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Semaglutide

Semaglutide

Ozempic Rybelsus Wegovy

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Updated: December 06, 2025

Overview

Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist developed for the treatment of type 2 diabetes mellitus and chronic weight management. It mimics the action of endogenous GLP-1, enhancing glucose-dependent insulin secretion, suppressing glucagon secretion, and slowing gastric emptying. Approved by the FDA in 2017, semaglutide has demonstrated significant benefits in glycemic control and weight reduction. It is available in both injectable (subcutaneous) and oral formulations, offering flexibility in administration. Clinical trials have also shown cardiovascular benefits in patients with established cardiovascular disease.

Drug Class

Glucagon-like peptide-1 (GLP-1) receptor agonist Therapeutic categories: • Antidiabetic agent • Anti-obesity medication

Mechanism of Action

Semaglutide binds to and activates the GLP-1 receptor, a membrane-bound cell surface receptor coupled to adenylyl cyclase via G proteins. This results in: • Increased intracellular cAMP in pancreatic beta cells, enhancing glucose-dependent insulin secretion • Suppression of glucagon secretion from pancreatic alpha cells • Slowed gastric emptying • Central nervous system effects promoting satiety and reducing appetite

Pharmacokinetics

Absorption: • Subcutaneous: Bioavailability ~89% • Oral (Rybelsus): Bioavailability ~0.4-1% (enhanced with absorption enhancers) Distribution: • Extensive tissue distribution • ~99% plasma protein bound Metabolism: • Proteolytic cleavage and sequential beta-oxidation • No significant hepatic metabolism Excretion: • Primarily via urine (3% unchanged) and feces Half-life: • ~7 days (allows once-weekly dosing)

Pharmacodynamics

Key physiological effects: • Dose-dependent reduction in HbA1c (1-2% decrease) • Progressive weight loss (5-15% body weight) • Delayed gastric emptying (effects diminish with chronic use) • Reduced postprandial glucose excursions • Potential cardiovascular benefits through weight loss and direct effects

Indications

• Type 2 diabetes mellitus: Adjunct to diet and exercise to improve glycemic control • Chronic weight management: For adults with BMI ≥30 kg/m² or ≥27 kg/m² with weight-related comorbidities (Wegovy) • Cardiovascular risk reduction: In adults with type 2 diabetes and established cardiovascular disease (Ozempic)

Contraindications

Absolute: • Personal or family history of medullary thyroid carcinoma (MTC) • Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) Relative: • History of pancreatitis • Severe gastrointestinal disease (e.g., gastroparesis) • Severe renal impairment (eGFR <30 mL/min/1.73m²)

Dosage & Administration

Type 2 diabetes (Ozempic): • Initial: 0.25 mg SC once weekly for 4 weeks • Maintenance: 0.5-2 mg SC once weekly Type 2 diabetes (Rybelsus): • Initial: 3 mg PO daily for 30 days • Maintenance: 7-14 mg PO daily Weight management (Wegovy): • Initial: 0.25 mg SC weekly for 4 weeks • Titrate monthly: 0.5 mg → 1 mg → 1.7 mg → 2.4 mg weekly

Special Populations

Pediatric: • Safety and effectiveness not established for weight management in pediatric patients Geriatric: • No dosage adjustment required Renal impairment: • No dose adjustment for mild to moderate impairment • Use caution in severe impairment Hepatic impairment: • No dose adjustment needed

Adverse Effects

Common (>10%): • Gastrointestinal: Nausea (15-20%), vomiting, diarrhea, constipation • Decreased appetite • Headache Serious (<1%): • Pancreatitis • Diabetic retinopathy complications • Acute kidney injury • Gallbladder disease • Thyroid C-cell tumors (in rodent studies)

Drug Interactions

• Insulin/insulin secretagogues: Increased risk of hypoglycemia (dose reduction may be needed) • Oral medications: May delay absorption of concurrently administered oral drugs • Warfarin: Potential for altered INR (monitor closely) • CYP450 substrates: Unlikely to cause significant interactions

Warnings & Precautions

• Boxed Warning: Thyroid C-cell tumors observed in rodent studies • Pancreatitis: Discontinue if suspected • Diabetic retinopathy: Monitor patients with history of retinopathy • Acute kidney injury: Monitor in patients with renal impairment • Hypersensitivity reactions: Including anaphylaxis and angioedema

Pregnancy & Lactation

Pregnancy: • Not recommended during pregnancy • Limited human data • FDA removed pregnancy categories; consider risks vs benefits Lactation: • Unknown if excreted in human milk • Consider risks vs benefits

Monitoring Parameters

• HbA1c (every 3-6 months) • Fasting plasma glucose • Body weight/BMI • Renal function • Thyroid nodules (baseline and periodic physical exams) • Signs of pancreatitis • Hypoglycemia in combination therapy

Patient Counseling

• Proper injection technique (if using SC formulation) • Take oral formulation on empty stomach with ≤4 oz water • Gradual dose escalation to minimize GI effects • Recognize symptoms of hypoglycemia • Importance of adherence to diet/exercise • Report persistent severe abdominal pain • Medication adherence for weekly dosing

Storage & Stability

• Unopened pens/vials: Refrigerate at 2-8°C (36-46°F) • In-use pens: May store at room temperature (≤30°C/86°F) for up to 56 days • Oral tablets: Store at room temperature • Protect from light and excessive heat

Clinical Pearls

• Start with low doses to minimize GI side effects • Weight loss effects may plateau after 12-16 weeks • Consider dose reduction if persistent GI intolerance occurs • More effective for weight loss than other GLP-1 RAs • May reduce cardiovascular events in high-risk patients • Oral formulation should be taken ≥30 minutes before first food/drink

References

• Davies M, et al. Semaglutide 2.4 mg once a week in adults with overweight or obesity. NEJM 2021;384:989-1002 • Marso SP, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. NEJM 2016;375:1834-44 • Ozempic Prescribing Information. Novo Nordisk. 2023 • Wegovy Prescribing Information. Novo Nordisk. 2023