GLP-1 Use and Fatigue

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May 26, 2025

Fatigue or low energy is a commonly reported side effect among users of GLP-1 receptor agonists like semaglutide (Ozempic/Wegovy) or tirzepatide (Mounjaro/Zepbound), but it is not as well characterized or studied as gastrointestinal effects. Here’s what is currently known:

🔍 What We Know About Fatigue and GLP-1 Use

✅ Prevalence
Fatigue is reported in 3–11% of patients in clinical trials of GLP-1 drugs.
In the STEP trials (Wegovy), fatigue was reported in around 10% of users.
In SURMOUNT-1 (Zepbound), fatigue occurred in about 11% of participants in the highest dose group.
It is more likely to be reported early in treatment, especially during dose escalation.

✅ Mechanisms (Hypotheses)
Fatigue may be multifactorial:
Caloric restriction: Rapid appetite suppression and weight loss can create a calorie deficit, leading to low energy.
Gastrointestinal upset: Nausea or decreased nutrient intake can cause weakness or fatigue.
Electrolyte imbalance: Vomiting or low food intake may alter electrolytes (e.g., sodium, potassium).
Blood glucose changes: Especially in people with diabetes, glucose levels may drop.
Central nervous system effects: GLP-1 receptors in the brain may influence fatigue pathways (less well studied).

🕒 Is It Long Lasting?
In most cases, fatigue improves over time as the body adjusts.
For some, especially those with rapid weight loss or high doses, fatigue may persist for weeks to months.
Long-term, persistent fatigue is less common but can occur.

💡 What Can Be Done About It?
Slower titration of the GLP-1 dose may reduce fatigue severity.
Ensure adequate caloric and protein intake, even with reduced appetite.
Hydration and electrolyte balance (e.g., supplementing sodium, potassium, magnesium if needed).
Physical activity: Mild exercise can improve energy levels once tolerable.
Check thyroid and iron status: Underlying issues (like hypothyroidism, anemia) may be unmasked or worsened.
Timing: Some people find adjusting the time of injection (e.g., at night) helpful.

🧪 Are There Any Clinical Trials on GLP-1–Related Fatigue?
As of now:
No trials are dedicated solely to GLP-1–induced fatigue, but it is often recorded as an adverse event in larger trials.
A few relevant ongoing or completed studies include:
STEP 1–8 trials (semaglutide) – fatigue appears in secondary safety outcomes.
SURMOUNT trials (tirzepatide) – same situation.
Real-world observational studies are beginning to explore quality-of-life and side effect profiles.
If you’re interested, I can help look up specific trials on fatigue in GLP-1 users via ClinicalTrials.gov or recent conference abstracts.

📌 Summary
Prevalence
~3–11% report fatigue, higher during early treatment or dose escalation
Duration
Often short-lived; resolves in weeks for most
Mechanisms
Caloric deficit, dehydration, CNS effects, nutrient deficiency
Management
Nutrition, slower titration, activity, hydration, bloodwork
Trials
No dedicated trials, but fatigue is tracked in major studies like STEP and SURMOUNT

Audio Overview (Google NotebookLM)
(11 minutes 46 seconds)