How should tirzepatide (glucagon-like peptide-1 (GLP-1) receptor agonist) be used in patients with gastroparesis?

Tirzepatide Should Not Be Used in Patients with Gastroparesis

Tirzepatide is contraindicated in patients with gastroparesis and should not be used in this population due to its mechanism of action that further delays gastric emptying. 1, 2

Mechanism and Rationale for Contraindication

Tirzepatide, a dual GIP/GLP-1 receptor agonist, significantly delays gastric emptying through its pharmacological action. This effect is most pronounced after the first dose and diminishes somewhat over time but remains clinically significant 3. For patients with pre-existing gastroparesis, this medication would exacerbate their condition by:

• Further slowing gastric motility
• Potentially worsening nausea and vomiting
• Compromising nutritional status
• Potentially affecting absorption of other medications

Evidence Supporting Contraindication

The 2025 American Diabetes Association Standards of Care explicitly states that dual GIP and GLP-1 receptor agonists are "not recommended for individuals with gastroparesis" 1. This represents the most current and authoritative guidance on the subject.

Additionally, clinical practice guidelines for gastrointestinal motility disorders recommend avoiding medications that can worsen gastric emptying, specifically listing GLP-1 receptor agonists among medications to avoid in patients with gastroparesis 2.

Alternative Approaches for Diabetes Management in Gastroparesis

For patients with both diabetes and gastroparesis who need glucose-lowering therapy, consider these alternatives:

1. DPP-4 inhibitors: These have a neutral effect on gastric emptying and are generally well-tolerated in gastroparesis 1

2. Insulin therapy: Carefully titrated insulin regimens remain appropriate for patients with gastroparesis 1

3. Pioglitazone: May be considered if not contraindicated by other factors such as heart failure 1

4. Sulfonylureas: May be appropriate in select patients with careful monitoring for hypoglycemia 1

Management of Gastroparesis

For patients with gastroparesis who cannot use tirzepatide, focus on:

• Dietary modifications: Small, frequent meals (5-6 per day), low-fat, low-fiber diet, increased liquid calories, and avoidance of carbonated beverages 2

• Prokinetic agents: Metoclopramide (10 mg orally, 30 minutes before meals and at bedtime) remains the only FDA-approved medication for gastroparesis, though its use is limited to 12 weeks due to risk of tardive dyskinesia 2

• Alternative prokinetics: Erythromycin (40-250 mg orally 3 times daily) may be considered as an alternative first-line agent, though tachyphylaxis limits long-term use 2

• Antiemetics: Phenothiazines, trimethobenzamide, or serotonin receptor antagonists may help control nausea and vomiting 2

Monitoring and Follow-up

If a patient with undiagnosed gastroparesis is inadvertently started on tirzepatide:

• Monitor for worsening of gastroparesis symptoms (nausea, vomiting, early satiety, bloating)
• Discontinue tirzepatide if symptoms worsen
• Consider gastric emptying scintigraphy to confirm diagnosis
• Implement appropriate gastroparesis management

Special Considerations

While one small study suggested that exenatide (another GLP-1 receptor agonist) might not worsen gastric emptying in patients with pre-existing gastroparesis 4, this finding has not been replicated with tirzepatide, which has more potent effects on gastric motility due to its dual receptor activity. The American College of Cardiology expert consensus still recommends caution when using GLP-1 receptor agonists in patients with clinically significant gastroparesis 1.

The risk-benefit analysis clearly favors avoiding tirzepatide in patients with gastroparesis, as there are multiple alternative glucose-lowering medications available that do not carry this specific risk.