What are the key considerations and facts to know when prescribing GLP-1 (Glucagon-like peptide-1) medications, such as liraglutide (Victoza) or semaglutide (Ozempic), to a patient with type 2 diabetes or obesity?

Key Considerations for GLP-1 Medications

Primary Indications and Patient Selection

GLP-1 receptor agonists should be prescribed for adults with type 2 diabetes who have established cardiovascular disease or are at high cardiovascular risk, and for obesity management in patients with BMI ≥30 kg/m² or BMI ≥27 kg/m² with weight-related comorbidities. 1, 2

For Type 2 Diabetes:

• Prioritize GLP-1 RAs when patients have established atherosclerotic cardiovascular disease (ASCVD), heart failure with preserved ejection fraction (HFpEF), or chronic kidney disease 1
• Consider when patients have end-organ damage (left ventricular hypertrophy, retinopathy) or multiple CV risk factors (age, hypertension, smoking, dyslipidemia, obesity) 1
• Use irrespective of need for additional glucose lowering and irrespective of baseline A1C 1

For Obesity Management:

• BMI ≥30 kg/m² qualifies without additional requirements 1, 2
• BMI ≥27 kg/m² requires at least one weight-related comorbidity (hypertension, dyslipidemia, obstructive sleep apnea, cardiovascular disease) 1, 2
• Must be combined with reduced-calorie diet and minimum 150 minutes/week physical activity 1, 2

Medication Selection Algorithm

Choose tirzepatide 15mg weekly as first-line for maximum weight loss (20.9% at 72 weeks), but prioritize semaglutide 2.4mg weekly for patients with established cardiovascular disease due to proven 20% reduction in cardiovascular death, nonfatal MI, or stroke. 2

Tirzepatide (Dual GIP/GLP-1 Agonist):

• Superior weight loss: 20.9% at 72 weeks with 15mg dose 2
• Greater HbA1c reduction: 1.87-2.24% 2
• Better cardiometabolic improvements: waist circumference, triglycerides, fasting glucose 2
• Cost: ~$1,272-$1,283 per 30-day supply 2

Semaglutide 2.4mg Weekly (Wegovy):

• Weight loss: 14.9% at 68 weeks, with 64.9% achieving ≥10% loss 2
• Proven cardiovascular benefit: HR 0.74 (95% CI 0.58-0.95) for CV death/MI/stroke in SUSTAIN-6 2
• 20% reduction in cardiovascular events in SELECT trial (HR 0.80) 1, 2
• Cost: ~$1,619 per 30-day supply 1

Liraglutide 3.0mg Daily (Saxenda):

• Weight loss: 5.2-6.1% 2
• Consider when weekly injections not tolerated 2
• Cost: ~$1,619 per 30-day supply 1

Absolute Contraindications

Never prescribe GLP-1 RAs to patients with personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 (MEN2). 1, 2, 3

Additional contraindications:

• Severe hypersensitivity to semaglutide or any ingredient 3
• Type 1 diabetes or diabetic ketoacidosis 3

Dosing and Titration

Semaglutide 2.4mg Titration Schedule:

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

Tirzepatide Titration Schedule:

• Start: 5mg weekly 2
• Increase by 2.5mg every 4 weeks based on tolerance 2
• Maximum: 15mg weekly 2

Slow titration minimizes gastrointestinal side effects, which occur in 53% of patients but are typically mild-to-moderate and transient. 2

Critical Medication Adjustments

When Starting with Insulin or Sulfonylureas:

• Reduce basal insulin by 20% immediately to prevent hypoglycemia 2
• Discontinue or reduce sulfonylurea doses by 50% 2
• Monitor glucose daily for first 2 weeks 2

Medications to Discontinue:

• Stop DPP-4 inhibitors before initiating GLP-1 RAs 2
• Never combine two GLP-1 receptor agonists simultaneously 2

Common and Serious Adverse Effects

Gastrointestinal (Most Common):

