How to manage fatigue in patients taking Glucagon-like peptide-1 (GLP-1) agonists?

Managing Fatigue in Patients Taking GLP-1 Receptor Agonists

Fatigue in patients taking GLP-1 receptor agonists should be managed by first ruling out serious complications, then addressing the most common underlying mechanisms including delayed gastric emptying, dehydration, and electrolyte imbalances.

Understanding Fatigue with GLP-1 Receptor Agonists

Fatigue is a common side effect experienced by patients taking GLP-1 receptor agonists that can significantly impact quality of life. Several mechanisms may contribute to this symptom:

Primary Mechanisms of GLP-1-Associated Fatigue

1. Gastrointestinal Effects

   • Delayed gastric emptying (gastroparesis) 1
   • Nausea, vomiting, and diarrhea leading to dehydration 2, 3
   • Reduced caloric intake due to appetite suppression 4

2. Metabolic Effects

   • Rapid weight loss causing temporary energy deficit 5
   • Potential hypoglycemia when combined with insulin or sulfonylureas 6

Diagnostic Approach

When a patient on GLP-1 receptor agonists reports fatigue:

1. Assess Severity and Pattern

   • Duration and timing of fatigue in relation to medication dosing
   • Impact on daily activities and quality of life

2. Rule Out Serious Complications

   • Acute kidney injury (from dehydration due to GI side effects) 2
   • Hypoglycemia (especially if on combination therapy) 6
   • Pancreatitis (abdominal pain, elevated lipase) 3
   • Heart failure exacerbation (particularly in patients with pre-existing HFrEF) 1

3. Evaluate for Contributing Factors

   • Medication dosage and duration of therapy
   • Recent dose increases
   • Concomitant medications
   • Hydration status
   • Nutritional intake

Management Algorithm

Step 1: Address Immediate Concerns

• For severe fatigue with dehydration signs:
  • IV fluid rehydration if clinically indicated
  • Electrolyte replacement as needed
  • Consider temporary dose reduction or medication holiday

Step 2: Optimize Medication Regimen

• Adjust Dosing Schedule:

  • Consider administering GLP-1 RA in the evening to minimize daytime fatigue
  • Ensure proper dose titration (starting low and gradually increasing)

• Medication Adjustments:

  • For patients with diabetes and heart failure with reduced ejection fraction (HFrEF), consider switching to an SGLT2 inhibitor, as GLP-1 RAs should be used with caution in these patients 1, 5
  • For patients taking GLP-1 RAs for weight loss only, consider temporary dose reduction

Step 3: Supportive Measures

• Nutritional Support:

  • Small, frequent meals to minimize gastric distention
  • Adequate protein intake (1-1.2 g/kg/day)
  • Complex carbohydrates for sustained energy

• Hydration:

  • Minimum 2L of fluid daily
  • Electrolyte-containing beverages if experiencing GI symptoms

• Physical Activity:

  • Gradual introduction of light exercise
  • Start with 10-15 minutes of walking daily and increase gradually

Step 4: Monitor and Follow-up

• Reassess symptoms within 2 weeks of implementing changes
• Consider laboratory testing (CBC, comprehensive metabolic panel, TSH) if fatigue persists

Special Considerations

For Perioperative Patients

• Fatigue may be exacerbated in the perioperative period
• Consider holding GLP-1 RAs for at least three half-lives before elective procedures to reduce risk of gastric stasis and associated complications 1

For Patients with Heart Failure

• Use GLP-1 RAs with caution in patients with established HFrEF due to potential worsening of outcomes 1, 5
• Monitor closely for heart failure symptoms including fatigue and exercise intolerance

Common Pitfalls to Avoid

1. Failing to recognize dehydration as a cause of fatigue in patients with GI side effects
2. Overlooking hypoglycemia in patients on combination therapy with insulin or sulfonylureas
3. Discontinuing medication prematurely rather than addressing manageable side effects
4. Not distinguishing between fatigue from the medication versus fatigue from underlying disease progression

When to Consider Medication Change

Consider switching to a different GLP-1 RA or alternative medication class if:

• Fatigue persists despite supportive measures for >4 weeks
• Patient experiences severe fatigue significantly impacting quality of life
• Signs of serious adverse effects develop (acute kidney injury, severe dehydration)

By following this structured approach, clinicians can effectively manage fatigue in patients taking GLP-1 receptor agonists while maintaining the metabolic and cardiovascular benefits these medications provide.