What is Rybelsus (semaglutide), a glucagon-like peptide-1 (GLP-1) receptor agonist?

Rybelsus (Semaglutide): An Oral GLP-1 Receptor Agonist

Rybelsus is the first FDA-approved oral glucagon-like peptide-1 (GLP-1) receptor agonist for the treatment of type 2 diabetes, offering an injectable-free alternative with effective glycemic control and weight reduction benefits. 1

Mechanism of Action

Rybelsus contains semaglutide, a GLP-1 analog with 94% sequence homology to human GLP-1 that:

• Selectively binds to and activates the GLP-1 receptor 2
• Stimulates insulin secretion and lowers glucagon secretion in a glucose-dependent manner 2
• Causes a minor delay in gastric emptying in the early postprandial phase 2
• Has a long half-life due to albumin binding, which results in decreased renal clearance and protection from metabolic degradation 2
• Is stabilized against degradation by the DPP-4 enzyme 2

Unique Oral Formulation

Rybelsus overcomes the challenge of oral peptide delivery through:

• Co-formulation with sodium N-(8-[2-hydroxybenzoyl]amino) caprylate (SNAC), an absorption enhancer 3
• SNAC facilitates semaglutide absorption across the gastric epithelium 4
• Absolute bioavailability of 89% when taken properly 2

Clinical Effects

Rybelsus demonstrates significant benefits for patients with type 2 diabetes:

• Reduces fasting and postprandial glucose concentrations 2
• Decreases HbA1c by approximately 1.0-1.1 percentage points compared to 0.1-0.2 percentage points with placebo 5
• Promotes weight loss of approximately 3.4-3.7 kg compared to 0.9-1.1 kg with placebo 5
• Increases both first- and second-phase insulin secretion 2
• Lowers fasting and postprandial glucagon concentrations 2

Dosing and Administration

For optimal absorption and effectiveness:

• Available in three doses: 3 mg, 7 mg, and 14 mg tablets 4
• Should be taken at least 30 minutes before the first food, beverage, or other oral medications of the day 1
• Requires gradual dose titration to minimize gastrointestinal side effects 4
• For patients fasting during Ramadan, experts recommend titrating to at least 7 mg approximately 2-3 weeks before Ramadan and dosing at Iftaar (breaking of fast) 6

Safety Profile

Common adverse effects and considerations:

• Gastrointestinal side effects are most common, particularly nausea, vomiting, diarrhea, and dyspepsia 6
• Low risk of hypoglycemia when used as monotherapy 1
• No dose adjustment required for patients with renal impairment, including end-stage renal disease 2
• No dose adjustment required for patients with hepatic impairment 2
• Does not prolong QTc intervals to any clinically relevant extent 2

Special Populations

Important considerations for specific patient groups:

• Effective in patients with moderate renal impairment (eGFR 30-59 mL/min per 1.73 m²) 5
• Should be discontinued at least 2 months before a planned pregnancy due to the long washout period 2
• Safety and efficacy have not been established in pediatric patients 2
• No overall differences in safety or efficacy were detected in geriatric patients, though greater sensitivity in some older individuals cannot be ruled out 2

Clinical Applications

Rybelsus is indicated for:

• Monotherapy in patients intolerant to metformin when diet and exercise do not provide adequate glycemic control 1
• Add-on combination therapy with other glucose-lowering agents, including insulin 1

The availability of an oral GLP-1 receptor agonist represents a significant advancement in diabetes management, potentially allowing earlier use of this class of medications in the treatment cascade due to wider acceptance from patients who prefer oral medications over injections 1.