What are the dosages and side effects of Glucagon-like peptide-1 (GLP-1) receptor agonist drugs?

GLP-1 Receptor Agonist Dosages and Side Effects

GLP-1 receptor agonists require slow dose titration starting at low doses and escalating over 4-5 weeks to minimize gastrointestinal side effects, with the most common adverse effects being nausea (15-44%), diarrhea (8-32%), and vomiting (5-25%), which are dose-dependent and typically transient. 1, 2, 3

Dosing Regimens by Agent

Semaglutide (Subcutaneous)

• Week 1: 0.25 mg weekly
• Week 2: 0.25 mg weekly
• Week 3: 0.5 mg weekly
• Week 4: 1.0 mg weekly
• Week 5 and beyond: 1.4-2.4 mg weekly (maximum dose for cardiovascular benefit: 14 mg weekly) 1

Liraglutide

• Week 1: 0.6 mg daily
• Week 2: 1.2 mg daily
• Week 3: 1.8 mg daily
• Week 4: 2.4 mg daily
• Week 5 and beyond: 3.0 mg daily (maximum dose) 1

Dulaglutide

• Initial: 0.75 mg weekly
• Titrate to: 1.5 mg weekly or maximally tolerated dose 1

Exenatide Weekly

• Standard dose: 2 mg weekly 1

Lixisenatide

• Initial: 10 mcg daily
• Titrate slowly to: 1 mg daily or maximally tolerated dose 1

Tirzepatide (Dual GLP-1/GIP Agonist)

• Starting dose: 2.5 mg weekly subcutaneously
• Titrate upward as tolerated 1

Common Gastrointestinal Side Effects

Nausea

• Occurs in 15-44% of patients, highest with semaglutide 2, 3
• Dose-dependent and more frequent with short-acting formulations 2
• Typically transient, diminishing over several weeks to months 2

Vomiting

• Reported in 5-25% of patients 1, 2, 3
• Highest rates with semaglutide (up to 25%) 1
• Dose-dependent 2

Diarrhea

• Affects 8-32% of patients 1, 2, 3
• More common with long-acting formulations 2
• Dose-dependent 2

Constipation

• Occurs in 10-30% of patients 1, 2

Other GI Effects

• Abdominal pain: 3-7% 3
• Dyspepsia: 6-7% 2
• Gastroesophageal reflux: 2-3% 2

Management of Gastrointestinal Side Effects

Start at the lowest dose and titrate slowly to improve tolerability 1, 2. Additional strategies include:

• Reduce meal portion sizes 1, 2
• Limit alcohol and carbonated beverages 2
• Avoid high-fat foods 2
• Reassure patients that symptoms typically diminish over weeks to months 2

In placebo-controlled trials, 3.1-3.8% of patients discontinued due to gastrointestinal adverse reactions 3.

Hypoglycemia Risk

GLP-1 receptor agonists do not cause hypoglycemia when used alone or with metformin/thiazolidinediones due to their glucose-dependent mechanism of action 1, 2, 4.

However, when combined with:

• Sulfonylureas: Documented symptomatic hypoglycemia occurs in 17-24% of patients 3
• Basal insulin: Documented symptomatic hypoglycemia occurs in 17-30% of patients 3

Reduce the dose of sulfonylurea or insulin when initiating GLP-1 receptor agonists to minimize hypoglycemia risk 1, 2.

Cardiovascular Effects

• Heart rate increase: Typically 2-5 beats per minute 2, 3, 5
• Cardiovascular benefits: Reduced risk of MI, stroke, and CV death in patients with type 2 diabetes and established cardiovascular disease 1, 2

Rare but Serious Adverse Effects

Pancreatitis

• Acute pancreatitis has been linked to GLP-1 receptor agonists, particularly exenatide 2, 4
• Discontinue immediately if pancreatitis is suspected and do not restart if confirmed 1
• Patients with history of pancreatitis should use with caution 2

Gallbladder Disease

• Cholelithiasis reported in 1.5% of patients on semaglutide 0.5 mg and 0.4% on 1 mg 3
• Cholecystitis requiring cholecystectomy can occur 2, 5
• Monitor for signs and symptoms of gallbladder disease 1

Thyroid Concerns

• Thyroid C-cell tumors observed in rodent studies 2
• Contraindicated in patients with personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 (MEN2) 1, 2

Acute Kidney Injury

• Primarily occurs through dehydration from nausea, vomiting, and diarrhea 2, 4
• Monitor hydration status, especially during dose escalation 5
• Some cases reported in patients on concomitant medications affecting renal function 5

Diabetic Retinopathy Complications

• Reported with semaglutide (injectable) 1
• Monitor patients with pre-existing diabetic retinopathy 1

Renal Dosing Adjustments

• Dulaglutide: Not recommended if eGFR <45 mL/min/1.73 m² 1
• Exenatide and lixisenatide: Not recommended if eGFR <30 mL/min/1.73 m² 1, 2
• Liraglutide: Use caution if eGFR 15-29 mL/min/1.73 m²; not recommended if eGFR <15 mL/min/1.73 m² 1
• Semaglutide: No dosage adjustment required if eGFR ≥30 mL/min/1.73 m² 1

Absolute Contraindications

• Personal or family history of medullary thyroid carcinoma 1, 2
• Multiple endocrine neoplasia type 2 (MEN2) 1, 2
• Serious hypersensitivity reaction to the drug 1
• Pregnancy or breastfeeding 1
• Severe renal impairment or end-stage renal failure (for exenatide and lixisenatide) 1

Special Cautions

Gastroparesis

• Avoid in patients with clinically meaningful gastroparesis 1
• GLP-1 receptor agonists delay gastric emptying, though this effect is usually transient with longer-acting agents 1

Surgical Procedures

• Risk of pulmonary aspiration during general anesthesia or deep sedation due to delayed gastric emptying 5
• Instruct patients to inform healthcare providers prior to planned surgeries 5
• Available data are insufficient to recommend specific preoperative fasting modifications or temporary discontinuation 5

Prior Gastric Surgery

• Use with caution in patients with prior gastric surgery, including bariatric surgery 1

Other Common Adverse Effects

• Injection site reactions: 0.2% of patients (discomfort, erythema) 3
• Fatigue, dysgeusia, dizziness: Frequency >0.4% 3
• Headache: 8-16% 1
• Alopecia: 1-6% with tirzepatide 1

Laboratory Monitoring

• Amylase and lipase: Mean increases of 13% and 22% respectively with semaglutide 3
• Serum creatinine: Monitor for acute renal failure, especially with dehydration 5
• Serum bicarbonate: Monitor when using phentermine-topiramate combinations 1

Real-World Discontinuation Rates

20-50% of patients discontinue GLP-1 receptor agonists within the first year in real-world practice, primarily due to gastrointestinal side effects and cost 6. Real-world weight loss tends to be lower than in clinical trials unless patients are highly adherent 6.