Newly Published GLP-1 Receptor Agonist Side Effects
GLP-1 receptor agonists have significant side effects including thyroid C-cell tumors, pancreatitis, diabetic retinopathy complications, gastrointestinal disturbances, gallbladder disease, and acute kidney injury that must be carefully monitored to reduce morbidity and mortality. 1, 2
FDA Black Box Warnings and Major Side Effects
Serious Concerns
- Thyroid C-cell tumors: GLP-1 receptor agonists carry an FDA Black Box Warning for increased risk of thyroid C-cell tumors. They are contraindicated in patients with personal or family history of medullary thyroid carcinoma and in patients with multiple endocrine neoplasia syndrome type 2 1
- Pancreatitis: Acute pancreatitis has been reported with GLP-1 agonist use. Patients should be monitored for persistent severe abdominal pain (sometimes radiating to the back, with or without vomiting). If pancreatitis is suspected, discontinue immediately 2
- Diabetic retinopathy complications: Particularly concerning in patients with pre-existing diabetic retinopathy. The SUSTAIN-6 trial showed semaglutide was associated with increased risk of diabetic retinopathy complications versus placebo 1, 2
- Acute kidney injury: Postmarketing reports indicate risk of acute kidney injury and worsening of chronic renal failure, sometimes requiring hemodialysis. Most cases occurred in patients experiencing severe gastrointestinal side effects leading to dehydration 2
Cardiovascular Effects
- Increased heart rate: GLP-1 receptor agonists can increase heart rate by 3-10 beats/minute 1
- Blood pressure effects: These medications typically lower systolic blood pressure by 2-3 mmHg 1
Gastrointestinal Side Effects
Gastrointestinal disturbances are the most commonly reported adverse effects 1, 3:
- Nausea and vomiting: Most frequent side effects, typically dose-dependent and more common with short-acting formulations 1
- Diarrhea: Common and can contribute to dehydration risk 1
- Dyspepsia and gastrointestinal reflux: May require management with dietary modifications 1
- Constipation: Less common but reported 1
- Delayed gastric emptying: Not recommended in patients with clinically significant gastroparesis 1
Management of Gastrointestinal Side Effects
- Start at low doses and titrate slowly
- Reduce meal size
- Limit alcohol and carbonated drinks
- Avoid high-fat diets
- Monitor for dehydration, especially in elderly patients 1
Other Important Side Effects
- Gallbladder disease: Increased risk of cholelithiasis 1
- Hypoglycemia: Minimal risk when used as monotherapy but increased risk when combined with insulin or sulfonylureas 1
- Hypersensitivity reactions: Including anaphylaxis and angioedema 2
- Weight loss: While often a desired effect, can be concerning in elderly patients with unexplained weight loss 1
Special Populations and Considerations
Renal Impairment
- Exenatide: Not recommended if eGFR <30 mL/min/1.73m²
- Lixisenatide: Use with caution if eGFR <30 mL/min/1.73m²
- Other GLP-1 receptor agonists: Can be used with dose adjustment 1
Elderly Patients
- GLP-1 receptor agonists may not be preferred in older adults experiencing unexplained weight loss
- Gastrointestinal side effects may be less tolerable in this population 1
Patients with Heart Failure
- GLP-1 receptor agonists should be used with caution in patients with established heart failure with reduced ejection fraction (HFrEF) and recent decompensation 1
Monitoring Recommendations
Before initiation:
- Screen for personal/family history of medullary thyroid carcinoma or MEN2
- Evaluate baseline renal function
- Complete eye examination if not done within past 12 months, especially for patients with existing diabetic retinopathy 1
During treatment:
- Monitor for signs/symptoms of pancreatitis
- Watch for dehydration, especially with gastrointestinal side effects
- Regular eye examinations for patients with history of diabetic retinopathy
- Monitor renal function, particularly when initiating or escalating doses 2
The side effect profile of GLP-1 receptor agonists requires careful patient selection and monitoring to minimize risks while maximizing benefits for glycemic control, cardiovascular outcomes, and weight management.