What side effects necessitate discontinuation of tirzepatide (glucagon-like peptide-1 (GLP-1) receptor agonist) in a patient with type 2 diabetes or obesity?

Side Effects Requiring Discontinuation of Tirzepatide

Discontinue tirzepatide immediately if pancreatitis is suspected, and do not restart if pancreatitis is confirmed. 1

Absolute Indications for Discontinuation

Pancreatitis

• Suspected or confirmed acute pancreatitis mandates immediate and permanent discontinuation of tirzepatide. 1, 2
• Rates of acute pancreatitis are extremely low (≤1%) but represent a serious adverse event requiring cessation. 3
• Do not restart tirzepatide if pancreatitis is confirmed. 1

Serious Hypersensitivity Reactions

• History of serious hypersensitivity reaction to tirzepatide is an absolute contraindication and requires discontinuation. 1

Thyroid Concerns

• Discontinue if medullary thyroid carcinoma is diagnosed or suspected, particularly in patients with personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 (MEN2). 1, 2
• Tirzepatide increases risk of thyroid C-cell tumors and should be permanently stopped in these circumstances. 2

Serious Adverse Events Requiring Strong Consideration for Discontinuation

Life-Threatening Electrolyte Disturbances

• Severe gastrointestinal symptoms causing profound electrolyte imbalances (hypokalemia, hypomagnesemia, hypocalcemia) leading to cardiac arrhythmias require immediate discontinuation. 4
• A recent case report documented ventricular fibrillation and cardiac arrest from tirzepatide-induced severe vomiting and diarrhea causing critical electrolyte depletion. 4
• This risk is particularly elevated with the 15 mg dose. 4

Acute Kidney Injury

• Acute kidney injury from severe dehydration secondary to gastrointestinal side effects warrants discontinuation, especially in patients with pre-existing renal impairment. 2, 5
• Monitor renal function closely when severe nausea, vomiting, or diarrhea occurs. 2

Symptomatic Gallbladder Disease

• Acute cholecystitis or symptomatic cholelithiasis requiring intervention should prompt discontinuation. 2, 3
• While rates are low (≤1%), gallbladder disorders can occur and may necessitate stopping the medication. 2, 3

Severe Gastrointestinal Complications

• Ileus, small bowel obstruction, or suspected appendicitis require immediate discontinuation. 2, 6
• A recent case report documented appendicitis developing one week after tirzepatide initiation, with dramatic improvement after discontinuation. 6
• Delayed gastric emptying can alter gastrointestinal motility and increase risk of these complications. 6

Dose-Dependent Side Effects Requiring Discontinuation Consideration

Intolerable Gastrointestinal Symptoms

• Gastrointestinal adverse events are dose-dependent: 39% at 5 mg, 46% at 10 mg, and 49% at 15 mg. 3
• Drug discontinuation due to adverse events is highest with the 15 mg dose (10%). 3, 7
• Nausea, vomiting, and diarrhea are most frequent and may be severe enough to warrant stopping therapy. 2, 8, 3

Symptomatic Cardiac Arrhythmias

• If cardiac arrhythmia or tachycardia becomes symptomatic, discontinuation should be considered after monitoring and attempting management with beta blockers. 2
• Increased heart rate may occur and requires monitoring. 2

Severe Hypoglycemia

• While rare when tirzepatide is used alone, severe hypoglycemia can occur when combined with insulin or insulin secretagogues. 1, 2, 3
• Incidence of mild hypoglycemia is highest with the 10 mg dose (22.6%). 3
• At the 15 mg dose, hypoglycemia risk increases significantly (pooled RR=3.83). 7
• Consider discontinuation if severe hypoglycemia occurs despite dose reduction of concomitant insulin or sulfonylureas. 1

Clinical Context and Monitoring

Pre-existing Conditions Requiring Heightened Vigilance

• Patients with gastroparesis should not receive tirzepatide due to delayed gastric emptying effects. 1, 2
• Those with prior gastric surgery, including bariatric surgery, require extreme caution. 1
• Severe renal impairment patients need careful monitoring for dehydration and electrolyte disturbances. 2

Perioperative Considerations

• Discontinuation should be considered before surgical procedures requiring general anesthesia due to increased risk of pulmonary aspiration from delayed gastric emptying. 1, 2

Common Pitfalls to Avoid

• Do not continue tirzepatide through severe gastrointestinal symptoms hoping for tolerance development—this can lead to life-threatening electrolyte disturbances and cardiac arrest. 4
• Do not restart tirzepatide after confirmed pancreatitis—this is an absolute contraindication. 1
• Do not ignore worsening symptoms in patients on the 15 mg dose—this dose has the highest discontinuation rate and most severe adverse events. 3, 7, 4
• Monitor electrolytes vigilantly in patients with severe GI symptoms, particularly those on high doses or with additional risk factors. 4