What is the plan for prescribing Glucagon-like peptide-1 (GLP-1) receptor agonists, such as liraglutide (exenatide) or semaglutide, to a patient with type 2 diabetes mellitus?

GLP-1 Receptor Agonist Prescribing Plan for Type 2 Diabetes

For patients with type 2 diabetes, prioritize GLP-1 receptor agonists when additional glycemic control is needed after metformin, particularly if cardiovascular disease is present, weight loss is desired, or hypoglycemia risk must be minimized. 1

When to Prescribe GLP-1 Receptor Agonists

Primary Indications (Strong Recommendations)

Prescribe GLP-1 RAs in these clinical scenarios:

• Type 2 diabetes with established atherosclerotic cardiovascular disease (ASCVD) - This is the highest priority indication, as liraglutide and semaglutide reduce cardiovascular death, nonfatal MI, or nonfatal stroke by 20-26% 1, 2

• Inadequate glycemic control (HbA1c >7%) on metformin monotherapy - GLP-1 RAs reduce HbA1c by 0.5-1.6% and should be preferred over sulfonylureas due to lower hypoglycemia risk and weight loss benefits 1

• Type 2 diabetes with obesity (BMI ≥30) or overweight (BMI ≥27) with comorbidities - Semaglutide 2.4mg achieves 14.9% weight loss, and tirzepatide achieves 20.9% weight loss 1, 2

• Patients requiring treatment intensification before insulin - GLP-1 RAs are the preferred first injectable therapy, even before basal insulin 1, 3

• Patients on basal insulin requiring prandial control - Add GLP-1 RA before adding prandial insulin to minimize hypoglycemia and weight gain 1

Secondary Indications

• High hypoglycemia risk (elderly, renal impairment, erratic meal patterns) - GLP-1 RAs have glucose-dependent mechanisms with minimal intrinsic hypoglycemia risk 1, 4

• Chronic kidney disease with eGFR 15-59 mL/min/1.73m² - Liraglutide, dulaglutide, and semaglutide require no dose adjustment and reduce albuminuria 1, 2

• NAFLD/NASH with type 2 diabetes - Semaglutide achieves NASH resolution in 59% of patients at 0.4mg/day 2

When NOT to Prescribe GLP-1 Receptor Agonists

Absolute Contraindications

Do not prescribe GLP-1 RAs in these situations:

• Personal or family history of medullary thyroid cancer 1, 2, 5

• Multiple endocrine neoplasia syndrome type 2 (MEN2) 1, 2, 5

• Pregnancy or breastfeeding 1

• Type 1 diabetes (not FDA-approved for this indication) 1

Relative Contraindications and Cautions

Exercise extreme caution or avoid in:

• Active or suspected pancreatitis - Discontinue immediately if pancreatitis is suspected and do not restart if confirmed 1

• Severe gastroparesis or gastrointestinal motility disorders - GLP-1 RAs delay gastric emptying and may worsen symptoms 1, 2

• Recent heart failure decompensation - Avoid GLP-1 RAs in this acute setting 2

• End-stage renal disease on dialysis - Limited data for liraglutide and semaglutide; exenatide and lixisenatide are contraindicated 1

• Severe renal impairment (eGFR <30 mL/min/1.73m²) for lixisenatide 1

• eGFR <45 mL/min/1.73m² for dulaglutide (not recommended) 1

• History of severe hypersensitivity reaction to the drug 1

Specific Agent Selection Algorithm

Step 1: Determine Primary Treatment Goal

For cardiovascular risk reduction with established ASCVD:

• First choice: Semaglutide 2.4mg weekly (proven 20% CV event reduction) 1, 2
• Second choice: Liraglutide 1.8mg daily (26% CV event reduction) 1

For maximum weight loss (obesity management):

• First choice: Tirzepatide 15mg weekly (20.9% weight loss) 1, 2
• Second choice: Semaglutide 2.4mg weekly (14.9% weight loss) 1, 2

