COMPOUND

Compounds / GLP-1 agonists

Semaglutide (Oral)

Oral Semaglutide (Rybelsus / Wegovy pill)

GLP-1 agonists Oral FDA approved

First oral GLP-1 receptor agonist. Co-formulated with the absorption enhancer SNAC (salcaprozate sodium) to enable peptide absorption across gastric mucosa. Approved as Rybelsus for T2D (2019) and CV risk reduction (2025); approved as Wegovy pill at 25 mg for chronic weight management (Dec 22, 2025): the first oral GLP-1 for obesity.

At a glance

Half-life
~7 days ~1 week elimination half-life, independent of route. Drug present in circulation ~5 weeks after last dose. Steady state in 4-5 weeks of daily dosing.
Routes
Oral
Evidence base
2 studies 2 human

Mechanism

GLP-1 analogue (94% sequence homology to native GLP-1) co-formulated with salcaprozate sodium (SNAC) which acts locally in the stomach to transiently raise pH and chaperone semaglutide across gastric epithelium. Once absorbed, mechanism is identical to SC semaglutide: glucose-dependent insulin secretion, glucagon suppression, delayed gastric emptying, and hypothalamic appetite center modulation. Albumin binding (>99%) protects from renal clearance and DPP-4 degradation, yielding a ~1-week elimination half-life identical to SC. OASIS 4: 25mg -13.6% vs -2.2% placebo at 64 weeks. PIONEER 6: MACE non-inferior to placebo in T2D with high CV risk.

Dosing

Any amounts shown here are reported from published studies only. 2 of 2 catalogued studies involved human subjects. COMPOUND does not publish its own dosing guidance.

Where a study reports an amount, it appears in that study's entry below, attributed to the source.

Published evidence

  1. Human RCT 2025

    Oral Semaglutide at a Dose of 25 mg in Adults with Overweight or Obesity (OASIS 4)

    Garvey WT, Frias JP, Jastreboff AM, et al. NEJM

    n=307, 71-week RCT; primary endpoint at week 64: oral semaglutide 25mg -13.6% vs placebo -2.2% (p<0.001). Significantly more participants achieved ≥20% weight loss vs placebo. GI AEs 74% vs 42%.

    PMID 40934115

  2. Human RCT 2019

    Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes (PIONEER 6)

    Husain M, Birkenfeld AL, Donsmark M, et al. NEJM

    PIONEER 6 (n=3,183 T2D, mean 15.9 mo): MACE non-inferior to placebo (HR 0.79, 95% CI 0.57-1.11).

    PMID 31185157

Reported side effects

Nausea
Very common Moderate · Rybelsus 14mg: 20% vs placebo 6%. OASIS 4 (25mg): GI events 74% vs 42% placebo. Dose-dependent; peaks in escalation; mostly resolves.
Abdominal pain
Common Moderate · 11% at 14mg vs 4% placebo (Rybelsus PI Table 2).
Diarrhea
Common Mild · 10% at 14mg vs 4% placebo.
Decreased appetite
Common Mild · 9% at 14mg vs 1% placebo. The wanted effect for weight loss; can become problematic if it leads to dehydration/AKI.
Vomiting
Common Moderate · 8% at 14mg vs 3% placebo.
Constipation
Common Mild · 5-6% at therapeutic doses vs 2% placebo. Longest duration of GI AEs.
Pancreatitis
Rare Serious · 0.1 events per 100 patient-years vs <0.1 placebo. The Rybelsus label directs discontinuation if pancreatitis is suspected.
Diabetic retinopathy complications
Occasional Serious · 4.2% vs 3.8% comparator. Monitor patients with prior retinopathy.
Cholelithiasis
Occasional Moderate · 1% at 7mg in placebo-controlled trials.
Acute kidney injury
Rare Serious · Volume-depletion mediated. Higher risk in renal impairment + GI dehydration.
Hypoglycemia (with sulfonylurea/insulin)
Common Serious · Rybelsus + insulin: 26-30% plasma glucose <54 mg/dL over 52 weeks vs 32% placebo.
Thyroid C-cell tumors
Rare Serious · BOXED WARNING. Rodent carcinogenicity; human relevance unknown. Contraindicated with personal/family hx of MTC or MEN-2.

Interactions

  • Levothyroxine Absorption interference

    Levothyroxine and oral semaglutide both require empty-stomach dosing with water alone. Cannot be taken at the same time. Levothyroxine AUC increased 33% when co-administered.

  • Oral medications (general) Absorption interference

    Oral semaglutide affects absorption of co-administered oral drugs via gastric emptying delay AND requires a 30-minute fast after dosing.

  • Insulin or sulfonylurea Synergy

    Increased risk of hypoglycemia, including severe hypoglycemia.

  • Semaglutide (SC) Redundant

    Same active ingredient (semaglutide) via different routes, producing additive systemic exposure. Co-administration not recommended.

Storage

Store at 68-77°F (20-25°C). Keep tablets in original blister until immediately before use to protect from moisture (SNAC is hygroscopic).