Does NAD (nicotinamide adenine dinucleotide) supplementation reduce fatigue in patients taking a glucagon‑like peptide‑1 (GLP‑1) receptor agonist?

No Evidence Supports NAD Supplementation for GLP-1-Related Fatigue

There is no clinical evidence that NAD (nicotinamide adenine dinucleotide) supplementation reduces fatigue in patients taking GLP-1 receptor agonists. The available research on NAD supplementation has not studied this specific population or clinical scenario.

Why This Question Cannot Be Answered with Current Evidence

The evidence base presents two completely separate domains that do not intersect:

GLP-1 Receptor Agonist Side Effect Profile

• Fatigue is not a commonly reported adverse effect of GLP-1 receptor agonists. The predominant side effects are gastrointestinal, including nausea (17-44%), diarrhea (12-32%), vomiting (7-25%), and constipation (10-23%) 1.
• Other documented side effects include headache, increased heart rate (3-10 beats/min), and blood pressure reduction (2-3 mm Hg systolic) 2, 3.
• The most serious but rare risks include pancreatitis and gallbladder disease 3, 1.

NAD Supplementation Research Populations

• NAD supplementation studies have focused on chronic fatigue syndrome, Parkinson's disease, older adults, and long-COVID—none of which involved patients on GLP-1 receptor agonists 4, 5, 6.
• In chronic fatigue syndrome, NADH 20mg daily showed minimal benefit, with only a decrease in anxiety (-1.0 points) and maximum heart rate after stress testing (-8.1 bpm), but no improvement in fatigue intensity, functional performance, or quality of life 5.
• In long-COVID patients, nicotinamide riboside (NR) 2000mg daily increased NAD+ levels 2.6-3.1 fold but showed no significant improvement in fatigue severity compared to placebo (p=0.59) 6.

Critical Analysis of NAD for Fatigue

The evidence for NAD supplementation treating fatigue is weak even in populations where fatigue is the primary complaint:

• A systematic review of NAD supplementation found that while it was generally safe, the clinical benefits were inconsistent and most studies showed only modest improvements in quality of life parameters, not fatigue specifically 4.
• The most common side effects of NAD supplementation include muscle pain, nervous disorders, fatigue, sleep disturbance, and headaches 4—ironically, fatigue itself is a reported adverse effect.
• Long-term safety data in humans remains limited, with concerns about potential risks including accumulation of toxic metabolites and promotion of cellular senescence 7.

What to Do Instead

If a patient on a GLP-1 receptor agonist reports fatigue, investigate other causes:

• Rule out hypoglycemia if the patient is on concomitant insulin or sulfonylureas, as GLP-1 RAs increase hypoglycemia risk when combined with these agents 3, 1.
• Assess for dehydration from gastrointestinal side effects (nausea, vomiting, diarrhea), which are common during dose titration 3, 1.
• Evaluate thyroid function, as GLP-1 receptors are expressed in the thyroid and may have pleiotropic effects 1.
• Consider medication-induced sleep disturbance or other metabolic factors unrelated to the GLP-1 RA itself.
• Review the patient's overall medication regimen for other potential causes of fatigue 1.

Common Pitfalls to Avoid

• Do not attribute fatigue to GLP-1 receptor agonists without ruling out other causes, as fatigue is not a characteristic side effect of this drug class 3, 1.
• Do not recommend NAD supplementation based on theoretical mechanisms when no clinical evidence supports its use in this population 4, 5, 6.
• Do not ignore the possibility that fatigue may be related to the underlying condition (obesity, type 2 diabetes, cardiovascular disease) rather than the medication 3, 1.