What is the safety profile and most common side effects of Glucagon-like peptide-1 (GLP-1) medications, such as exenatide, liraglutide, and semaglutide, for patients with type 2 diabetes?

Safety Profile and Common Side Effects of GLP-1 Medications

GLP-1 receptor agonists commonly cause gastrointestinal side effects including nausea, vomiting, and diarrhea, which typically occur during the initial treatment phase and gradually diminish over time. 1

Mechanism of Action and Types

GLP-1 receptor agonists work by:

• Stimulating glucose-dependent insulin secretion 1
• Reducing glucagon secretion in a glucose-dependent manner 1
• Delaying gastric emptying 1
• Promoting satiety and reducing food intake via central appetite suppression 1
• Promoting weight loss of approximately 2-4 kg 2

Available GLP-1 receptor agonists include:

• Daily administration: liraglutide, lixisenatide, exenatide twice daily 1
• Weekly administration: dulaglutide, exenatide extended-release, semaglutide 1
• Oral formulation: semaglutide 1

Common Side Effects

Gastrointestinal Effects

• Nausea (40-44% of patients) 3, 1
• Vomiting (13-18% of patients) 3
• Diarrhea (13-18% of patients) 3
• Dyspepsia (6-7% of patients) 3
• Gastroesophageal reflux disease (2-3% of patients) 3
• Constipation (reported with some agents) 3

These gastrointestinal symptoms:

• Occur mainly in the initial stage of treatment 1
• Gradually diminish as treatment continues 3
• May be more pronounced with semaglutide compared to liraglutide 4

Other Common Side Effects

• Headache (9-14% of patients) 3
• Dizziness (9% of patients) 3
• Feeling jittery (9% of patients) 3
• Asthenia/fatigue (4-5% of patients) 3
• Hyperhidrosis (3% of patients) 3
• Decreased appetite (reported in some patients) 3

Serious Adverse Events and Contraindications

Contraindications 1

• History of serious hypersensitivity reaction to the drug
• Personal or family history of medullary thyroid cancer
• Multiple endocrine neoplasia syndrome type 2 (MEN2)
• Severe renal impairment or end-stage renal disease (specifically for exenatide and lixisenatide)

Cautions 1

• Use liraglutide with caution in patients with history of pancreatitis
• Use liraglutide and semaglutide with caution in patients with severe renal impairment
• Increased hypoglycemia risk when combined with insulin or sulfonylureas
• Shorter-acting agents may delay gastric emptying and slow absorption of other medications
• Caution in patients with prior gastric surgery
• Semaglutide has been associated with diabetic retinopathy complications

Post-Marketing Adverse Events 3

• Allergic/hypersensitivity reactions (injection-site reactions, urticaria, angioedema, anaphylaxis)
• Drug-induced thrombocytopenia
• Acute pancreatitis (including hemorrhagic and necrotizing pancreatitis)
• Cholecystitis and cholelithiasis requiring cholecystectomy
• Altered renal function
• Pulmonary aspiration in patients undergoing elective surgeries

Cardiovascular and Renal Effects

• Several GLP-1 receptor agonists (liraglutide, semaglutide, dulaglutide) have demonstrated cardiovascular benefits 1
• These agents reduce the risk of major adverse cardiovascular events in patients with type 2 diabetes 1
• GLP-1 receptor agonists reduce albuminuria and slow eGFR decline 1
• No increased risk of heart failure hospitalization observed in cardiovascular outcome trials 1

Special Populations

Renal Impairment

• Exenatide and lixisenatide are contraindicated in severe renal impairment 1
• Liraglutide and semaglutide should be used with caution in severe renal impairment 1
• GLP-1 receptor agonists have shown benefits in patients with chronic kidney disease 1

Heart Failure

• GLP-1 receptor agonists should be used with caution in patients with recent heart failure decompensation 1
• Unlike some other diabetes medications, they do not increase risk of heart failure 1

Non-alcoholic Fatty Liver Disease (NAFLD)

• GLP-1 receptor agonists may decrease hepatic steatosis in patients with NAFLD 1
• Semaglutide has shown the most robust evidence for NASH resolution 1

Practical Considerations

Dose Titration

• Gradual dose titration is recommended to minimize gastrointestinal side effects 2
• Nausea and other GI effects tend to diminish over time with continued therapy 3

Monitoring

• Monitor for signs of pancreatitis (persistent severe abdominal pain) 1
• Consider dose reduction of insulin or sulfonylureas when adding GLP-1 receptor agonists to prevent hypoglycemia 1
• Monitor for retinopathy complications with semaglutide, especially with rapid glucose reduction 1

Patient Selection

• Particularly beneficial for patients who need weight loss 1, 5
• Effective as monotherapy or in combination with other antidiabetic drugs 1, 5
• Minimal risk of hypoglycemia when used alone 1

By understanding the safety profile and common side effects of GLP-1 receptor agonists, healthcare providers can better select appropriate patients for therapy and manage side effects to improve adherence and outcomes.