Semaglutide - Drug Monograph

Introduction

Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist approved for the treatment of type 2 diabetes mellitus and chronic weight management. As a once-weekly subcutaneous injection or daily oral formulation, it represents a significant advancement in metabolic disease management with demonstrated cardiovascular benefits in appropriate patient populations.

Mechanism of Action

Semaglutide acts as a GLP-1 receptor agonist that enhances glucose-dependent insulin secretion, suppresses inappropriate glucagon secretion, slows gastric emptying, and reduces appetite through central nervous system effects. It mimics the action of endogenous GLP-1 but is resistant to degradation by dipeptidyl peptidase-4 (DPP-4), resulting in an extended half-life suitable for once-weekly administration.

Indications

• Type 2 Diabetes Mellitus: As an adjunct to diet and exercise to improve glycemic control
• Chronic Weight Management: For adults with obesity (BMI ≥30 kg/m²) or overweight (BMI ≥27 kg/m²) with at least one weight-related comorbidity
• Cardiovascular Risk Reduction: To reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes and established cardiovascular disease

Dosage and Administration

• Type 2 Diabetes: Initiate at 0.25 mg once weekly for 4 weeks, then increase to 0.5 mg once weekly. May further increase to 1 mg or 2 mg once weekly based on glycemic response
• Weight Management: Initiate at 0.25 mg once weekly for 4 weeks, titrate monthly to target maintenance dose of 2.4 mg once weekly

• Initiate at 3 mg once daily for 30 days, then increase to 7 mg once daily. May further increase to 14 mg once daily if needed

• Administer subcutaneous injections on the same day each week
• Oral formulation must be taken on an empty stomach with no more than 4 ounces of water at least 30 minutes before food, beverage, or other medications
• Rotate injection sites (abdomen, thigh, or upper arm)

Pharmacokinetics

• Absorption: Subcutaneous bioavailability ~89%; Oral bioavailability ~1-2% (enhanced with absorption enhancer)
• Distribution: Volume of distribution ~12.4 L; >99% plasma protein bound
• Metabolism: Proteolytic cleavage and beta-oxidation without specific cytochrome P450 involvement
• Elimination: Half-life ~1 week; renal elimination (3% unchanged)
• Time to Peak: Subcutaneous: 1-3 days; Oral: 1 hour

Contraindications

• Personal or family history of medullary thyroid carcinoma
• Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
• History of hypersensitivity to semaglutide or any product components
• Pregnancy (based on animal data showing fetal harm)

Warnings and Precautions

• Pancreatitis: Discontinue if suspected
• Diabetic Retinopathy: Monitor patients with history of retinopathy
• Hypoglycemia: Increased risk when used with insulin or insulin secretagogues
• Acute Kidney Injury: Monitor renal function in patients reporting severe gastrointestinal reactions
• Acute Gallbladder Disease: Increased risk observed in clinical trials
• Suicidal Behavior and Ideation: Monitor for emergence or worsening of depression

Drug Interactions

• Insulin and Insulin Secretagogues: May increase hypoglycemia risk (consider dose reduction)
• Oral Medications: Delayed gastric emptying may affect absorption of concomitantly administered oral drugs
• Warfarin: Monitor INR more frequently during initiation and titration
• Drugs with Narrow Therapeutic Index: Requires careful monitoring due to potential altered absorption

Adverse Effects

• Gastrointestinal: Nausea (20-44%), vomiting (9-24%), diarrhea (15-30%), constipation (10-20%)
• Other: Headache, fatigue, dyspepsia, dizziness

• Pancreatitis (1.0-1.5%)
• Cholelithiasis (1.5%)
• Acute kidney injury (0.5%)
• Hypersensitivity reactions
• Diabetic retinopathy complications

Monitoring Parameters

• Glycemic Control: HbA1c every 3 months until stable
• Weight: Regular monitoring
• Renal Function: Serum creatinine at baseline and as clinically indicated
• Pancreatitis Symptoms: Monitor for persistent severe abdominal pain
• Thyroid Nodules: Baseline neck examination, monitor for symptoms
• Depression and Suicidal Ideation: Regular mental health assessment
• Cardiovascular Status: Blood pressure, heart rate monitoring

Patient Education

• Proper injection technique and rotation of injection sites
• Oral formulation administration requirements (empty stomach, timing)
• Recognition and management of hypoglycemia symptoms
• Importance of gradual dose titration to minimize gastrointestinal effects
• Need to report persistent severe abdominal pain, depression, or suicidal thoughts
• Continued adherence to dietary and exercise recommendations
• Importance of regular follow-up and monitoring
• Pregnancy prevention and planning

References

1. FDA Prescribing Information: Ozempic® (semaglutide) injection 2. FDA Prescribing Information: Rybelsus® (oral semaglutide) 3. FDA Prescribing Information: Wegovy® (semaglutide) injection 4. Marso SP, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016;375:1834-1844 5. Wilding JPH, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021;384:989-1002 6. Davies M, et al. Efficacy and Safety of Semaglutide Compared with Liraglutide and Placebo for Weight Loss. JAMA. 2021;325(14):1403-1413 7. Aroda VR, et al. Comparative Efficacy and Safety of Once-Weekly Semaglutide Versus Once-Daily Sitagliptin as Add-on to Metformin in Patients with Type 2 Diabetes. Diabetes Obes Metab. 2018;20(3):610-619