Side Effects of Semaglutide
Gastrointestinal side effects—particularly nausea, vomiting, diarrhea, and constipation—are the most common adverse effects of semaglutide, occurring in the majority of patients but typically being dose-dependent and transient. 1
Common Gastrointestinal Side Effects
Nausea, vomiting, diarrhea, constipation, and abdominal pain dominate the adverse effect profile and are typically dose-dependent, more pronounced during initial treatment or dose escalation. 2
Esophageal reflux occurs due to delayed gastric emptying, a primary mechanism of GLP-1 receptor agonists. 2
Slow dose titration (starting at 0.25 mg weekly for 4 weeks, then 0.5 mg, then 1 mg if needed) minimizes these gastrointestinal side effects, which typically improve with continued use. 2
Abdominal pain and flatulence are also frequently reported. 2
Serious Adverse Events Requiring Monitoring
Semaglutide carries a 38% higher risk of serious adverse events compared to placebo, including pancreatitis, gallbladder disease, acute myocardial infarction, and gastroenteritis. 2
Gallbladder Disease
Increased risk of cholelithiasis (gallstones) and cholecystitis requires monitoring, related to rapid weight loss and altered bile composition. 2
Regular monitoring for signs of gallbladder disease is advised. 2
Pancreatitis
Acute pancreatitis has been reported in clinical trials, though causality has not been definitively established. 2, 3
Use with caution in patients with a history of pancreatitis. 2
Acute Kidney Injury
Risk of acute kidney injury from dehydration secondary to severe gastrointestinal effects, particularly in patients with pre-existing kidney disease. 2
Monitor renal function closely when initiating or escalating doses, especially in patients reporting severe gastrointestinal reactions. 2
Ensuring adequate fluid intake is crucial to prevent dehydration-related kidney injury. 2
Diabetic Retinopathy Complications
Increased risk of diabetic retinopathy complications, particularly in patients with preexisting retinopathy and high HbA1c at treatment initiation. 2, 4
Patients with a history of diabetic retinopathy should be monitored closely for progression. 2
This may be due to a nonspecific effect of rapid decrease in glycemic parameters. 4
Cardiovascular Considerations
While semaglutide reduces cardiovascular death, myocardial infarction, and stroke in patients with established cardiovascular disease (6.6% vs 8.9% placebo, HR 0.74), acute myocardial infarction has been reported as an adverse event in trials. 1, 2
Elevated heart rate is a common side effect requiring monitoring. 2
More patients discontinued treatment in the semaglutide group because of adverse events, mainly gastrointestinal. 1
Thyroid Concerns and Absolute Contraindications
Semaglutide is absolutely contraindicated in patients with personal or family history of medullary thyroid carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) due to the risk of thyroid C-cell tumors based on rodent studies. 2, 5
This carries an FDA Black Box Warning. 2
Hypothyroidism events (all grade 1 or 2) occur in approximately 8.1% of patients. 2
Hypoglycemia Risk
Semaglutide carries very low intrinsic hypoglycemia risk as it stimulates insulin secretion in a glucose-dependent manner. 2
Increased risk of hypoglycemia occurs only when combined with insulin or insulin secretagogues (sulfonylureas or glinides). 2
Reduce insulin dose by 20% and sulfonylurea dose by 50% when starting semaglutide. 5
Gastroparesis and Gastric Emptying
Semaglutide is not recommended in patients with clinically meaningful gastroparesis as it delays gastric emptying and will worsen symptoms. 2, 5
Severe constipation, small bowel obstruction, or ileus progression may occur. 2
Use caution in patients with prior gastric surgery, including bariatric surgery. 2
Drug Interactions and Absorption Issues
Semaglutide delays absorption of concomitantly administered oral medications due to delayed gastric emptying, particularly those with narrow therapeutic index like warfarin. 2
For oral hormonal contraceptive users, switch to a non-oral contraceptive method or add a barrier method for 4 weeks after initiation and after each dose escalation due to potential reduced efficacy. 2, 5
Other Notable Adverse Effects
Injection site reactions occur with subcutaneous administration. 2
Insomnia has been reported. 2
Suicidal ideation has been reported in clinical trials. 2
Severe allergic reactions are possible. 2
Pregnancy and Breastfeeding
- Pregnancy and breastfeeding are absolute contraindications as safety has not been established in these populations. 2, 5
Renal Impairment Considerations
Semaglutide can be used in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) or end-stage renal disease without dose adjustment, unlike exenatide. 2, 5
However, careful monitoring of renal function is required due to increased risk of gastrointestinal side effects and potential dehydration. 2, 5
Monitoring Recommendations
Assess efficacy and safety at least monthly for the first 3 months, then at least quarterly thereafter. 2
Monitor renal function, especially with severe gastrointestinal symptoms. 2
Check for signs of gallbladder disease periodically. 2
Monitor for elevated heart rate. 2
Assess gastrointestinal symptoms at each visit during dose titration. 5
Monitor body weight every 4 weeks. 5
Critical Pitfalls to Avoid
Never start at high doses—starting at 0.25 mg weekly bypasses the body's adaptation period to delayed gastric emptying, which is the primary mechanism causing gastrointestinal symptoms. 2
If 3 or more consecutive doses are missed, restart the titration schedule rather than resuming at the previous dose. 2
If a patient tolerates a submaximal dose well and achieves adequate response, continuing that dose long-term is acceptable rather than escalating. 2
Counsel patients on warning signs of pancreatitis (severe abdominal pain), gallbladder disease, and dehydration, advising them to seek immediate medical attention if symptoms occur. 5