Can nicotinamide adenine dinucleotide (NAD+) supplementation reduce fatigue associated with glucagon‑like peptide‑1 (GLP‑1) receptor agonist therapy?

NAD+ Supplementation for GLP-1 Receptor Agonist-Associated Fatigue

There is no evidence supporting NAD+ supplementation to reduce fatigue associated with GLP-1 receptor agonist therapy, and this approach should not be recommended based on current medical literature.

Evidence Gap and Clinical Reality

The question assumes a connection between two unrelated therapeutic areas:

• GLP-1 receptor agonists do not cause fatigue as a primary adverse effect. The most common side effects are gastrointestinal: nausea, vomiting, diarrhea, dyspepsia, and constipation, occurring in 15-20% of patients 1. These are dose-dependent and typically resolve with slow titration 1.

• NAD+ supplementation studies have focused on chronic fatigue syndrome, aging, and metabolic conditions—not medication-related fatigue 2, 3. No published research examines NAD+ for GLP-1 RA side effects.

What the Evidence Actually Shows

GLP-1 Receptor Agonist Side Effect Profile

The documented adverse effects include 1:

• Nausea and vomiting (most common)
• Diarrhea and constipation
• Gastrointestinal reflux
• Cardiac arrhythmia/tachycardia (heart rate increases 3-10 bpm) 4, 5
• Rare: pancreatitis, gallbladder disorders 1, 4

Fatigue is not listed among the common or significant adverse effects in major guidelines 1.

NAD+ Supplementation Evidence

NAD+ (specifically NADH) has been studied for:

• Chronic fatigue syndrome: One trial showed decreased anxiety and maximum heart rate after stress testing, but no improvement in overall fatigue intensity, functional performance, or quality of life 6.
• General populations: Safe and well-tolerated, with potential benefits for muscle insulin sensitivity and inflammatory markers, but evidence remains limited 2, 3.

Common side effects of NAD+ supplementation include muscle pain, nervous disorders, fatigue (ironically), sleep disturbance, and headaches 2—which could potentially worsen rather than improve patient symptoms.

Clinical Algorithm for Managing GLP-1 RA-Related Symptoms

If a patient reports fatigue while on GLP-1 RA therapy:

1. Investigate alternative causes first 7:

   • Hypoglycemia (though rare with GLP-1 RAs alone)
   • Dehydration from gastrointestinal side effects
   • Rapid weight loss
   • Underlying cardiovascular disease progression
   • Concurrent medications
   • Unrelated medical conditions

2. Optimize GLP-1 RA dosing 1:

   • Ensure slow titration from low starting doses
   • Consider reducing dose temporarily if symptoms are severe
   • Evaluate timing of administration

3. Manage gastrointestinal symptoms aggressively 1:

   • Reduce meal size
   • Limit alcohol and carbonated drinks
   • Avoid high-fat diet
   • These interventions may indirectly improve energy levels

4. Consider medication alternatives only if symptoms persist 1:

   • SGLT2 inhibitors (particularly in heart failure or CKD)
   • DPP-4 inhibitors
   • Other glucose-lowering agents based on comorbidities

Critical Pitfall

Do not attribute non-specific symptoms to GLP-1 RAs without proper evaluation. The comprehensive safety analysis of GLP-1 RAs across 175 health outcomes did not identify fatigue as a significant risk 7. Pursuing unproven supplements like NAD+ delays appropriate diagnosis and management of the actual underlying problem.