Can GLP-1 Receptor Agonists Cause Fatigue?
Yes, GLP-1 receptor agonists can cause fatigue, though it is not among the most common adverse effects. According to FDA labeling for semaglutide (Ozempic), fatigue is specifically listed as an adverse reaction occurring with a frequency >0.4% 1.
Frequency and Clinical Significance
- Fatigue occurs in a small but measurable proportion of patients taking GLP-1 receptor agonists, with a frequency exceeding 0.4% based on FDA drug labeling 1.
- This adverse effect is substantially less common than the primary gastrointestinal side effects (nausea, vomiting, diarrhea), which occur in 32.7-36.4% of patients 1.
Context and Differential Considerations
When evaluating fatigue in patients on GLP-1 receptor agonists, consider these alternative or contributing mechanisms:
Hypoglycemia-related fatigue: While GLP-1 receptor agonists have a low intrinsic hypoglycemia risk as monotherapy, the risk increases significantly when combined with insulin or sulfonylureas 2, 1. Documented symptomatic hypoglycemia occurred in 17.3-24.4% of patients when semaglutide was co-administered with a sulfonylurea 1.
Gastrointestinal symptom burden: The high frequency of nausea (occurring in 32.7-36.4% of patients) and vomiting may indirectly contribute to fatigue through reduced oral intake, dehydration, or general malaise 1.
Rapid weight loss effects: GLP-1 receptor agonists produce substantial weight loss (14.9% with semaglutide 2.4 mg over 68 weeks, up to 20.9% with tirzepatide) 3, 4. Rapid caloric restriction and metabolic adaptation during significant weight loss can manifest as fatigue.
Cardiovascular considerations: In patients with heart failure, particularly HFrEF, the LIVE and FIGHT trials showed no improvement in functional capacity or quality of life with liraglutide 2. The LIVE trial noted no changes in quality of life at 24 weeks, which could encompass fatigue-related symptoms 2.
Clinical Management Approach
When a patient on GLP-1 receptor agonist therapy reports fatigue:
Rule out hypoglycemia first: Check blood glucose levels, especially if the patient is on concurrent insulin or sulfonylureas. Consider reducing doses of these medications proactively 2, 1.
Assess for dehydration and electrolyte abnormalities: Particularly during initial titration when gastrointestinal symptoms are most prominent, monitor renal function and hydration status 4.
Evaluate adequacy of caloric intake: Ensure the patient is consuming sufficient calories despite appetite suppression, as excessive caloric restriction can cause fatigue independent of the medication.
Consider medication-related fatigue: If other causes are excluded and fatigue is significantly impacting quality of life, this represents a direct adverse effect of the GLP-1 receptor agonist that may warrant dose reduction or discontinuation.
Important Caveats
The cardiovascular benefits of GLP-1 receptor agonists (13-26% reduction in major adverse cardiovascular events) 5, 6 and mortality benefits (12% reduction in all-cause death, 13% reduction in cardiovascular death) 6 must be weighed against tolerability concerns like fatigue.
Fatigue should not be automatically attributed to the GLP-1 receptor agonist without excluding other common causes in this patient population, including uncontrolled diabetes, cardiovascular disease progression, or concurrent medications.
Unlike gastrointestinal side effects that typically diminish over time with continued use 4, 5, the natural history of GLP-1 receptor agonist-associated fatigue is not well-characterized in the literature.