What are the contraindications for tirzepatide (glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist) in patients with various medical histories and demographics?

Contraindications for Tirzepatide

Tirzepatide is absolutely contraindicated in patients with a personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2 (MEN2), and should be avoided in patients with gastroparesis or prior gastric surgery. 1

Absolute Contraindications

• Personal or family history of medullary thyroid carcinoma (MTC) is an absolute contraindication to tirzepatide, as animal studies have demonstrated thyroid C-cell tumor risk 1, 2, 3
• Multiple Endocrine Neoplasia syndrome type 2 (MEN2) is an absolute contraindication due to the same thyroid cancer concerns 1, 2, 3
• Gastroparesis or prior gastric surgery should prompt avoidance of tirzepatide, as the medication significantly delays gastric emptying through GLP-1 receptor activation 1

Relative Contraindications and Precautions

History of Pancreatitis

• Use tirzepatide with extreme caution in patients with a history of acute pancreatitis and monitor closely 1
• If pancreatitis is suspected (persistent severe abdominal pain), discontinue tirzepatide immediately 1
• Rates of acute pancreatitis are extremely low (≤1%) across all doses, but causality has not been definitively established 4, 2

Gallbladder Disease

• Use caution in patients with history of cholelithiasis, as acute gallbladder disease can occur with an incidence ≤1% across all doses 1, 4
• Gallbladder disorders including cholelithiasis and cholecystitis are usually asymptomatic but require monitoring 2

Severe Renal Impairment

• Monitor renal function in patients with renal impairment and use with caution in severe renal impairment or end-stage renal disease 1
• However, GLP-1 receptor agonists have been studied with eGFR as low as 15 mL/min/1.73 m² and retain glucose-lowering potency across the range of eGFR 1
• Unlike some medications, specific dose adjustments for renal function are not prominently mentioned in guidelines for tirzepatide 2

Diabetic Retinopathy

• Monitor patients with history of diabetic retinopathy for progression 1

Pregnancy and Contraception

• Women using oral contraceptives should switch to non-oral methods or add barrier contraception for 4 weeks after initiation and each dose escalation, as tirzepatide may affect oral contraceptive absorption due to delayed gastric emptying 5

Medication Interactions Requiring Dose Adjustment

Hypoglycemia Risk

• Reduce dose of sulfonylurea or insulin when initiating tirzepatide to prevent hypoglycemia, as concomitant use increases risk of severe hypoglycemia 1
• Tirzepatide does not cause hypoglycemia per se due to its glucose-dependent mechanism, but combination therapy significantly increases risk 1
• Reduce basal insulin by 20% when starting tirzepatide, and strongly consider discontinuing prandial insulin entirely 1

Contraindicated Combinations

• Do not combine tirzepatide with other GLP-1 receptor agonists or dipeptidyl peptidase-4 inhibitors 1

Perioperative Considerations

• For elective surgery requiring general anesthesia, discontinue tirzepatide at least 3 weeks (three half-lives) before surgery due to delayed gastric emptying and aspiration risk 5, 3
• Retained gastric contents are documented even after extended fasting periods, with 24.2% of patients showing increased residual gastric content versus 5.1% of controls 5, 2
• Consider gastric ultrasound pre-operatively to assess residual gastric contents 3

Common Pitfalls to Avoid

• Do not assume normal fasting eliminates aspiration risk in patients on tirzepatide—delayed gastric emptying persists even with extended discontinuation 5, 2
• Do not overlook the need for insulin/sulfonylurea dose reduction when initiating tirzepatide, as this is the primary cause of hypoglycemia with this medication 1
• Do not prescribe tirzepatide without screening for MTC/MEN2 family history, as this represents an absolute contraindication that cannot be overridden 1, 2, 3