What are the serious adverse events associated with semaglutide (glucagon-like peptide-1 receptor agonist) and tirzepatide (dual glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptor agonist)?

Serious Adverse Events of Semaglutide and Tirzepatide

Both semaglutide and tirzepatide are associated with significant gastrointestinal adverse events, with tirzepatide showing a higher risk of GI side effects (RR 2.94) compared to semaglutide (RR 1.68), while both medications carry black box warnings for thyroid C-cell tumors. 1

Common Serious Adverse Events for Both Medications

• Gastrointestinal Effects: Nausea, vomiting, diarrhea, constipation, and esophageal reflux are the most common adverse effects for both medications, with tirzepatide showing higher rates of these effects compared to semaglutide 2, 1

• Thyroid C-cell Tumors: Both medications carry black box warnings regarding the risk of thyroid C-cell tumors observed in rodents, and are contraindicated in patients with personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 3, 2

• Pancreatitis: Both medications have been associated with pancreatitis in clinical trials, though causality has not been definitively established 2, 4

• Acute Kidney Injury: Caution is advised when initiating or increasing doses in patients with kidney disease due to potential risk of acute kidney injury 2, 4

• Gallbladder Disorders: Both medications may cause cholelithiasis and gallstone-related complications, with semaglutide showing a 2.6 times higher risk of gallbladder-related disorders compared to placebo 2, 1

Semaglutide-Specific Serious Adverse Events

• Diabetic Retinopathy Complications: Semaglutide has been associated with diabetic retinopathy complications, particularly in patients with a history of diabetic retinopathy at baseline (8.2% with semaglutide vs. 5.2% with placebo) 5, 4

• Hypersensitivity Reactions: Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with GLP-1 receptor agonists including semaglutide 4

• Cardiovascular Events: In clinical trials, semaglutide showed a hazard ratio of 0.74 (95% CI, 0.58-0.95) for major adverse cardiovascular events, indicating potential cardiovascular benefit 5

Tirzepatide-Specific Serious Adverse Events

• Delayed Gastric Emptying Complications: Tirzepatide may cause more pronounced delayed gastric emptying through GLP-1 receptor activation, potentially leading to ileus and small bowel obstruction 3

• Medication Absorption Issues: Due to delayed gastric emptying, tirzepatide may affect the absorption of other oral medications, particularly those with narrow therapeutic indices such as warfarin 5, 3

• Cardiovascular Effects: Increased heart rate (tachycardia) may occur and should be monitored, especially in patients with pre-existing cardiovascular conditions 3, 2

Comparative Safety Profile

• Gastrointestinal Adverse Events: In head-to-head studies, tirzepatide showed similar or slightly higher rates of gastrointestinal adverse events compared to semaglutide (nausea: 17-22% vs. 18%; diarrhea: 13-16% vs. 12%; vomiting: 6-10% vs. 8%) 6

• Serious Adverse Events: In comparative trials, serious adverse events were reported in 5-7% of patients receiving tirzepatide compared to 3% of those receiving semaglutide 6

• Hypoglycemia: Risk of hypoglycemia (blood glucose <54 mg/dL) was low with both medications but varied by dose with tirzepatide (0.2-1.7%) and semaglutide (0.4%) 6

Risk Mitigation Strategies

• Start at a low dose and titrate upward slowly to improve tolerability of both medications 2

• Reduce meal size and avoid high-fat diets to help manage gastrointestinal symptoms 2

• Monitor patients with a history of pancreatitis closely when using either medication 5, 2

• For patients with a history of diabetic retinopathy, careful monitoring is recommended when using semaglutide due to potential worsening of retinopathy 5, 4

• Use both medications with caution in patients with severe renal impairment or end-stage renal disease 5

• Monitor for hypoglycemia when either medication is used in combination with insulin or insulin secretagogues; lower doses of these medications may be required 5

Special Populations and Contraindications

• Contraindications for both medications:

  • History of serious hypersensitivity reaction to the drug 5
  • Personal or family history of medullary thyroid cancer 5
  • Multiple endocrine neoplasia syndrome type 2 5

• Use with caution in:

  • Patients with history of pancreatitis 5
  • Patients with severe renal impairment 5
  • Patients with prior gastric surgery 5
  • Patients with clinically meaningful gastroparesis 5