What is the proper protocol for using Glucagon-like peptide-1 (GLP1) agonists, such as liraglutide (Victoza) or semaglutide (Wegovy), for weight loss?

GLP-1 Agonist Protocol for Weight Loss

Primary Medication Selection

For weight loss in patients without diabetes, prioritize tirzepatide 15mg weekly as first-line therapy, achieving superior weight loss of 20.9% compared to semaglutide 2.4mg weekly (14.9%) and liraglutide 3.0mg daily (5.24-6.1%). 1

Medication Hierarchy for Weight Loss

• First choice: Tirzepatide (Zepbound) - Demonstrates greatest weight loss (20.9% at 72 weeks) with superior cardiometabolic benefits including greater waist circumference reduction, triglyceride reduction, and fasting glucose control 1
• Second choice: Semaglutide 2.4mg weekly (Wegovy) - Produces 14.9-17.4% weight loss at 68 weeks, with proven cardiovascular benefits (20% reduction in cardiovascular death, nonfatal MI, or stroke) in patients with established cardiovascular disease 1, 2
• Third choice: Liraglutide 3.0mg daily (Saxenda) - FDA-approved since 2014 for weight management, achieving 5.24-6.1% weight loss, but requires daily injections 1, 3

Patient Eligibility Criteria

Initiate GLP-1 agonists in patients with BMI ≥30 kg/m² or BMI ≥27 kg/m² with at least one weight-related comorbidity (hypertension, dyslipidemia, obstructive sleep apnea, cardiovascular disease). 1

Pre-Initiation Screening Requirements

• Absolute contraindications to identify:

  • Personal or family history of medullary thyroid cancer 1, 2
  • Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) 1, 2
  • Serious hypersensitivity to the medication 2

• Baseline assessments:

  • Lipid panel (total cholesterol, LDL, HDL, triglycerides) to assess cardiovascular risk 1
  • Screen for gastroparesis or severe gastrointestinal motility disorders, as these medications delay gastric emptying and may worsen symptoms 1
  • Evaluate for history of pancreatitis (use with caution, not absolute contraindication) 1
  • Document symptoms of nausea, vomiting, or abdominal distention 4
  • Assess concomitant medications that delay gastric emptying (opioids, proton pump inhibitors, tricyclic antidepressants) 4

Dosing and Titration Protocols

Tirzepatide (Zepbound) Dosing

Start at 5mg subcutaneously weekly, titrate upward every 4 weeks based on tolerance to maximum dose of 15mg weekly. 1

• Week 0-4: 5mg weekly
• Week 5-8: 10mg weekly (if tolerated)
• Week 9+: 15mg weekly (maintenance dose) 1

Semaglutide 2.4mg (Wegovy) Dosing

Start at 0.25mg weekly for 4 weeks, then increase by 0.25-0.5mg increments every 4 weeks until reaching 2.4mg weekly maintenance dose after 16 weeks. 1

• Week 0-4: 0.25mg weekly
• Week 5-8: 0.5mg weekly
• Week 9-12: 1.0mg weekly
• Week 13-16: 1.7mg weekly
• Week 17+: 2.4mg weekly (maintenance) 1

Liraglutide 3.0mg (Saxenda) Dosing

Start at 0.6mg daily subcutaneously for 1 week, increase by 0.6mg weekly until reaching 3.0mg daily maintenance dose. 3, 2

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

Discontinue liraglutide if patient has not achieved at least 4% weight loss after 16 weeks at the 3.0mg dose. 3

Administration Instructions

• Inject subcutaneously in abdomen, thigh, or upper arm at any time of day, independently of meals 2
• Rotate injection sites within the same region to reduce risk of cutaneous amyloidosis 2
• Inspect solution before each injection - only use if clear, colorless, and contains no particles 2
• Never share pens between patients, even if needle is changed 2

Missed Dose Management

• If 1-2 doses missed: Resume at same dose with next scheduled injection 1
• If 3+ consecutive doses missed: Consider restarting titration schedule to mitigate gastrointestinal symptoms 1, 2

Mandatory Lifestyle Interventions

GLP-1 agonists must be combined with reduced-calorie diet and increased physical activity - medications alone are insufficient and require lifelong use to maintain weight loss. 1, 5

