How do you prescribe GLP-1 (Glucagon-like peptide-1) receptor agonists, such as liraglutide (Victoza) or semaglutide (Ozempic), to a patient with type 2 diabetes mellitus and potential comorbidities like cardiovascular disease or impaired renal function?

How to Prescribe GLP-1 Receptor Agonists

Patient Selection and Eligibility

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 at least one weight-related comorbidity. 1, 2

Primary Indications:

• Type 2 diabetes with established ASCVD – Prioritize GLP-1 RAs irrespective of baseline A1C or need for additional glucose lowering 1
• Type 2 diabetes with chronic kidney disease (eGFR ≥15 mL/min/1.73 m²) – No dose adjustment required across all CKD stages 3, 4
• Obesity management – BMI ≥30 kg/m² without additional requirements, or BMI ≥27 kg/m² with comorbidities (hypertension, dyslipidemia, cardiovascular disease) 2
• Heart failure with preserved ejection fraction – Consider for symptom improvement 1

Absolute Contraindications:

• Personal or family history of medullary thyroid carcinoma 5, 3
• Multiple endocrine neoplasia syndrome type 2 (MEN2) 5, 3
• History of severe hypersensitivity reaction to the specific GLP-1 RA 5

Relative Cautions:

• History of pancreatitis – Use with caution, though causality not definitively established 1
• Severe gastroparesis or clinically meaningful GI motility disorders 1
• Recent heart failure decompensation – Wait until clinical stability 4
• History of proliferative diabetic retinopathy (caution with semaglutide or dulaglutide) 1

Agent Selection Algorithm

Choose semaglutide 2.4mg weekly for patients with established cardiovascular disease requiring proven cardiovascular benefit, with a 20% reduction in cardiovascular death, nonfatal MI, or nonfatal stroke (HR 0.80). 2

Decision Tree:

1. If established cardiovascular disease is present:

   • First choice: Semaglutide 2.4mg weekly (Wegovy) – proven 26% MACE reduction (HR 0.74) 2, 3
   • Alternative: Liraglutide 1.8mg daily – also has cardiovascular benefit 3, 4

2. If maximum weight loss is the primary goal:

   • First choice: Tirzepatide 15mg weekly – achieves 20.9% weight loss at 72 weeks 2
   • Second choice: Semaglutide 2.4mg weekly – achieves 14.9% weight loss at 68 weeks 2
   • Third choice: Liraglutide 3.0mg daily – achieves 5.2-6.1% weight loss 2

3. If chronic kidney disease is present (eGFR <60 mL/min/1.73 m²):

   • Prioritize semaglutide, liraglutide, or dulaglutide – no dose adjustment required and MACE reduction greater in CKD patients 3, 4
   • Avoid exenatide once-weekly if eGFR <45 mL/min/1.73 m² 1

4. If patient refuses injections:

   • Oral semaglutide 14mg daily – less potent for weight loss but provides meaningful HbA1c reduction (~1.4%) 2

Dosing and Titration Protocols

Semaglutide (Injectable) Titration Schedule:

Start semaglutide at 0.25mg subcutaneously once weekly for exactly 4 weeks to minimize gastrointestinal side effects, then follow the standard escalation schedule. 3, 5

• Weeks 1-4: 0.25mg weekly 3, 5
• Weeks 5-8: 0.5mg weekly (standard maintenance dose for diabetes) 3
• Weeks 9-12: 1.0mg weekly (if additional glycemic control needed) 3, 5
• Weeks 13-16: 1.7mg weekly (for obesity management) 2
• Week 17+: 2.4mg weekly (maximum dose for obesity/cardiovascular benefit) 2, 3

Tirzepatide Titration Schedule:

Start tirzepatide at 5mg weekly and escalate every 4 weeks based on tolerance to maximize efficacy. 2

• Weeks 1-4: 5mg weekly 2
• Weeks 5-8: 10mg weekly 2
• Weeks 9+: 15mg weekly (maximum dose) 2

Liraglutide Dosing:

• Start at 0.6mg daily for 1 week 3
• Increase to 1.2mg daily 3
• Maximum: 1.8mg daily (for diabetes) or 3.0mg daily (for obesity) 2, 3

Pre-Treatment Screening and Baseline Assessment

Before initiating GLP-1 RA therapy, screen for absolute contraindications and obtain baseline metabolic parameters. 2

Required Screening:

• Personal and family history of medullary thyroid cancer or MEN2 5, 3
• History of pancreatitis – use with caution if present 1
• Baseline HbA1c and fasting glucose 2
• Comprehensive metabolic panel including eGFR and liver enzymes 2
• Lipid panel (total cholesterol, LDL, HDL, triglycerides) 2
• Blood pressure 2
• Current medication review – identify weight-promoting medications and insulin secretagogues 2

Document:

• History of gastroparesis or severe GI motility disorders 1
• History of diabetic retinopathy (caution with semaglutide) 1, 5
• Recent heart failure decompensation 4

Concomitant Medication Adjustments

When initiating GLP-1 RAs with insulin or sulfonylureas, reduce these medications immediately to prevent hypoglycemia. 1, 3

Insulin Adjustments:

• Reduce basal insulin by 20% when starting GLP-1 RA 1, 3
• For patients with HbA1c <8%, consider more aggressive 30% reduction 2
• Strongly consider discontinuing prandial insulin entirely or reduce each dose by 50% 2

Sulfonylurea Adjustments:

• Discontinue or reduce sulfonylurea dose by 50% when initiating GLP-1 RA 1, 2

Other Medications:

• Discontinue DPP-4 inhibitors before starting GLP-1 RA – no additional benefit from combination 2
• Do not combine with other GLP-1 RAs – overlapping mechanisms create redundancy and potential harm 2
• Oral contraceptives: Women should switch to non-oral methods or add barrier contraception for 4 weeks after initiation and each dose escalation (tirzepatide) 2

