Wegovy (Semaglutide 2.4 mg) for Obesity Management
Indications
Wegovy is FDA-approved for chronic weight management in adults with BMI ≥30 kg/m² (obesity) or BMI ≥27 kg/m² with at least one weight-related comorbidity such as hypertension, type 2 diabetes, or dyslipidemia. 1, 2 The medication must be used as an adjunct to a reduced-calorie diet (approximately 500 kcal daily deficit) and increased physical activity (minimum 150 minutes per week of moderate-intensity exercise). 1, 2
For patients with established cardiovascular disease and BMI ≥27 kg/m², Wegovy provides an additional indication: reducing the risk of cardiovascular death, myocardial infarction, and stroke, with a 20% relative risk reduction demonstrated in the SELECT trial. 2
Dosing Schedule
The titration protocol requires a 16-week escalation to minimize gastrointestinal adverse effects: 1, 2, 3
- Weeks 1–4: 0.25 mg subcutaneously once weekly
- Weeks 5–8: 0.5 mg once weekly
- Weeks 9–12: 1.0 mg once weekly
- Weeks 13–16: 1.7 mg once weekly
- Week 17 onward: 2.4 mg once weekly (maintenance dose)
Administer the injection subcutaneously in the abdomen, thigh, or upper arm on the same day each week, at any time of day, with or without meals. 2 Patients unable to tolerate the 2.4 mg dose may remain on 1.7 mg if this provides adequate benefit. 4
Missed-dose management: If ≤5 days have elapsed since the missed dose, administer as soon as possible and resume the regular schedule; if >5 days, skip the missed dose and give the next dose on the originally scheduled day. 2
Contraindications
Absolute contraindications: 1, 2
- Personal or family history of medullary thyroid carcinoma (MTC)
- Multiple endocrine neoplasia syndrome type 2 (MEN 2)
- Severe hypersensitivity reaction to semaglutide
These restrictions are based on animal studies demonstrating thyroid C-cell tumor formation with GLP-1 receptor agonists. 1, 2
- History of pancreatitis (causality not definitively established, but use with vigilance)
- Symptomatic gallbladder disease (Wegovy increases cholelithiasis and cholecystitis risk by approximately 38% versus placebo)
- Severe gastroparesis or clinically significant gastrointestinal motility disorders
Common Adverse Effects
Gastrointestinal symptoms dominate the adverse-event profile and are dose-dependent: 1, 2, 5
- Nausea: 18–44% of patients
- Diarrhea: 12–32%
- Vomiting: 8–25%
- Constipation: 10–23%
- Abdominal pain and bloating: common
These effects are typically mild-to-moderate, occur most frequently during dose escalation, and resolve within 4–8 weeks after reaching a new dose level. 1, 2 Slow titration over 16 weeks is the most effective strategy to mitigate gastrointestinal symptoms. 1, 2
Serious but rare adverse events: 1, 2
- Pancreatitis (reported in clinical trials; causality not proven)
- Gallbladder disease (cholelithiasis, cholecystitis)
- Acute kidney injury (secondary to dehydration from gastrointestinal effects)
Discontinuation rates: Approximately 34 more patients per 1,000 discontinue semaglutide versus placebo due to adverse events, primarily gastrointestinal. 2
Monitoring Recommendations
During titration (first 16 weeks): 2, 6, 3
- Assess every 4 weeks for gastrointestinal tolerance, weight loss progress, and blood pressure
- Monitor blood glucose closely in patients with type 2 diabetes, especially those on insulin or sulfonylureas, to prevent hypoglycemia
- Evaluate for signs of pancreatitis (persistent severe abdominal pain) or gallbladder disease (right-upper-quadrant pain with fever)
After reaching maintenance dose: 2, 6
- Reassess at least every 3 months for continued weight loss, cardiovascular risk factors, medication adherence, and adverse effects
- Monitor blood pressure as weight loss may necessitate antihypertensive medication adjustment
- Evaluate nutritional status to ensure adequate protein intake and prevent lean body mass loss
Treatment response evaluation: 1, 2
- Assess efficacy at 12–16 weeks on the maximum tolerated therapeutic dose
- Discontinue therapy if weight loss is <5% of initial body weight after 3 months at therapeutic dose, as early non-responders are unlikely to benefit from continued treatment
No routine laboratory monitoring is required for Wegovy in patients without diabetes, unlike SGLT2 inhibitors. 2 However, renal function should be monitored if gastrointestinal adverse effects cause dehydration. 2
Concomitant Medication Adjustments
For patients with type 2 diabetes: 2, 3
- Reduce basal insulin by approximately 20% when initiating Wegovy to prevent hypoglycemia
- Discontinue sulfonylureas or reduce dose by 50% before starting Wegovy due to additive hypoglycemia risk
- Stop all DPP-4 inhibitors (e.g., sitagliptin, linagliptin) as concurrent use provides no additional benefit
For patients on oral contraceptives: 3
- Wegovy may reduce oral contraceptive effectiveness due to delayed gastric emptying
- Add a barrier method for 4 weeks after initiation and each dose escalation, or switch to non-oral contraception
