 days.[1]
This 3-fold accumulation is clinically meaningful: patients beginning at 0.25 mg/week may experience equivalent systemic exposure to ~0.75 mg/week after 4–5 weeks. This is the pharmacokinetic basis for the step-up dosing schedule — starting low limits peak concentration overshoot while the drug accumulates to steady state.
| Compound | Mechanism | Half-life | Max Approved Dose | Route |
|---|---|---|---|---|
| Semaglutide | GLP-1R agonist | ~7 days | 2.4 mg/week (Wegovy) | SC / Oral |
| Tirzepatide | GIP/GLP-1R dual agonist | ~5 days | 15 mg/week (Zepbound) | SC |
| Liraglutide | GLP-1R agonist | ~13 hours | 3 mg/day (Saxenda) | SC |
| Retatrutide | GLP-1R / GIPR / GCGR triple agonist | ~6 days (Phase 2 data) | Not yet approved | SC |
The Halflife app calculates your projected plasma levels, dose accumulation to steady state, and clearance timeline after stopping — based on published FDA PK data.
Get the App — FreeSemaglutide carries a boxed warning for thyroid C-cell tumors based on rodent data; human risk is uncertain. Common adverse effects include nausea, vomiting, diarrhea, and constipation — these are GI and generally dose-dependent and transient. Serious but less common adverse effects include pancreatitis, gallbladder disease (cholelithiasis, cholecystitis), diabetic retinopathy complications (in T2D patients with pre-existing retinopathy and rapid glucose lowering), and acute kidney injury (often secondary to dehydration from GI effects). Risk of hypoglycemia is low when used without concomitant insulin or sulfonylureas. Source: FDA prescribing information, Ozempic and Wegovy.