Administration Instructions

Administer GLP-1 RAs subcutaneously once weekly at any time of day, with or without meals, rotating injection sites. 5, 6

Injection Technique:

• Injection sites: Abdomen, thigh, or upper arm 5
• Rotate sites with each injection 5
• Once weekly agents: Can be given any day of the week, same day each week 5, 6
• Daily agents (liraglutide): Same time each day 6

Missed Dose Protocol:

• If ≤4 days since missed dose: Administer as soon as possible 2
• If >4 days since missed dose: Skip and resume at next scheduled dose 2
• If 2 consecutive doses missed: Resume at same dose if previously tolerated 2
• If ≥3 consecutive doses missed: Consider restarting titration schedule 1, 2

Monitoring Schedule

Monitor patients every 4 weeks during titration phase, then every 3 months after reaching maintenance dose. 2

During Titration (First 3-4 Months):

• Every 4 weeks: 2
  • Weight and blood pressure 2
  • Gastrointestinal tolerance and adverse effects 2
  • Signs of pancreatitis (persistent severe abdominal pain) 2
  • Signs of gallbladder disease 2
  • Home glucose monitoring (especially if on insulin/sulfonylureas) 1

Maintenance Phase (After Reaching Target Dose):

• Every 3 months minimum: 2
  • Weight stability 2
  • HbA1c (for diabetes patients) 2
  • Blood pressure 2
  • Cardiovascular risk factors 2
  • Medication adherence 2
  • Adverse effects 2

Critical Decision Points:

• At 12-16 weeks: Evaluate treatment efficacy 2
  • If weight loss <5% at therapeutic dose: Consider discontinuation and alternative approaches 2
  • If HbA1c not at goal after 3 months at maximum tolerated dose: Consider adding or intensifying other glucose-lowering medications 2

Patient Education and Counseling

Counsel patients that GLP-1 RAs must be used lifelong in conjunction with lifestyle modifications, as discontinuation results in regain of one-half to two-thirds of lost weight within 1 year. 2

Essential Counseling Points:

1. Gastrointestinal Effects:

   • Nausea occurs in 17-44% of patients, typically mild-to-moderate and transient 2
   • Symptoms usually decrease over time with continued exposure 2
   • Mitigation strategies: slow titration, reduce meal size, limit alcohol and carbonated beverages 2

2. Hypoglycemia Prevention (if on insulin/sulfonylureas):

   • Instruct patients to monitor glucose more closely for first 4 weeks 1
   • Do not skip meals 2
   • Carry quick-acting carbohydrates (15-20g glucose tablets) 2
   • Recognize symptoms: shakiness, sweating, confusion 2

3. Warning Signs Requiring Immediate Medical Attention:

   • Pancreatitis: Persistent severe abdominal pain 2, 5
   • Gallbladder disease: Right upper quadrant pain, nausea, vomiting 2
   • Acute kidney injury: Decreased urine output, severe dehydration 5

4. Lifestyle Requirements:

   • Diet: 500-kcal reduction below daily requirements 2
   • Physical activity: Minimum 150 minutes/week 2
   • Resistance training: To preserve lean body mass 2

5. Long-Term Expectations:

   • Medication must be used lifelong to maintain benefits 2
   • Weight regain occurs rapidly after discontinuation 2
   • Cost: approximately $1,272-$1,619 per month 2

Perioperative Management

For elective surgery requiring anesthesia, discontinue semaglutide or tirzepatide at least 3 weeks before surgery due to delayed gastric emptying and aspiration risk. 2

Preoperative Discontinuation:

• Semaglutide/tirzepatide: Hold for 3 weeks (three half-lives) 2
• Liraglutide: Hold for 3 days 2
• For diabetic patients: Consult endocrinology to weigh risks/benefits and consider bridging therapy 2
• Consider gastric ultrasound pre-operatively to assess residual gastric contents 2

Special Populations

Chronic Kidney Disease:

• No dose adjustment required for semaglutide, liraglutide, or dulaglutide across all CKD stages, including eGFR <30 mL/min/1.73 m² 3, 4
• MACE reduction greater in patients with eGFR <60 mL/min/1.73 m² 3, 4
• Avoid exenatide once-weekly if eGFR <45 mL/min/1.73 m² 1

Elderly Patients:

• Low intrinsic hypoglycemia risk makes GLP-1 RAs particularly appropriate for elderly patients 4
• HbA1c target: <7.5-8.0% acceptable for elderly with long-standing or complicated disease 4
• Monitor more vigilantly for dehydration from GI side effects 2

Cardiovascular Disease:

• Prioritize agents with proven cardiovascular benefit: semaglutide, liraglutide, or dulaglutide 3, 4
• Avoid in patients with recent heart failure decompensation 4

Pregnancy Planning:

• Discontinue GLP-1 RAs at least 2 months before planned pregnancy due to long washout period 5

Common Pitfalls to Avoid

1. Do not wait for treatment failure on multiple oral agents before considering GLP-1 RAs – early initiation leads to better outcomes 2

2. Do not ignore perioperative aspiration risk – retained gastric contents documented even after extended fasting 2

3. Do not unnecessarily withhold GLP-1 RAs based on mild renal impairment – no dose adjustment required 3, 4

4. Do not combine with other GLP-1 RAs or DPP-4 inhibitors – pharmacologically redundant 2

5. Do not advance dose if persistent severe abdominal pain – may indicate pancreatitis 2

6. Do not delay follow-up beyond 3 months in maintenance phase – may miss treatment failure 2

7. Do not prescribe for patients with personal/family history of medullary thyroid cancer or MEN2 – absolute contraindication 5, 3