Expected Efficacy
Wegovy produces substantial and sustained weight loss: 1, 2, 5, 4
- Mean weight loss of 14.9–16.0% at 68 weeks in patients without diabetes (versus 2.4–5.7% with placebo)
- 64.9% of patients achieve ≥10% weight loss
- 38.5% achieve ≥20% weight loss
Real-world data from the WeGoTogether program demonstrate mean weight loss of 13.4% at 6 months, 17.6% at 12 months, and 20.4% at 24 months. 7 Weight loss is consistently greater in non-diabetic patients (6.1–17.4%) compared to those with diabetes (4.0–6.2%). 2
Cardiovascular benefits beyond weight loss: 2
- 26% reduction in major adverse cardiovascular events (cardiovascular death, nonfatal MI, nonfatal stroke) in patients with type 2 diabetes and established cardiovascular disease (HR 0.74; 95% CI 0.58–0.95)
- 20% reduction in the same composite outcome in patients with obesity and cardiovascular disease without diabetes (HR 0.80)
- Improvements in blood pressure, lipid profiles, inflammatory markers (C-reactive protein), and insulin sensitivity
Alternative Weight-Loss Medications
When Wegovy is unavailable, not tolerated, or provides inadequate response, consider these alternatives: 1, 2
Tirzepatide (Zepbound) 15 mg weekly
- Superior weight loss: 20.9% at 72 weeks (6% absolute advantage over semaglutide)
- Dual GIP/GLP-1 receptor agonist with broader cardiometabolic benefits
- Preferred when maximum weight loss is the primary goal (e.g., BMI >35 kg/m² with severe obesity-related complications)
- Similar adverse-event profile to semaglutide
- Cost: approximately $1,272 per 30-day supply
Liraglutide (Saxenda) 3.0 mg daily
- Mean weight loss of 5.2–6.1% at 56 weeks
- Daily subcutaneous injection (less convenient than weekly options)
- Reserved for patients requiring daily dosing or who cannot tolerate weekly injections
- Cost: approximately $1,619 per 30-day supply
Phentermine-topiramate ER (Qsymia)
- Mean weight loss of approximately 9% with the 15 mg/92 mg dose
- Contraindicated in patients with cardiovascular disease, uncontrolled hypertension, hyperthyroidism, or glaucoma
- Requires blood pressure monitoring every 2–4 weeks during titration
- Suggested when GLP-1 receptor agonists fail or are contraindicated
Naltrexone-bupropion ER (Contrave)
- Mean weight loss of 3.0% (modest efficacy)
- Concerning safety profile with potentially severe neuropsychiatric disorders
- Treatment discontinuation rates 129 more per 1,000 patients versus placebo
- Generally not prioritized due to inferior efficacy and safety compared to GLP-1 receptor agonists
Orlistat (Xenical, Alli)
- The AGA guideline suggests against the use of orlistat due to modest efficacy and poor tolerability
- Not recommended as a first-line option
Lifelong Treatment Requirement
Wegovy must be considered lifelong therapy to maintain weight loss. 2, 6 After discontinuation, patients regain approximately 50–67% of lost weight within 1 year, with reversal of cardiometabolic improvements. 2 Patients should be counseled that antiobesity medications must be used in conjunction with sustained lifestyle changes and may need to be used indefinitely. 2
Special Populations
Chronic kidney disease: No dose adjustment is required for any degree of renal impairment, including eGFR <30 mL/min/1.73 m² and end-stage renal disease. 2 Wegovy reduces albuminuria by 20.6% and slows eGFR decline. 2
Cardiovascular disease: Wegovy is specifically indicated for patients with established cardiovascular disease and BMI ≥27 kg/m² to reduce major adverse cardiovascular events. 2
Peri-operative management: Discontinue Wegovy at least 3 weeks (three half-lives) before elective surgery requiring anesthesia due to delayed gastric emptying and aspiration risk, even after extended fasting periods. 2
Cost Considerations
The average wholesale price for Wegovy is approximately $1,557–$1,619 per 30-day supply, with a National Average Drug Acquisition Cost (NADAC) of approximately $1,296. 2 Insurance authorization may be challenging, particularly for obesity management without diabetes. 2 Patients should explore patient assistance programs if they qualify. 3
Clinical Pitfalls to Avoid
- Do not initiate Wegovy at the maintenance dose (2.4 mg), as this markedly increases gastrointestinal adverse events and discontinuation rates; slow titration over 16 weeks is essential. 2
- Do not prescribe Wegovy to patients with personal or family history of medullary thyroid carcinoma or MEN 2—these are absolute contraindications. 1, 2
- Do not delay follow-up beyond 3 months in the maintenance phase, as this may miss treatment failure or adverse effects. 2, 6
- Do not wait longer than 3–4 months to assess initial treatment response; early non-responders (<5% weight loss after 3 months) are unlikely to benefit from continued therapy. 1, 2
- Do not overlook the need to reduce or discontinue sulfonylureas or insulin when starting Wegovy in patients with diabetes, as this significantly raises hypoglycemia risk. 2, 3