For glycemic control with moderate weight loss:

• Semaglutide 1mg weekly (HbA1c reduction 1.48%, weight loss 7%) 1
• Dulaglutide 1.5mg weekly (HbA1c reduction similar to semaglutide) 1
• Liraglutide 1.8mg daily (HbA1c reduction up to 1.6%) 1, 6

For patients refusing injections:

• Oral semaglutide 14mg daily (HbA1c reduction ~1.4%, less weight loss than injectable) 1, 5, 7

Step 2: Consider Renal Function

eGFR ≥60 mL/min/1.73m²: All agents appropriate 1, 2

eGFR 45-59 mL/min/1.73m²:

• Preferred: Liraglutide, semaglutide, dulaglutide (no dose adjustment) 1, 2
• Avoid: Exenatide once-weekly 1

eGFR 30-44 mL/min/1.73m²:

• Preferred: Liraglutide, semaglutide (no dose adjustment) 1, 2
• Avoid: Dulaglutide, exenatide once-weekly 1

eGFR 15-29 mL/min/1.73m²:

• Use with caution: Liraglutide, semaglutide 1
• Contraindicated: Lixisenatide, exenatide 1

eGFR <15 or dialysis:

• Limited data; generally avoid 1

Prescribing Protocol

Liraglutide (Victoza) Dosing 8

Initiation:

• Start 0.6mg subcutaneous daily for 1 week (not effective for glycemic control, only for GI tolerance)
• Increase to 1.2mg daily after 1 week
• Increase to 1.8mg daily after at least 1 additional week if needed

Administration:

• Inject subcutaneously in abdomen, thigh, or upper arm once daily at any time, independent of meals
• Rotate injection sites within same region to reduce cutaneous amyloidosis risk

Missed dose:

• Resume normal schedule with next dose; do not double up
• If >3 days missed, restart at 0.6mg daily and re-titrate

Semaglutide (Ozempic) Dosing 9

Initiation:

• Start 0.25mg subcutaneous weekly for 4 weeks
• Increase to 0.5mg weekly after 4 weeks
• Increase to 1mg weekly after at least 4 additional weeks if needed
• For obesity: Continue titration to 1.7mg weekly, then 2.4mg weekly (each step 4 weeks apart) 2

Administration:

• Inject subcutaneously in abdomen, thigh, or upper arm once weekly at any time, with or without meals
• If dose missed, administer within 5 days; if >5 days, skip and resume normal schedule

Oral Semaglutide (Rybelsus) Dosing 5, 7

Initiation:

• Start 3mg daily for 30 days
• Increase to 7mg daily, then 14mg daily if needed (each step minimum 30 days)

Critical administration instructions:

• Take on empty stomach upon waking with up to 4 oz (120 mL) water only
• Wait at least 30 minutes before eating, drinking, or taking other medications
• Food and excess liquid drastically reduce absorption

Dulaglutide (Trulicity) Dosing 1

Initiation:

• Start 0.75mg subcutaneous weekly
• Increase to 1.5mg weekly as tolerated
• Maximum 4.5mg weekly if additional control needed

Tirzepatide (Mounjaro/Zepbound) Dosing 2

Initiation:

• Start 5mg subcutaneous weekly for 4 weeks (FDA-approved starting dose)
• Increase to 10mg weekly after 4 weeks
• Increase to 15mg weekly after additional 4 weeks if needed for maximum effect

Monitoring Requirements

Initial Phase (First 3 Months)

Every 4 weeks during titration:

• Weight and blood pressure 2
• Gastrointestinal tolerance assessment 1, 2
• Fasting glucose or continuous glucose monitoring 1
• Signs/symptoms of pancreatitis (persistent severe abdominal pain) 1

At 12-16 weeks (on maximum tolerated dose):

