What proton pump inhibitor (PPI) is best to use with Mounjaro (tirzepatide)?

PPI Selection with Mounjaro (Tirzepatide)

Any standard proton pump inhibitor can be safely used with Mounjaro, as there are no known drug interactions between tirzepatide and PPIs; however, if you need to choose a specific agent, pantoprazole 40mg daily is an excellent first-line option due to its minimal drug interaction profile and proven safety record. 1, 2

Why PPIs Are Safe with Mounjaro

• Mounjaro (tirzepatide) is a GLP-1 receptor agonist that does not undergo hepatic cytochrome P450 metabolism, eliminating the potential for CYP-mediated drug interactions with PPIs 2
• Unlike antiplatelet agents (clopidogrel), where PPI selection matters significantly, there are no pharmacokinetic or pharmacodynamic concerns when combining any PPI with tirzepatide 3

Recommended PPI Options

First-Line Choice: Pantoprazole

• Pantoprazole 40mg once daily is recommended as a preferred option due to its exceptionally low potential for drug-drug interactions and extensive safety data 1, 2, 4
• Pantoprazole has been shown in numerous interaction studies to have no clinically significant drug interactions, making it ideal for patients on multiple medications 4, 5
• Take 30 minutes before breakfast for optimal absorption 6

Alternative Standard PPIs (All Equally Appropriate)

• Omeprazole 20mg daily - the reference standard PPI with equivalent efficacy 1, 2
• Esomeprazole 20mg daily - higher potency option (equivalent to 32mg omeprazole) 1, 2
• Lansoprazole 30mg daily - intermediate potency (equivalent to 27mg omeprazole) 1, 2
• Rabeprazole 20mg daily - most potent traditional PPI (equivalent to 36mg omeprazole) 1, 2

Emerging Option: Potassium-Competitive Acid Blockers

• Vonoprazan offers more rapid and potent acid suppression than traditional PPIs, with advantages including acid stability, no prodrug activation required, and less effect from CYP2C19 genetic polymorphisms 1, 2
• Particularly effective for H. pylori eradication (92% vs 80% with PPIs) if that is a concurrent indication 1

Clinical Decision Algorithm

Step 1: Assess if PPI is truly needed

• GLP-1 agonists like Mounjaro can cause nausea and GI upset, but this typically improves with continued use 2
• Only prescribe PPI if there is documented GERD, peptic ulcer disease, or other acid-related indication 2

Step 2: Choose based on patient-specific factors

• If patient is on clopidogrel: Avoid omeprazole and esomeprazole; use pantoprazole instead 2
• If patient has multiple medications: Pantoprazole preferred due to minimal interaction potential 4, 7
• If cost is a concern: Generic omeprazole is least expensive 8
• If patient needs IV formulation: Pantoprazole available in both oral and IV forms 5, 8

Step 3: Standard dosing

• Use equivalent doses: omeprazole 20mg = pantoprazole 40mg = lansoprazole 30mg = esomeprazole 20mg = rabeprazole 20mg 1, 6
• Administer 30-60 minutes before first meal of the day 1, 2

Important Caveats

• The concern about PPI-clopidogrel interactions does NOT apply to Mounjaro - this is only relevant for patients on dual antiplatelet therapy 3, 2
• Long-term PPI use carries risks (cardiovascular disease, fractures, infections) regardless of which PPI is chosen, so regularly reassess the ongoing need 1, 2
• All PPIs are metabolized by CYP2C19, and genetic polymorphisms can affect efficacy, but this is not influenced by concurrent Mounjaro use 2, 7
• Avoid routine prophylactic PPI use without clear indication - the gastrointestinal side effects of Mounjaro typically do not require PPI therapy and often resolve spontaneously 2