How is semaglutide, a 31 amino acid peptide, absorbed when ingested orally?

Oral Semaglutide Absorption Mechanism

Oral semaglutide is absorbed through the stomach wall using a specialized co-formulation with the absorption enhancer SNAC (sodium N-(8-[2-hydroxybenzoyl] amino) caprylate), which facilitates transcellular absorption of this large peptide molecule across the gastric epithelium. 1, 2

The Challenge of Peptide Absorption

• Peptides like semaglutide (31 amino acids) are normally degraded rapidly in the gastrointestinal tract and cannot cross the intestinal barrier effectively due to their large molecular size and hydrophilic nature 3
• The standard route for GLP-1 receptor agonists has been subcutaneous injection precisely because oral administration of unmodified peptides results in negligible bioavailability 1, 2

SNAC Technology: The Key to Oral Absorption

• SNAC is a small fatty acid derivative that is co-formulated with oral semaglutide in a 1:300 ratio (semaglutide:SNAC) to enable gastric absorption 3
• SNAC works through two primary mechanisms:
  • Local buffering effect: Creates a protective microenvironment in the stomach that raises pH locally, reducing enzymatic degradation of semaglutide 3
  • Enhanced transcellular absorption: Facilitates the transport of semaglutide across gastric epithelial cells through transient and reversible changes in membrane fluidity 3

Absorption Characteristics

• Absorption occurs primarily in the stomach, not the small intestine, which is why specific dosing instructions are critical 1, 2
• Patients must take oral semaglutide on an empty stomach with no more than 120 mL (4 oz) of water, then wait 30 minutes before eating or drinking anything else 3
• This strict administration protocol is necessary because food, beverages, or other oral medications significantly reduce semaglutide absorption by interfering with the SNAC mechanism 3

Pharmacokinetic Profile

• Despite the absorption enhancement, oral semaglutide has much lower bioavailability (approximately 1%) compared to subcutaneous administration 3
• To compensate for lower bioavailability, oral semaglutide is dosed at 14 mg daily to achieve plasma concentrations comparable to subcutaneous semaglutide 1.0 mg weekly 2
• Plasma exposure levels, not route of administration, determine clinical efficacy—nearly identical exposure-response relationships exist for oral versus subcutaneous semaglutide for HbA1c reduction, weight loss, and adverse events 4

Clinical Equivalence Despite Different Routes

• At therapeutic doses, oral semaglutide (14 mg daily) achieves non-inferior glycemic control compared to subcutaneous liraglutide 1.8 mg daily, with estimated HbA1c reductions of -1.58% versus -1.62% respectively at 6 months 2, 4
• Weight loss is actually superior with oral semaglutide compared to subcutaneous liraglutide (-4.4 kg vs -3.1 kg at 26 weeks) 2
• The gastrointestinal side effect profile is similar between oral and subcutaneous formulations when plasma concentrations are equivalent 4

Important Caveats

• Body weight is the most important variable affecting semaglutide exposure for both formulations—higher body weight reduces drug exposure 4
• The complex dosing requirements for oral semaglutide (empty stomach, limited water, 30-minute wait) may reduce adherence compared to once-weekly subcutaneous injection 3
• Oral semaglutide demonstrated cardiovascular non-inferiority to placebo in the PIONEER-6 trial, though this was a shorter trial than the cardiovascular outcome studies for subcutaneous semaglutide 5