• HbA1c to assess efficacy 1, 2
• Lipid panel 2
• Renal function (eGFR, urine albumin-to-creatinine ratio) 1, 2
• Evaluate for treatment intensification if HbA1c not at goal 1, 2

Maintenance Phase

Every 3 months minimum:

• Weight, blood pressure, HbA1c 1, 2
• Cardiovascular risk factor assessment 2
• Medication adherence and tolerance 2
• Adjust antihypertensive medications as weight decreases 2

Annually:

• Comprehensive metabolic panel with renal function 1
• Lipid panel 2
• Thyroid function if clinically indicated 2

Combination Therapy Considerations

With Insulin

When adding GLP-1 RA to existing insulin:

• Reduce basal insulin by 20% immediately to prevent hypoglycemia 2
• Discontinue or reduce prandial insulin by 50% 2
• Monitor glucose closely (daily fasting, pre-meal, bedtime) for first 2 weeks 2
• If glucose <70 mg/dL, reduce insulin further by 10-20% 2

Never combine:

• Two GLP-1 RAs together (pharmacologically redundant and potentially harmful) 2
• GLP-1 RA with DPP-4 inhibitor (overlapping mechanism) 2

With Other Glucose-Lowering Agents

Safe combinations:

• Metformin (preferred background therapy) 1
• SGLT2 inhibitors (complementary mechanisms, additive CV benefit) 1
• Basal insulin (reduce insulin dose as above) 1

Use caution with:

• Sulfonylureas or meglitinides - reduce dose by 50% to prevent hypoglycemia 1

Common Pitfalls and How to Avoid Them

Gastrointestinal Intolerance

Problem: Nausea, vomiting, diarrhea occur in 17-44% of patients 2

Solutions:

• Always use slow titration schedule (do not skip steps) 1, 2
• Counsel patients that GI effects are typically mild-to-moderate, transient, and decrease over time 1, 2
• Recommend smaller, more frequent meals and avoiding high-fat foods 2
• Limit alcohol and carbonated beverages 2
• If intolerable, hold at current dose for additional 2-4 weeks before advancing 2

Perioperative Management

Problem: Delayed gastric emptying increases aspiration risk even with extended fasting 2

Solutions:

• For elective surgery requiring anesthesia, discontinue semaglutide 3 weeks before (three half-lives) 2
• For weekly agents, stop at least 1-2 weeks before surgery 2
• Consider gastric ultrasound pre-operatively to assess residual contents 2
• For diabetic patients, consult endocrinology for bridging therapy 2

Weight Regain After Discontinuation

Problem: Patients regain 50-67% of lost weight within 1 year of stopping 2

Solutions:

• Counsel patients upfront that lifelong treatment is typically necessary 2
• If discontinuation required, taper gradually rather than stopping abruptly 2
• Intensify lifestyle interventions immediately upon stopping 2
• Establish monthly weight monitoring for 6 months after discontinuation 2

Inadequate Response

Problem: <5% weight loss or HbA1c not at goal after 3 months at maximum dose 2

Solutions:

• Verify medication adherence and proper administration technique 2
• For oral semaglutide, confirm patient following strict administration instructions 5, 7
• Consider switching to higher-efficacy agent (e.g., from liraglutide to semaglutide 2.4mg or tirzepatide) 2
• Add complementary therapy (SGLT2 inhibitor, basal insulin) 1, 2
• Evaluate for metabolic surgery if BMI ≥30 1, 2

Cost and Insurance Barriers

Problem: Monthly costs $1,300-$1,600 without insurance 2

Solutions:

• Document medical necessity: failed lifestyle modifications, HbA1c >7% on metformin, cardiovascular disease, obesity with comorbidities 2
• Use manufacturer patient assistance programs 2
• For diabetes indication, insurance coverage typically better than for obesity alone 2
• Consider starting with lower-cost agents (liraglutide, dulaglutide) if tirzepatide/semaglutide 2.4mg denied 2