What are the adverse effects of Glucagon-like peptide-1 (GLP-1) agonists, such as exenatide (Byetta), liraglutide (Victoza), and semaglutide (Ozempic)?

Adverse Effects of GLP-1 Receptor Agonists

Gastrointestinal side effects are the most common adverse reactions of GLP-1 receptor agonists, with nausea, vomiting, and diarrhea occurring in up to 44% of patients, which are dose-dependent and typically more frequent with short-acting than long-acting formulations. 1

Common Gastrointestinal Adverse Effects

• Nausea: Occurs in up to 44% of patients, most common with semaglutide (ROR 7.41) 1, 2, 3
• Vomiting: Reported in 13-18% of patients, highest with semaglutide (ROR 6.67) 1, 2, 3
• Diarrhea: Affects 13-18% of patients, more common with long-acting formulations 1, 2, 4
• Constipation: Occurs in approximately 10-30% of patients 1, 5
• Dyspepsia: Reported in 6-7% of patients 1, 2
• Abdominal pain: Most prevalent GI symptom in real-world data (57.6%), with upper abdominal pain highest with liraglutide 5, 3
• Gastroesophageal reflux: Reported in 2-3% of patients 1, 3

These GI symptoms are typically dose-dependent and more frequent with short-acting than long-acting formulations. Slow dose titration helps improve gastrointestinal tolerability 1, 4.

Management of Gastrointestinal Side Effects

• Start GLP-1 receptor agonist at low dose and titrate upward slowly 1
• Reduce meal size to minimize symptoms 1
• Limit alcohol and carbonated drinks to reduce reflux 1
• Avoid high-fat diet to reduce constipation 1
• Most GI symptoms are transient and diminish over several weeks to months 1

Cardiovascular Effects

• Heart rate increase: Typically increases by approximately 5 bpm 1
• Cardiac arrhythmia/tachycardia: If symptomatic, monitor and consider beta blockers 1
• Cardiovascular benefits: GLP-1 receptor agonists have demonstrated cardiovascular benefits in patients with type 2 diabetes at high cardiovascular risk 1

Rare but Serious Adverse Effects

• Acute pancreatitis: Linked to exenatide in FDA reports and observational studies, with liraglutide showing highest risk (ROR 32.67) 1, 3, 6
• Gallbladder disorders: Including cholelithiasis requiring cholecystectomy 1
• Renal effects: Acute kidney injury reported with exenatide, primarily through hemodynamic derangement due to severe GI symptoms 7
• Thyroid concerns: GLP-1 receptor agonists carry a black box warning regarding risk of thyroid C-cell tumors in rodents (human relevance not determined) 1

Contraindications and Special Populations

• Pancreatitis history: Use with caution in patients with history of pancreatitis 1
• Gastroparesis: Avoid in patients with gastroparesis 1
• Thyroid concerns: Not recommended in patients at risk for thyroid C-cell tumors (e.g., multiple endocrine neoplasia) 1
• Chronic kidney disease: GLP-1 receptor agonists can be used in CKD with appropriate dose adjustments, but exenatide is not recommended if eGFR <30 ml/min/1.73m² 1

Comparative Safety Profiles

• Semaglutide: Highest risk of nausea, vomiting, diarrhea, and constipation 3
• Liraglutide: Highest risk of upper abdominal pain and pancreatitis, highest severe rate of GI adverse events (23.31%) 3
• Exenatide: Lower overall GI adverse event profile except for gastroparesis 5, 3
• Dulaglutide: Lowest severe rate of GI adverse events (12.29%) 3

Hypoglycemia Risk

• GLP-1 receptor agonists do not cause hypoglycemia when used alone or with metformin/thiazolidinediones 1
• When combined with insulin or sulfonylureas, dose reductions of these medications may be necessary to avoid hypoglycemia 1

Timing of Adverse Effects

• Most gastrointestinal adverse events tend to occur within one month of starting therapy 3
• GI symptoms typically diminish over time with continued treatment 2, 4

Understanding these adverse effects is crucial for appropriate patient selection and management, with careful consideration of individual risk factors and comorbidities to optimize treatment outcomes and minimize complications.