Side Effects of Semaglutide
Most Common Side Effects
Gastrointestinal symptoms—particularly nausea, vomiting, diarrhea, constipation, and abdominal pain—are the most frequent adverse effects of semaglutide, occurring in 25-44% of patients, and are dose-dependent and typically most pronounced during initial treatment or dose escalation. 1, 2
Gastrointestinal Effects Management
- Start at low doses (0.25 mg weekly) and titrate slowly every 4 weeks to minimize GI symptoms, as slow titration is the single most effective intervention for reducing these adverse effects 1, 3
- Reduce meal size significantly and avoid high-fat foods entirely, as fat delays gastric emptying and worsens symptoms 1, 3
- Limit or eliminate alcohol and carbonated drinks to reduce reflux and nausea 1, 3
- Avoid semaglutide entirely in patients with pre-existing gastroparesis, as it will worsen symptoms through delayed gastric emptying 1, 2
Serious Adverse Events
Semaglutide carries a 38% higher risk of serious adverse events compared to placebo, including specific concerns that require monitoring 2:
Gallbladder Disease
- Increased risk of cholelithiasis (gallstones) and cholecystitis, with odds ratio of 2.06 for gallstone formation 2, 4
- Monitor for right upper quadrant pain, though gallbladder disorders are unusual to be symptomatic 1
Pancreatitis
- Acute pancreatitis is a rare but serious adverse effect linked to GLP-1 receptor agonists 1, 2
- Use with caution in patients with history of pancreatitis and discontinue immediately if severe abdominal pain develops 2, 5
Diabetic Retinopathy Complications
- Patients with existing diabetic retinopathy require close monitoring for progression, particularly if also treated with insulin 2, 5, 6
- The rapid improvement in glycemic control may paradoxically worsen retinopathy 5
Acute Kidney Injury
- Risk of acute kidney injury, particularly from severe gastrointestinal side effects leading to dehydration 2, 7, 6
- Monitor renal function closely, especially in patients with pre-existing kidney disease or those experiencing persistent vomiting/diarrhea 2
Cardiovascular Considerations
Despite concerns, semaglutide demonstrates net cardiovascular benefit, with major cardiovascular events occurring in 6.5% of treated patients versus 8.0% in placebo groups 2:
- Cardiac arrhythmia/tachycardia may occur; if symptomatic, monitor and consider beta blockers 1
- Reduces risk of cardiovascular death, myocardial infarction, and stroke in high-risk patients 1, 2
Absolute Contraindications
Semaglutide is absolutely contraindicated in the following situations 2:
- Personal or family history of medullary thyroid cancer (carries FDA Black Box Warning for thyroid C-cell tumors based on rodent studies) 2
- Multiple endocrine neoplasia syndrome type 2 2, 6
- Pregnancy or breastfeeding 2, 6
Other Notable Side Effects
Hypoglycemia Risk
- Risk increases significantly when combined with insulin, sulfonylureas, or glinides; dose reduction of these medications is required 2
- Blood glucose monitoring is essential in combination therapy 7
Additional Adverse Effects
- Injection site reactions 2
- Insomnia 2
- Potential risk of suicidal ideation (requires monitoring) 2
- Dyspepsia and gastroesophageal reflux 1
Discontinuation Rates
Gastrointestinal side effects lead to medication discontinuation in a significant proportion of patients, with odds ratio of 3.77 for discontinuation due to GI symptoms compared to placebo 4. However, these symptoms are typically transient and improve with continued use 5.
Critical Clinical Pitfalls to Avoid
- Never use in patients with clinically meaningful gastroparesis 2
- Delayed gastric emptying may reduce efficacy of oral contraceptives; consider switching to non-oral contraceptive methods or adding barrier methods for 4 weeks after initiation and each dose escalation 2
- Semaglutide may delay absorption of concomitantly administered oral medications 2
- Ensure adequate hydration and monitor for electrolyte disturbances if vomiting is persistent 3
When to Seek Immediate Medical Attention
Discontinue semaglutide and seek urgent evaluation for 3:
- Persistent severe abdominal pain (concern for pancreatitis)
- Severe, persistent, or worsening GI symptoms despite interventions
- Signs of dehydration or acute kidney injury