Can tirzepatide (glucagon-like peptide-1 receptor agonist) cause fatigue?

Tirzepatide and Fatigue: Potential Association and Management

Yes, tirzepatide can cause fatigue as a side effect, though it is not among the most commonly reported adverse effects compared to gastrointestinal symptoms. While the primary adverse effects of tirzepatide are gastrointestinal in nature (nausea, vomiting, diarrhea), fatigue can occur as part of the medication's systemic effects.

Mechanism of Fatigue with Tirzepatide

Tirzepatide's fatigue-inducing effects may be related to several mechanisms:

1. Metabolic Effects:

   • As a dual GIP/GLP-1 receptor agonist, tirzepatide affects multiple metabolic pathways 1
   • Significant caloric reduction and rapid weight loss can lead to energy deficits
   • Changes in glucose metabolism may temporarily affect energy levels

2. Gastrointestinal Effects:

   • Delayed gastric emptying can reduce nutrient absorption 1
   • Nausea and reduced appetite may lead to inadequate caloric intake
   • Dehydration from gastrointestinal side effects may contribute to fatigue

3. Cardiovascular Effects:

   • GLP-1 receptors are located in the sinoatrial node and arterial walls 1
   • May affect heart rate and vascular function
   • Potential blood pressure changes could contribute to fatigue symptoms

Clinical Evidence and Prevalence

While the major clinical trials of tirzepatide (SURPASS and SURMOUNT programs) focused primarily on efficacy for weight loss and glycemic control, adverse events were documented 1. Tirzepatide demonstrated impressive weight loss results (up to 20.9% at the 15 mg dose) 1, but this substantial weight reduction may contribute to fatigue symptoms in some patients.

The most commonly reported adverse effects include:

• Nausea
• Vomiting
• Diarrhea
• Constipation
• Dyspepsia
• Gastrointestinal reflux 1

Fatigue may be an underreported side effect or may occur secondary to these primary adverse effects, particularly if they lead to reduced caloric intake, dehydration, or electrolyte imbalances.

Management of Tirzepatide-Associated Fatigue

If a patient experiences fatigue while taking tirzepatide, consider the following approach:

1. Dose Optimization:

   • Start at the lowest dose (5 mg) and titrate slowly 1
   • Consider extending the titration schedule if fatigue is significant
   • Find the minimum effective dose that balances weight loss benefits with side effects

2. Nutritional Support:

   • Ensure adequate protein intake despite reduced appetite
   • Monitor for signs of malnutrition, especially with significant weight loss 1
   • Consider small, frequent meals rather than larger ones

3. Hydration and Electrolytes:

   • Maintain proper hydration
   • Monitor and correct electrolyte imbalances if present
   • Consider electrolyte supplements if needed

4. Activity Management:

   • Gradually increase physical activity as tolerated
   • Balance rest periods with activity
   • Avoid overexertion during initial weight loss phase

5. Rule Out Other Causes:

   • Evaluate for other potential causes of fatigue (anemia, thyroid dysfunction, etc.)
   • Consider medication interactions
   • Assess for rare but serious adverse effects like rhabdomyolysis 2

Special Considerations

1. Monitoring Requirements:

   • Regular follow-up during dose titration
   • Assessment of nutritional status with significant weight loss
   • Screening for complications if fatigue is severe or persistent

2. Risk Factors for Increased Fatigue:

   • Rapid dose escalation
   • Pre-existing nutritional deficiencies
   • Concurrent medications with fatigue as a side effect
   • Dehydration or electrolyte imbalances

3. When to Consider Dose Reduction or Discontinuation:

   • Severe, persistent fatigue affecting daily activities
   • Signs of malnutrition or significant electrolyte abnormalities
   • Development of serious adverse effects like rhabdomyolysis 2

Conclusion

While tirzepatide offers significant benefits for weight loss and glycemic control, fatigue can occur as a side effect. This may be directly related to the medication's mechanism of action or secondary to other adverse effects such as reduced caloric intake or gastrointestinal symptoms. Proper dose titration, nutritional support, and monitoring can help manage this side effect while maintaining the therapeutic benefits of the medication.