What is the algorithm for using GLP-1 (Glucagon-Like Peptide-1) receptor agonists, such as liraglutide (Saxenda) (liraglutide) or semaglutide (Wegovy) (semaglutide), for weight management?

GLP-1 Weight Management Algorithm

Patient Selection and Eligibility

Initiate GLP-1 receptor agonists for chronic weight management in adults with BMI ≥30 kg/m² (obesity) or BMI ≥27 kg/m² with at least one weight-related comorbidity (hypertension, type 2 diabetes, dyslipidemia, obstructive sleep apnea, or cardiovascular disease). 1, 2

Pre-Treatment Requirements

• Document 3-6 months of failed lifestyle modification attempts (reduced-calorie diet, increased physical activity, behavioral interventions) with insufficient weight loss 2
• Review all current medications and minimize those promoting weight gain (e.g., replace mirtazapine or amitriptyline with alternative antidepressants) 1
• Obtain baseline laboratory testing: lipid panel (total cholesterol, LDL, HDL, triglycerides), HbA1c if diabetes suspected, liver function tests, and thyroid function 1

Absolute Contraindications

• Personal or family history of medullary thyroid cancer 1, 2, 3, 4
• Multiple endocrine neoplasia syndrome type 2 1, 2, 3, 4

Relative Cautions

• History of pancreatitis (use with caution, monitor closely) 1, 3
• Severe gastroparesis or gastrointestinal motility disorders 1
• Recent heart failure decompensation 3
• Gallbladder disease history (increased risk of cholelithiasis/cholecystitis) 1, 2

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Medication Selection Algorithm

First-Line Choice: Tirzepatide (Zepbound)

Prioritize tirzepatide 15mg weekly as the first-line agent due to superior weight loss (20.9% at 72 weeks) and greatest cardiometabolic benefits. 1, 2

Dosing Schedule:

• Start: 5mg subcutaneously once weekly 1, 2
• Titrate upward every 4 weeks based on tolerance 1
• Target: 10mg or 15mg weekly (maximum dose) 1, 2

Expected Outcomes:

• 8-12% weight loss at 6 months 3
• 20.9% weight loss at 72 weeks with 15mg dose 1, 2
• Superior triglyceride reduction, waist circumference reduction, and fasting glucose control compared to semaglutide 1

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Second-Line Choice: Semaglutide 2.4mg (Wegovy)

Use semaglutide 2.4mg weekly if tirzepatide is unavailable, not tolerated, or if the patient has established cardiovascular disease (proven cardiovascular benefit with 20% reduction in composite CV events). 1, 2

Dosing Schedule:

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

Expected Outcomes:

• 10-12% weight loss at 6 months 3
• 14.9% weight loss at 68 weeks 1, 2, 5
• 64.9% of patients achieve ≥10% total body weight loss 1

Cardiovascular Advantage:

• 20% reduction (HR 0.80) in composite cardiovascular death, nonfatal MI, or nonfatal stroke in patients with obesity and established CVD 1, 2
• Prioritize in patients with pre-existing cardiovascular disease 1, 2

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Third-Line Choice: Liraglutide 3.0mg (Saxenda)

Reserve liraglutide 3.0mg daily for patients who cannot tolerate weekly injections or strongly prefer daily dosing, recognizing lower efficacy. 2, 3

Dosing Schedule:

• Week 1: 0.6mg subcutaneously daily 2
• Week 2: 1.2mg daily 2
• Week 3: 1.8mg daily 2
• Week 4: 2.4mg daily 2
• Week 5+: 3.0mg daily (maintenance dose) 2

Expected Outcomes:

• 4-6% weight loss at 6 months 3
• 5.24-6.1% mean weight loss overall 2, 6

Discontinuation Rule:

• If patient has not lost at least 4% of body weight after 16 weeks at maximum dose, discontinue medication 3

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Special Population Considerations

Patients with Type 2 Diabetes and Obesity

Prioritize tirzepatide or semaglutide 2.4mg over lower-dose formulations due to greater HbA1c reduction and cardiovascular risk reduction. 1

• Tirzepatide reduces HbA1c by 1.87-2.24%, with 23.0-62.4% achieving HbA1c <5.7% 1
• Semaglutide reduces HbA1c by 1.48% compared to placebo 1
• Weight loss is consistently lower in diabetic patients (4-6.2%) compared to non-diabetic patients (6.1-17.4%) 1, 3
• Minimal hypoglycemia risk when used as monotherapy due to glucose-dependent mechanism 1
• Caution when combining with insulin or insulin secretagogues (increased hypoglycemia risk) 1

