What are the guidelines for initiating semaglutide (glucagon-like peptide-1 receptor agonist) for weight management in an adult patient with central obesity and comorbidities such as hypertension, diabetes, or dyslipidemia?

Semaglutide Initiation for Central Obesity

For an adult patient with central obesity and comorbidities such as hypertension, diabetes, or dyslipidemia, initiate semaglutide 2.4 mg weekly (Wegovy) if BMI ≥27 kg/m² with at least one weight-related comorbidity, starting at 0.25 mg weekly and titrating upward every 4 weeks to the maintenance dose of 2.4 mg. 1, 2, 3

Patient Eligibility Criteria

BMI Requirements:

• BMI ≥30 kg/m² qualifies for treatment without additional requirements 1, 2
• BMI ≥27 kg/m² with at least one weight-related comorbidity (hypertension, type 2 diabetes, or dyslipidemia) qualifies for treatment 1, 2, 4

Absolute Contraindications:

• Personal or family history of medullary thyroid cancer 1, 2
• Multiple endocrine neoplasia syndrome type 2 (MEN2) 1, 2
• History of severe hypersensitivity reaction to semaglutide 1

Pre-Treatment Screening

Required Laboratory Testing:

• Comprehensive metabolic panel including renal function (eGFR) and liver enzymes 1
• Lipid panel (total cholesterol, LDL, HDL, triglycerides) to assess baseline cardiovascular risk 1
• HbA1c and fasting glucose if diabetes is present or suspected 1
• Thyroid function testing to rule out medullary thyroid cancer risk 1

Clinical Assessment:

• Screen for history of pancreatitis (use with caution if present, though causality not definitively established) 1
• Evaluate for gastroparesis or severe gastrointestinal motility disorders 1
• Document cardiovascular disease status, as this influences treatment selection 1

Dosing and Titration Schedule

Standard Titration Protocol (16-week escalation to maintenance): 2, 3

• Weeks 1-4: 0.25 mg subcutaneously once weekly 2, 3
• Weeks 5-8: 0.5 mg once weekly 2, 3
• Weeks 9-12: 1.0 mg once weekly 2, 3
• Weeks 13-16: 1.7 mg once weekly 2
• Week 17 onward: 2.4 mg once weekly (maintenance dose) 2

Administration Details:

• Inject subcutaneously in the abdomen, thigh, or upper arm 3
• Administer at any time of day, with or without meals 3
• If a dose is missed, administer within 5 days of the missed dose 3
• If 2 consecutive doses are missed, resume at the same dose if previously tolerated 1
• If 3 or more consecutive doses are missed, consider restarting the titration schedule 1

Concomitant Medication Adjustments

For Patients with Type 2 Diabetes:

• Reduce basal insulin by 20% when initiating semaglutide to prevent hypoglycemia 1
• Discontinue or reduce sulfonylurea doses by 50% to prevent hypoglycemia 1
• Discontinue DPP-4 inhibitors before starting semaglutide (no additional benefit with concurrent use) 1, 2
• Do not combine with other GLP-1 receptor agonists (pharmacologically redundant and potentially harmful) 1, 2

For Patients on Antihypertensives:

• Monitor blood pressure closely as weight loss progresses, as antihypertensive medication requirements may decrease 1

Required Lifestyle Interventions

Semaglutide must be combined with the following lifestyle modifications: 1, 2

• Caloric deficit: 500-kcal reduction below daily requirements 1, 2
• Physical activity: Minimum 150 minutes per week 1, 2
• Resistance training: To preserve lean body mass during weight loss 1, 2

Monitoring Schedule

During Titration Phase (Weeks 1-16):

• Assess every 4 weeks for gastrointestinal tolerance, weight loss progress, and blood pressure 1, 2
• Monitor for signs of pancreatitis (persistent severe abdominal pain) and gallbladder disease 1, 2

After Reaching Maintenance Dose:

• Assess at least every 3 months for continued weight loss progress, cardiovascular risk factors, and medication adherence 1, 2
• Evaluate efficacy at 12-16 weeks on maximum tolerated dose: If weight loss is <5% after 3 months, discontinue and consider alternative approaches 1, 2

Expected Outcomes

Weight Loss Efficacy:

• Mean weight loss of 14.9% at 68 weeks compared to 2.4% with placebo 1, 5
• 86.4% of patients achieve ≥5% weight loss 5
• 69.1% achieve ≥10% weight loss 5
• 50.5% achieve ≥15% weight loss 5

Cardiovascular Benefits:

• 20% reduction in cardiovascular death, nonfatal MI, or nonfatal stroke (HR 0.80) in patients with established cardiovascular disease and BMI ≥27 1

Adverse Effects and Management

Most Common Adverse Events (Gastrointestinal):

• Nausea, vomiting, diarrhea, and constipation are the most frequently reported side effects 1, 6, 7
• These are typically transient, mild-to-moderate in severity, and subside with time 1, 5, 7
• Slow titration minimizes gastrointestinal side effects 1, 2

Mitigation Strategies:

• Reduce meal size 1
• Limit alcohol and carbonated beverages 1
• Reassure patients that symptoms typically decrease over time with continued exposure 1

Serious but Rare Risks:

• Pancreatitis (monitor for persistent severe abdominal pain) 1, 2
• Gallbladder disease (cholelithiasis, cholecystitis) 1, 2
• Acute kidney injury 1

Treatment Discontinuation:

• 4.5% of patients discontinue due to gastrointestinal events compared to 0.8% with placebo 5

Special Considerations

Renal Impairment:

• No dose adjustment required for any degree of renal impairment, including end-stage renal disease 1

Perioperative Management:

• Discontinue semaglutide at least 3 weeks (three half-lives) before elective surgery due to delayed gastric emptying and aspiration risk 1, 2
• Retained gastric contents documented even after extended fasting periods 1

Long-Term Treatment:

• Semaglutide requires lifelong use to maintain weight loss 1, 2
• Discontinuation results in regain of 50-67% of lost weight within 1 year 1, 2

Common Pitfalls to Avoid

• Do not skip the gradual titration schedule, as this significantly increases gastrointestinal side effects 1, 2
• Do not combine with other GLP-1 receptor agonists or DPP-4 inhibitors 2
• Do not ignore perioperative aspiration risk from delayed gastric emptying 1, 2
• Do not prescribe in patients with personal or family history of medullary thyroid cancer or MEN2 1, 2
• Do not delay follow-up beyond 3 months to assess treatment response 1, 2