Introduction
Wegovy (semaglutide) is a glucagon-like peptide-1 (GLP-1) receptor agonist approved by the FDA in June 2021 for chronic weight management in adults with obesity or overweight with at least one weight-related comorbidity. It represents a significant advancement in pharmacotherapy for obesity, offering substantial weight loss potential when used alongside reduced-calorie diet and increased physical activity.
Mechanism of Action
Semaglutide is a GLP-1 analog that activates GLP-1 receptors, mimicking the effects of endogenous GLP-1. Its mechanisms include:
- Enhancing glucose-dependent insulin secretion
- Suppressing glucagon secretion
- Slowing gastric emptying
- Reducing appetite and food intake through central nervous system effects
- Promoting satiety via direct action on hypothalamic appetite centers
The drug's weight loss effects are primarily mediated through reduced caloric intake rather than increased energy expenditure.
Indications
Wegovy is indicated for chronic weight management in:
- Adults with obesity (BMI ≥30 kg/m²)
- Adults with overweight (BMI ≥27 kg/m²) who have at least one weight-related comorbidity (e.g., hypertension, type 2 diabetes mellitus, dyslipidemia)
It should be used as an adjunct to reduced-calorie diet and increased physical activity.
Dosage and Administration
Initial titration schedule:- Week 1-4: 0.25 mg once weekly
- Week 5-8: 0.5 mg once weekly
- Week 9-12: 1.0 mg once weekly
- Week 13-16: 1.7 mg once weekly
- Week 17+: 2.4 mg once weekly (maintenance dose)
- Subcutaneous injection in abdomen, thigh, or upper arm
- May be administered without regard to meals
- Rotate injection sites
- If a dose is missed, administer within 5 days of missed dose
- Renal impairment: No dosage adjustment needed
- Hepatic impairment: No dosage adjustment needed
- Elderly: No dosage adjustment needed
- Pediatrics: Safety and effectiveness not established
Pharmacokinetics
Absorption: Bioavailability ~89% following subcutaneous administration; Tmax: 1-3 days Distribution: Plasma protein binding: ~99%; Steady state reached after 4-5 weeks Metabolism: Proteolytic cleavage followed by beta-oxidation of the fatty acid sidechain Elimination: Half-life: ~7 days; primarily eliminated via urine and feces Excretion: Renal clearance: 3%; Fecal excretion: majority of eliminated materialContraindications
- Personal or family history of medullary thyroid carcinoma
- Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
- Known hypersensitivity to semaglutide or any product components
- Pregnancy
Warnings and Precautions
Boxed Warning: Risk of thyroid C-cell tumors (based on rodent studies; human relevance unknown) Pancreatitis: Discontinue promptly if suspected Hypoglycemia: Increased risk when used with insulin secretagogues or insulin Acute kidney injury: Monitor renal function in patients reporting severe gastrointestinal reactions Diabetic retinopathy: Monitor patients with history of diabetic retinopathy Acute gallbladder disease: Has been reported in clinical trials Suicidal behavior and ideation: Monitor for emergence or worsening of depression or suicidal thoughtsDrug Interactions
Significant interactions:- Insulin and insulin secretagogues: Increased risk of hypoglycemia (may require dose reduction)
- Oral medications: Delayed gastric emptying may affect absorption of orally administered drugs
- Warfarin: Monitor INR more frequently during initiation and titration
- CYP450 substrates: Semaglutide does not inhibit or induce major CYP enzymes
Adverse Effects
Very common (≥10%):- Nausea (44%)
- Diarrhea (30%)
- Vomiting (24%)
- Constipation (24%)
- Abdominal pain (20%)
- Headache (14%)
- Fatigue (11%)
- Dyspepsia (10%)
- Dizziness (10%)
- Abdominal distension (10%)
- Eructation (10%)
- Hypoglycemia (in patients with type 2 diabetes)
- Pancreatitis
- Acute gallbladder disease
- Acute kidney injury
- Hypersensitivity reactions
- Increased heart rate
Monitoring Parameters
Baseline:- BMI calculation
- Thyroid function (calcitonin if indicated)
- Renal function
- Pancreatic enzymes (if symptoms develop)
- HbA1c (if diabetic)
- Lipid profile
- Blood pressure
- Weight and BMI at regular intervals
- Gastrointestinal symptoms
- Signs of pancreatitis
- Renal function in patients with gastrointestinal adverse reactions
- Blood glucose (especially with concomitant diabetes medications)
- Depression screening
- Gallbladder symptoms
Patient Education
Key points:- Administer once weekly on the same day each week
- Proper injection technique and site rotation
- Common gastrointestinal side effects usually diminish over time
- Report severe abdominal pain that may radiate to the back (pancreatitis)
- Monitor for symptoms of hypoglycemia if taking other diabetes medications
- Importance of concomitant lifestyle modifications
- Potential for drug interactions with oral medications
- Storage requirements: Refrigerate; may be kept at room temperature for up to 28 days
- Pregnancy prevention: Use effective contraception during treatment
- Report any symptoms of thyroid tumors (neck mass, dysphagia, dyspnea, persistent hoarseness)
References
1. FDA Prescribing Information: Wegovy (semaglutide) injection. 2021 2. Wilding JPH, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021;384:989-1002 3. Rubino D, et al. Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity. JAMA. 2021;325(14):1414-1425 4. Davies M, et al. Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet. 2021;397(10278):971-984 5. American Association of Clinical Endocrinology Consensus Statement. Endocr Pract. 2022;28(10):1-35 6. Product Monograph: Wegovy. Novo Nordisk Canada Inc. 2022