Patients with Established Cardiovascular Disease

Select semaglutide 2.4mg over tirzepatide due to proven cardiovascular outcome benefits (26% reduction in composite CV events, HR 0.74). 1, 2

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

Patients with Renal Impairment

• No dose adjustment required for semaglutide in any degree of renal impairment, including end-stage renal disease 4
• Use caution in patients who experience dehydration (risk of acute renal failure) 7

Patients with Hepatic Impairment

• No dose adjustment required for semaglutide or liraglutide 4, 7
• Use with caution due to limited experience 7

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Monitoring Schedule and Follow-Up

Initial Phase (First 16 Weeks)

• Assess every 3 months for weight loss progress, cardiovascular risk factors, and medication adherence 1
• Monitor for gastrointestinal side effects, particularly during dose escalation 1
• Evaluate efficacy at 12-16 weeks on maximum tolerated therapeutic dose 1

Maintenance Phase

• Continue assessments every 3 months 1
• Monitor blood pressure and adjust antihypertensive medications as needed 1
• Watch for signs of pancreatitis (persistent severe abdominal pain) 1, 2
• Monitor for gallbladder disease symptoms (right upper quadrant pain, nausea after fatty meals) 1, 2
• Check nutritional status and thyroid function periodically 1

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Managing Gastrointestinal Side Effects

Gastrointestinal symptoms (nausea, vomiting, diarrhea, constipation) occur in 17-40% of patients but are typically mild-to-moderate and transient. 1, 3

Mitigation Strategies:

• Slow titration minimizes symptoms (follow dosing schedules precisely) 1, 3
• Reduce meal size 1
• Limit alcohol and carbonated drinks 1
• Eat slowly and stop when comfortably full 1

Discontinuation rates due to adverse events: 34 more per 1000 patients with semaglutide compared to placebo. 1

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Treatment Intensification for Inadequate Response

If inadequate weight loss at maximum tolerated dose after 12-16 weeks, consider:

• Adding structured lifestyle management programs 1
• Referral for metabolic/bariatric surgery (especially if BMI >35 kg/m²) 1, 3
• Do NOT combine GLP-1 receptor agonists (pharmacologically redundant and potentially harmful) 1

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Perioperative Management

GLP-1 receptor agonists cause delayed gastric emptying, creating aspiration risk during anesthesia even with extended fasting. 1

• Retained gastric contents documented in 24.2% of semaglutide users versus 5.1% of controls, despite 10-14 day discontinuation and 12-hour fasting 1
• Discuss perioperative management with anesthesia team well in advance 1
• Consider extended medication discontinuation (timing varies by agent and procedure) 1

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Long-Term Use and Weight Maintenance

Counsel patients that GLP-1 receptor agonists must be used lifelong in conjunction with lifestyle changes; significant weight regain occurs after cessation (11.6% of lost weight regained after 52 weeks of stopping semaglutide). 1, 2

• Combine with reduced-calorie diet and increased physical activity throughout treatment 1, 2
• Include resistance training to preserve lean body mass 1
• Steady-state exposure achieved after 4-5 weeks of once-weekly administration 4
• Semaglutide remains in circulation for approximately 5 weeks after last dose (half-life ~1 week) 4

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Cost and Insurance Authorization

Average wholesale prices: ~$1,300-$1,600 per month without insurance. 1

• Insurance typically requires documentation of 3-6 months of failed lifestyle modifications 2
• Authorization may be more challenging for obesity management without diabetes 1
• Tirzepatide faces more authorization barriers despite superior efficacy 1

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Common Pitfalls to Avoid

• Do not use oral semaglutide for weight management (FDA-approved only for type 2 diabetes; less potent than injectable formulations) 1, 3
• Do not combine semaglutide with other GLP-1 receptor agonists or DPP-4 inhibitors (overlapping mechanisms) 1
• Do not use lower-dose semaglutide formulations (Ozempic 1mg) for weight management when higher-dose formulation (Wegovy 2.4mg) is indicated 1
• Do not restart at same dose if 3+ consecutive doses missed; consider restarting titration schedule 1
• Do not ignore gastrointestinal symptoms; inadequate titration delays maximum effectiveness 3