The Metabolic Shift

GLP-1 drugs—semaglutide, tirzepatide, retatrutide—do not just reduce appetite. They restructure metabolism.

Intake drops. Insulin sensitivity improves. The body shifts from storing fat to burning it. The liver produces less sugar. Fat oxidation increases. This is not passive weight loss from eating less. It is active metabolic reorganization.

That reorganization increases demand on NAD⁺.

The Double Pull

Burning fat is not simple combustion. It is a multi-step biochemical process that breaks fat molecules into smaller pieces your mitochondria can use for energy. That process requires NAD⁺ at multiple steps—NAD⁺ picks up electrons from the fat breakdown and carries them to the mitochondria. More fat burning means more NAD⁺ consumed.

Simultaneously, weight loss activates the enzymes that regulate how your body adapts to new metabolic demands—how it switches between fuel sources, responds to stress, and maintains flexibility. These enzymes (called sirtuins) consume NAD⁺ as their fuel.

Two accelerating processes. Same finite pool.

In someone with abundant NAD⁺, this works. In someone over 40—where NAD⁺ has already declined 50% or more—the math changes. You are pulling harder on a resource that was already thin.

The Wall

Clinicians prescribing GLP-1 drugs see a pattern.

Patients do well initially. Weight drops. Energy improves. Then, weeks or months in, something shifts. Progress stalls. Fatigue sets in—not the tiredness of caloric deficit, but something flatter, less responsive to rest. Cognitive fog. Exercise tolerance drops. The body feels like it is working harder to maintain a lower baseline.

This is the wall. It is real. Patients hit it. The pattern is consistent enough that clinicians recognize it.

Multiple factors likely contribute—caloric restriction, muscle loss, hormonal adaptation, micronutrient depletion. But one plausible contributor: NAD⁺.

The system wanted to run faster. Fat burning ramped up. The adaptive enzymes engaged. If the NAD⁺ supply could not keep pace, metabolism hit a ceiling. Not a failure of the drug's signal—a failure of the substrate required to sustain it.

This explanation is mechanistically coherent. It is not proven. But it suggests a strategy.

Why Co-Initiate

The conventional approach is to address problems when they emerge. Patient hits the wall, someone suggests supplementation or an IV infusion. Rescue mode.

This is backwards.

By the time symptoms appear, the depletion pattern may be established. The system has adapted to running on a thin NAD⁺ base. You are not preventing a problem; you are trying to reverse one.

Co-initiation means starting NAD⁺ support when GLP-1 therapy begins—before demand spikes, before the pool is drawn down.

The logic: if metabolic throughput is about to increase, ensure the NAD⁺ supply can handle it. Do not wait for the engine to sputter.

Practical Application

Baseline matters. Before starting GLP-1 therapy, consider where NAD⁺ status likely stands. Age over 40, history of chronic inflammation, post-viral syndromes, high alcohol use—all deplete NAD⁺. Someone starting tirzepatide at 55 with Long COVID history is not starting from the same baseline as a healthy 35-year-old.

Oral precursors as foundation. Nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN) at 300-500mg daily provides ongoing substrate. This is the maintenance layer—consistent support for increased metabolic demand without requiring clinical visits.

Injectable support for higher risk. For those starting with likely significant depletion—older patients, post-viral, chronic inflammation—subcutaneous or intramuscular NAD⁺ (100-250mg, 2-3x weekly) during the initial months provides more robust rebuilding. The goal is to get ahead of demand, not chase it.

Monitoring. Watch for the pattern: initial progress followed by disproportionate fatigue, stalls that do not respond to dose adjustment, cognitive symptoms that exceed what caloric deficit explains. These suggest NAD⁺ may be limiting.

The Retatrutide Consideration

Retatrutide—the triple-action drug hitting three different receptor types—amplifies the dynamic.

One of those receptors (glucagon) increases fat burning in the liver directly. The liver burns more fat. That is the mechanism behind retatrutide's superior weight loss. But liver fat-burning is NAD⁺-intensive. The liver is also where most NAD⁺ production and recycling occurs.

With retatrutide, you are increasing the demand for NAD⁺ at the site responsible for maintaining NAD⁺ supply. The math is tighter.

This does not make retatrutide problematic. It makes NAD⁺ support more important. The more potent the metabolic signal, the more the enabling infrastructure matters.

What NAD⁺ Support Is Not

NAD⁺ support is not a weight loss accelerator. It will not make GLP-1 therapy produce more dramatic results.

It is a capacity layer. It ensures the metabolic machinery can handle increased throughput without running into limits. The benefit is not more weight loss—it is sustainable weight loss. Cleaner adaptation. Less compensatory fatigue.

People lose weight on semaglutide without NAD⁺ supplementation. GLP-1 therapy works. But the quality of that transition—energy stability, cognitive clarity, durability of metabolic adaptation—may depend on whether NAD⁺ supply meets demand.

Limitations

The NAD⁺-depletion explanation for GLP-1 stalls is hypothesis, not established fact. No controlled trial has tested whether NAD⁺ supplementation prevents or reverses the wall.

The mechanistic logic is sound: increased fat burning consumes NAD⁺, adaptive enzymes consume NAD⁺, therefore increased demand on a depleted pool could cause problems. But "could" is not "does."

Individual response varies. Some patients on GLP-1s never hit a wall. Some hit it regardless of NAD⁺ status. This is one variable among many.

Cancer considerations apply here as elsewhere. NAD⁺ supports metabolism broadly. Active cancer is a contraindication. Cancer history warrants oncologist discussion.

References

• Cantó C, et al. NAD+ metabolism and the control of energy homeostasis. Cell Metabolism 2015.
• Yoshino J, et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science 2021.
• Guarente L. Sirtuins, aging, and metabolism. Cold Spring Harbor Symposia on Quantitative Biology 2011.
• Jastreboff AM, et al. Tirzepatide once weekly for the treatment of obesity. New England Journal of Medicine 2022.