Specific Lifestyle Requirements

• Resistance training is critical to preserve lean body mass, as GLP-1 agonists cause muscle loss alongside fat loss 1, 5
• Reduced-calorie eating pattern with focus on adequate protein intake to prevent nutritional deficiencies 5
• Monitor for nutrient deficiencies due to reduced calorie intake, particularly protein, vitamins, and minerals 5
• Address emotional triggers and disordered eating patterns before or during initiation 5

Gastrointestinal Side Effect Management

Nausea, vomiting, and diarrhea occur in 17-40% of patients, are dose-dependent, typically mild-to-moderate, and decrease over time. 1

Mitigation Strategies

• Slow titration is essential - the gradual dose escalation schedules above specifically minimize GI symptoms 1, 2
• Dietary modifications: Small, frequent meals; avoid high-fat foods; clear liquid diet during acute symptoms 5
• Pharmacologic management: Consider metoclopramide or erythromycin as prokinetic agents if symptoms persist 4
• Most GI effects resolve within 4-8 weeks of reaching stable dose 1

Serious Adverse Events Requiring Monitoring

Pancreatitis Risk

Monitor for persistent severe abdominal pain radiating to the back, with or without vomiting - discontinue immediately if pancreatitis suspected. 1, 2

• Pancreatitis reported in clinical trials but causality not definitively established 1
• Use with caution in patients with history of pancreatitis 1

Gallbladder Disease

Monitor for symptoms of cholelithiasis or cholecystitis - obtain gallbladder studies if suspected. 1, 2

• Increased risk of gallbladder disease including cholelithiasis and cholecystitis 1

Delayed Gastric Emptying

All GLP-1 agonists cause delayed gastric emptying that persists with chronic use, creating aspiration risk during anesthesia. 4, 3

• Scintigraphy studies show delayed gastric emptying even after 12-20 weeks of continuous use 4
• May affect absorption of oral medications with narrow therapeutic indices 1

Peri-Operative Management

For patients taking GLP-1 agonists for weight loss, hold medication for at least three half-lives before elective procedures (approximately 3 weeks for semaglutide, 1 week for liraglutide). 4

Pre-Operative Protocol

• Document: Indication, dose, date commenced, last dose taken, symptoms of nausea/vomiting/distention 4
• For weight loss indication: Hold for three half-lives to clear approximately 88% of drug 4
• Consider point-of-care gastric ultrasound to assess residual gastric contents if unable to hold medication adequately 4
• Use rapid-sequence intubation in high-risk patients to reduce aspiration risk 4

Cardiovascular Benefits

Semaglutide 2.4mg reduces cardiovascular death, nonfatal MI, or nonfatal stroke by 20% (HR 0.80) in patients with obesity and established cardiovascular disease. 1

• This cardiovascular benefit makes semaglutide the preferred choice over tirzepatide in patients with pre-existing cardiovascular disease 1
• Monitor blood pressure closely as weight loss progresses - antihypertensive medication requirements may decrease 1

Weight Maintenance and Long-Term Use

After cessation of semaglutide, significant weight regain occurs (11.6% of lost weight regained after 52 weeks), necessitating lifelong use. 1

• Counsel patients that these medications require indefinite continuation to maintain weight loss 1
• Real-world weight loss is modestly lower than clinical trials (2.2% at 72 weeks with standard diabetes doses) 6
• Only one-third of patients achieve ≥5% weight loss at 72 weeks in real-world settings with standard doses 6

Cost and Insurance Considerations

Average wholesale prices are approximately $1,272-$1,600 per month, with Medicare currently excluding coverage for obesity diagnosis alone. 1, 3

• Tirzepatide faces more authorization barriers than semaglutide 1
• Global shortages of GLP-1 receptor agonists currently exist 3
• Insurance coverage may be restricted to FDA-approved indications 3

Monitoring Requirements During Treatment

• Blood pressure - adjust antihypertensives as weight decreases 1
• Signs of pancreatitis - persistent severe abdominal pain 1
• Gallbladder symptoms - right upper quadrant pain, nausea after fatty meals 1
• Nutritional status - protein intake, vitamin/mineral deficiencies 5
• Body composition - muscle mass preservation through resistance training 5
• Gastrointestinal symptoms - particularly during dose escalation 1

Treatment Intensification

If inadequate response at maximum doses, consider adding metabolic surgery or additional pharmacologic agents rather than continuing ineffective monotherapy. 1