Side Effects of Rybelsus (Semaglutide)
Rybelsus (semaglutide) commonly causes gastrointestinal side effects and has a 38% higher risk of serious adverse events compared to placebo, with specific concerns including gallbladder disease, pancreatitis, and potential cardiovascular complications. 1, 2
Common Side Effects
Gastrointestinal Effects
- Nausea, vomiting, diarrhea, constipation, and esophageal reflux are the most frequent adverse effects, typically dose-dependent and more pronounced during initial treatment or dose escalation 3, 1
- These gastrointestinal side effects can be severe enough to cause discontinuation of therapy in some patients 1, 2
- Gradual dose titration may help mitigate these gastrointestinal side effects 1
Other Common Side Effects
- Injection site reactions (for injectable formulations) 1
- Elevated heart rate 3, 1
- Insomnia 1, 2
- Hypoglycemia (particularly when combined with insulin or insulin secretagogues) 3, 1
Serious Adverse Events
Gastrointestinal Complications
- Risk of severe constipation and small bowel obstruction/ileus progression 3, 4
- Pancreatitis has been reported in clinical trials, though causality has not been definitively established 3, 1
- Discontinue semaglutide if pancreatitis is suspected 3
Gallbladder Disease
- Increased risk of cholelithiasis (gallstones) and cholecystitis 3, 1
- May cause gallstone-related complications 3
- Monitor for right upper quadrant pain and other signs of gallbladder disease 4
Renal Effects
- Risk of acute kidney injury, particularly in patients with pre-existing kidney disease 3, 1
- Use caution when initiating or increasing dose in patients with kidney disease 3
Cardiovascular Effects
- While semaglutide has shown cardiovascular benefits in clinical trials, monitoring for elevated heart rate is recommended 1, 2
- Cardiac arrhythmias may occur and should be monitored, particularly in patients with pre-existing cardiovascular conditions 4
Thyroid Concerns
- Black box warning: Risk of thyroid C-cell tumors in rodents; human relevance not determined 3
- Contraindicated in patients with personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 1, 2
Diabetic Retinopathy
- Potential risk of diabetic retinopathy complications, particularly in patients with pre-existing retinopathy 3, 2
- Careful monitoring is recommended, especially if also treated with insulin 3
Medication Interactions
- Delayed gastric emptying may affect absorption of other oral medications 3, 1
- Particular attention should be paid to medications with narrow therapeutic indices (e.g., warfarin) 4
- Hormonal contraception efficacy may be affected for up to 4 weeks after dose changes 4, 2
- Increased risk of hypoglycemia when used with insulin, sulfonylureas, or glinides 2
Special Considerations and Contraindications
- Contraindicated in pregnancy and breastfeeding 2
- Contraindicated in patients with personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 1, 2
- Use caution in patients with severe gastroparesis 2
- Use caution in patients with prior gastric surgery, including bariatric surgery 2
- Use caution in patients with severe renal impairment 2
Monitoring Recommendations
- Assess efficacy and safety at least monthly for the first 3 months and at least quarterly thereafter 3
- Monitor for persistent gastrointestinal symptoms 1, 4
- Monitor renal function, especially in patients experiencing severe gastrointestinal side effects that could lead to dehydration 2
- Monitor for signs of gallbladder disease 1, 4
- For patients with diabetes, monitor glycemic control closely as rebound hyperglycemia may occur after discontinuation 4