• Nausea: 17-44% of patients 2
• Diarrhea: 12-32% 2
• Vomiting: 7-25% 2
• Constipation: 10-23% 2
• Management: slow titration, reduce meal size, limit alcohol and carbonated beverages 2

Serious but Rare:

• Pancreatitis: Discontinue immediately if persistent severe abdominal pain occurs 1, 3
• Gallbladder disease (cholelithiasis, cholecystitis) 1, 2
• Acute kidney injury: Monitor renal function, especially with severe GI symptoms 3
• Diabetic retinopathy complications: Monitor patients with history 3

Cardiovascular and Metabolic Benefits

GLP-1 RAs provide cardioprotection through multiple mechanisms beyond weight loss: improved myocardial substrate utilization, anti-inflammatory effects, reduced ischemia injury, and improved lipid profiles. 2

Specific Benefits:

• Semaglutide reduces HFpEF symptoms: 13.7-point improvement in Kansas City Cardiomyopathy Questionnaire vs 6.4 points with placebo 1
• Reduces albuminuria and slows eGFR decline in CKD 2
• No dose adjustment needed across all CKD stages, including eGFR <30 mL/min/1.73 m² 2
• Improves blood pressure, requiring antihypertensive adjustment monitoring 2

Perioperative Management

Discontinue semaglutide/tirzepatide at least 3 weeks (three half-lives) before elective surgery due to delayed gastric emptying and aspiration risk, even with extended fasting. 2

• Liraglutide: hold 3 days before surgery 2
• Retained gastric contents documented in 24.2% of semaglutide users vs 5.1% controls despite 10-14 day discontinuation and 12-hour fasting 2
• Consider gastric ultrasound pre-operatively 2

Monitoring Schedule

Initial Titration Phase (First 16 weeks):

• Every 4 weeks: assess GI tolerance, weight loss progress, blood pressure 2
• Monitor for pancreatitis, gallbladder symptoms 2

Maintenance Phase:

• Every 3 months minimum: weight, blood pressure, cardiovascular risk factors, medication adherence 2
• Evaluate efficacy at 12-16 weeks on maximum tolerated dose 2
• Discontinue if <5% weight loss after 3 months at therapeutic dose 2

Long-Term Treatment Considerations

GLP-1 RAs require lifelong treatment to maintain benefits—sudden discontinuation results in regain of one-half to two-thirds of lost weight within 1 year. 2

Weight Regain After Stopping:

• Semaglutide: 11.6% of lost weight regained after 52 weeks 2
• Patients must understand this is chronic disease management, not short-term therapy 2

Cost and Access:

• Average wholesale price: $1,272-$1,619 per 30-day supply 1, 2
• Insurance authorization often challenging, especially for obesity without diabetes 2
• Payors should cover evidence-based obesity treatments to reduce barriers 2

Special Populations

Chronic Kidney Disease:

• No dose adjustment required for semaglutide, liraglutide, or tirzepatide across all CKD stages 2
• Preferred over other agents due to renal benefits and low hypoglycemia risk 2

Pregnancy and Breastfeeding:

• Stop semaglutide 2 months before planned pregnancy 3
• Unknown if passes into breast milk—discuss feeding options with provider 3

Women on Oral Contraceptives (Tirzepatide):

• Switch to non-oral methods or add barrier contraception for 4 weeks after initiation and each dose escalation 2

Common Pitfalls to Avoid

1. Failing to reduce insulin/sulfonylureas when initiating—leads to hypoglycemia 2
2. Not counseling patients about lifelong treatment necessity—leads to disappointment with weight regain 2
3. Advancing dose too quickly—increases GI side effects and discontinuation 2
4. Ignoring perioperative aspiration risk—can cause serious complications 2
5. Waiting too long to assess treatment response—early non-responders unlikely to benefit 2
6. Combining two GLP-1 RAs—pharmacologically redundant and potentially harmful 2