What are the contraindications for semaglutide and tirzepatide?

Contraindications for Semaglutide and Tirzepatide

Absolute Contraindications

Both semaglutide and tirzepatide are absolutely contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN2). 1

• This contraindication is based on preclinical rodent data showing dose- and duration-dependent thyroid C-cell tumors and carries an FDA Black Box Warning 1, 2
• The contraindication applies even if the patient has not been genetically tested for MEN2 3
• Pregnancy and breastfeeding are absolute contraindications for both medications 2, 3

Relative Contraindications and Severe Cautions

Renal Impairment

• Severe renal impairment or end-stage renal disease (ESRD): Semaglutide and tirzepatide can be used with caution, unlike exenatide and lixisenatide which are contraindicated 1, 2
• Monitor renal function closely, especially when initiating or escalating doses, due to increased risk of acute kidney injury from dehydration secondary to gastrointestinal side effects 2, 4

Gastrointestinal Conditions

• History of pancreatitis: Use semaglutide with caution; both medications have not been adequately studied in patients with prior pancreatitis 1, 2, 5
• Clinically meaningful gastroparesis: Not recommended, as both agents delay gastric emptying and will worsen symptoms 1, 2
• Prior gastric surgery (including bariatric surgery): Requires extreme caution due to altered gastric anatomy and delayed emptying effects 1, 2

Ophthalmologic Concerns

• Diabetic retinopathy: Semaglutide has been associated with diabetic retinopathy complications, potentially related to rapid glucose reduction; close monitoring required 1, 2

Common and Serious Adverse Effects

Gastrointestinal Effects (Most Common)

• Nausea, vomiting, diarrhea, and constipation occur in the majority of patients but are typically dose-dependent and transient 1
• Tirzepatide shows greater GI adverse event risk (RR 2.94) compared to semaglutide (RR 1.68) versus placebo 6
• In head-to-head comparison, nausea occurred in 17-22% with tirzepatide vs 18% with semaglutide; diarrhea in 13-16% vs 12%; vomiting in 6-10% vs 8% 7

Serious Adverse Events Requiring Monitoring

• Cholelithiasis and cholecystitis: Semaglutide increases gallbladder-related disorders by over 2.6 times (95% CI 1.40-4.82); tirzepatide shows no significant biliary risk 1, 6
• Acute pancreatitis: Reported in clinical trials, though causality remains unestablished 2, 4
• Acute kidney injury: Risk particularly high from dehydration secondary to severe gastrointestinal effects 2, 4

Drug Interactions and Special Considerations

Hypoglycemia Risk

• When combined with insulin or insulin secretagogues (sulfonylureas, glinides): Increased hypoglycemia risk requires dose reduction of these concomitant medications 1, 2
• Hypoglycemia occurred in 0.2-1.7% with tirzepatide and 0.4% with semaglutide in head-to-head trials 7

Oral Contraceptive Interactions

• For patients using oral hormonal contraceptives: Switch to non-oral contraception or add barrier method for 4 weeks after initiation and after each dose escalation due to delayed gastric emptying affecting absorption 1, 2

Medication Absorption

• Both agents delay gastric emptying and may slow absorption of concomitantly administered oral medications, particularly those with narrow therapeutic index (e.g., warfarin) 1, 2

Critical Dosing Considerations to Minimize Adverse Events

Start at the lowest dose and escalate gradually to minimize gastrointestinal side effects:

• Semaglutide: Start 0.25 mg weekly for 4 weeks, then 0.5 mg, then 1.0 mg if needed; maximum 2.4 mg weekly for weight management 1, 2
• Tirzepatide: Start 2.5 mg weekly, escalate after at least 4 weeks at each dose level 1
• Starting at high doses bypasses the body's adaptation period to delayed gastric emptying and dramatically increases GI adverse events 2

Common Pitfalls to Avoid

• Do not prescribe to patients with family history of MTC without explicitly ruling out this contraindication 1, 3
• Do not overlook renal function monitoring in patients with pre-existing kidney disease or those experiencing severe GI symptoms that could lead to dehydration 2
• Do not combine with insulin or sulfonylureas without dose reduction of these agents to prevent hypoglycemia 1, 2
• Do not use in patients with active or suspected pancreatitis 5