What are the adverse events of Glucagon-like peptide-1 (GLP-1) receptor agonist (RA) agents?

Adverse Events of GLP-1 Receptor Agonists

GLP-1 receptor agonists cause gastrointestinal adverse events in 15-20% of patients, with nausea, vomiting, and diarrhea being the most common, typically occurring early in treatment and diminishing over weeks to months with slow dose titration. 1

Gastrointestinal Adverse Events

Common GI Effects

• Nausea and vomiting are the most frequently reported adverse effects, occurring in 15-20% of patients, and are dose-dependent 1
• Diarrhea affects approximately 15-20% of patients and shows dose-dependent occurrence 1
• Constipation occurs in up to 30% of patients in real-world cohorts 2
• Abdominal pain is reported in up to 57% of patients in real-world data 2
• Short-acting GLP-1 RAs (exenatide, lixisenatide) cause more nausea and vomiting than long-acting agents 3
• Long-acting agents are associated with more diarrhea but less nausea and vomiting 4

Timing and Severity

• Most gastrointestinal adverse events occur within the first month of treatment 3
• Symptoms are typically transient and diminish over several weeks to months with gradual dose escalation 3
• The majority of GI events are mild in severity 5

Agent-Specific GI Profiles

• Semaglutide has the highest risk of nausea (ROR 7.41), vomiting (ROR 6.67), constipation (ROR 6.17), and delayed gastric emptying 6, 7
• Liraglutide has the highest risk of upper abdominal pain (ROR 4.63) and the highest severe rate of GI adverse events at 23.31% 7
• Dulaglutide has the lowest severe rate of GI adverse events at 12.29% 7
• Exenatide once weekly causes fewer GI adverse events (34%) compared to exenatide twice daily (45%) or liraglutide (41%) 5

Serious Gastrointestinal Complications

Pancreatitis

• Acute pancreatitis is a rare but serious complication that requires immediate discontinuation of the GLP-1 RA 8, 9
• The American Association of Clinical Endocrinologists recommends using GLP-1 RAs with caution in patients with a history of pancreatitis 10
• Liraglutide has the highest risk of pancreatitis (ROR 32.67) among GLP-1 RAs 7
• Exenatide is particularly associated with pancreatitis risk 10, 6
• Discontinue immediately if pancreatitis is suspected and do not restart if confirmed 9, 11, 12

Gastroparesis and Delayed Gastric Emptying

• GLP-1 RAs delay gastric emptying through inhibition of vagal activity 3
• Avoid GLP-1 RAs in patients with pre-existing gastroparesis 3
• Delayed gastric emptying can affect absorption of concomitant oral medications 10

Gallbladder Disease

• Acute cholecystitis and cholelithiasis have been reported with GLP-1 RA use 10, 9, 11
• The FDA has reported gallbladder disease in patients using liraglutide 10
• If cholelithiasis is suspected, obtain gallbladder studies and provide appropriate clinical follow-up 9, 11

Pulmonary Aspiration Risk

• Temporary discontinuation before elective surgery requiring general anesthesia may be necessary due to delayed gastric emptying and aspiration risk 10, 3
• Rare postmarketing reports of pulmonary aspiration exist in patients undergoing procedures despite adherence to fasting recommendations 9, 11, 12
• Instruct patients to inform healthcare providers prior to any planned surgeries if taking GLP-1 RAs 9, 11, 12

Renal Adverse Events

• Acute kidney injury has been reported postmarketing, sometimes requiring hemodialysis 9, 11, 12
• Most renal events occurred in patients experiencing nausea, vomiting, diarrhea, or dehydration 9, 11
• Some events occurred in patients taking medications affecting renal function (ACE inhibitors, NSAIDs, diuretics) 9
• GLP-1 RAs are not directly nephrotoxic, and altered renal function is often reversible with supportive treatment 9, 11
• Exenatide is not recommended in severe renal impairment (CrCl <30 mL/min) and should be used with caution in moderate impairment (CrCl 30-50 mL/min) 9
• Monitor renal function when initiating or escalating doses in patients with severe GI reactions 12

Cardiovascular and Metabolic Effects

• Heart rate increases by approximately 5 beats per minute but without associated adverse cardiovascular events 1
• GLP-1 RAs reduce major adverse cardiovascular events equally in patients over and under 65 years of age 8

Hypoglycemia Risk

• Hypoglycemia risk increases when GLP-1 RAs are combined with insulin secretagogues (sulfonylureas) or insulin 8, 1, 9, 11, 12
• In pediatric patients 10 years and older, hypoglycemia risk is higher with liraglutide regardless of insulin or metformin use 11
• Dose reduction of sulfonylureas or insulin may be necessary to mitigate hypoglycemia risk 8, 11

Hypersensitivity Reactions

• Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported postmarketing 9, 11, 12
• Discontinue GLP-1 RA immediately if hypersensitivity occurs and treat per standard of care 9, 11, 12
• Use caution in patients with prior anaphylaxis or angioedema to another GLP-1 RA 9, 11, 12

Other Adverse Events

Injection Site Reactions

• Occur in less than 1% of patients 1

Diabetic Retinopathy Complications

• Semaglutide was associated with more diabetic retinopathy complications (3.0%) compared to placebo (1.8%) in a 2-year trial 12
• The absolute risk increase was larger in patients with baseline diabetic retinopathy (8.2% vs 5.2%) 12
• Monitor patients with a history of diabetic retinopathy for progression 12

Weight Loss

• Weight loss is an expected effect but may be undesirable in older adults with unexplained weight loss or undernutrition 8
• GLP-1 RAs are not preferred in older adults experiencing unexplained weight loss or recurrent GI problems 8

Drug-Induced Thrombocytopenia

• Rare postmarketing reports of serious bleeding from immune-mediated thrombocytopenia with exenatide 9
• Discontinue immediately if suspected and do not re-expose the patient 9

Immunogenicity

• Patients may develop antibodies to exenatide, which in 1-4% of cases is associated with attenuated glycemic response 9
• Consider alternative therapy if glycemic control worsens 9

Risk Mitigation Strategies

Dose Titration

• Start at the lowest available dose and titrate slowly to minimize GI symptoms 8, 10, 3
• Up-titrate slowly to reduce nausea and vomiting 8
• The American College of Cardiology recommends gradual dose escalation 10

Dietary Modifications

• Reduce meal size, limit alcohol and carbonated drinks, and avoid high-fat diets 10, 3

Monitoring Requirements

• Monitor for signs of pancreatitis (persistent severe abdominal pain, sometimes radiating to the back, with or without vomiting) 9, 11, 12
• Monitor renal function when initiating or escalating doses, especially in patients with severe GI reactions 12
• Monitor for diabetic retinopathy progression in patients with baseline retinopathy 12

Contraindications and Cautions

• Contraindicated in patients with personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2 (MEN2) 8
• Contraindicated in pregnancy or breastfeeding 8
• Not recommended in patients with severe GI disease including gastroparesis 9
• Use with caution in patients with history of pancreatitis 10
• Care should be taken in patients with prior gastric surgery, including bariatric surgery 8

Background Medication Considerations

• Background treatment with metformin is associated with more nausea and vomiting 4
• Concomitant use with medications affecting renal function (ACE inhibitors, NSAIDs, diuretics) increases risk of renal events 9