Retatrutide + NAD+ Beginner Protocol for Energy Support During Fat Loss

Retatrutide and NAD+: Brief Overview

Retatrutide is an investigational triple agonist that engages the GIP, GLP-1, and glucagon receptors, developed by Eli Lilly and still in Phase 3 trials. It lowers appetite and raises fat-oxidation demand, largely through its glucagon arm.

NAD+ is a coenzyme present in every cell — the redox cofactor that beta-oxidation spends to turn mobilized fat into ATP.

Retatrutide and NAD+ are paired because retatrutide can mobilize fat faster than a depleted NAD+ pool burns it. When that happens, the user may still be in a deficit but feel flat, cold, foggy, restless, or underpowered. NAD+ support keeps the burn-to-ATP step from becoming the limiting factor, which keeps appetite control and oxidation capacity moving together.

No published trial has tested the combination directly. The rationale is mechanistic (beta-oxidation is NAD+-dependent) plus field observation. Injectable NAD+ is optional and does not move the scale faster; what it addresses is metabolic capacity during a deep deficit.

Evidence Status

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Protocol in Context

This is for retatrutide users who want:

• Clear structure with minimal complexity
• Appetite control without energy collapse
• A foundation for more advanced protocols later
• A conservative starting point before adding MOTS-c, L-Carnitine, or GH-axis support

The aim is a clean metabolic base: lower appetite, better glucose control, and enough redox capacity to use the fuel being released, held at a dose that leaves training output, sleep, and lean mass intact.

NAD+ Supports Retatrutide Driven Weight-Loss

Retatrutide drives fast weight loss, and burning that much stored fat for fuel leans hard on the cell’s energy machinery. NAD+/NADH recycling is load-bearing for that work. Using injectable NAD+ to keep that pathway clear is this protocol’s synthesis from mechanism and field use; no trial has measured it as an intervention in retatrutide users.

Retatrutide¹ ⁹ (LY3437943, developed by Eli Lilly) is a triple agonist that engages three receptors — GIP, GLP-1, and glucagon — at very different fractions across the dose range:

Numbers are modeled receptor engagement percentages at chronic steady state. The chain combines arm-level steady-state serum exposure, receptor EC50 values, the albumin/free-fraction conversion, and borrowed body-weight allometry.⁹ At GIPR and GCGR they approximate the fraction of receptor bound. At GLP-1R the figure is signal capacity rather than receptors bound—a binding read at 12 mg is closer to 10%.

The obese column is anchored to the Phase 2 cohort at about 109 kg and BMI 37. The lean column applies the donor weight model at about 75 kg.⁹

Two patterns matter for the dose decision.

First, GIPR engages fast. By 1 mg, the GIP receptor is already in the working range — held continuously every hour of every week, instead of in the brief meal-time pulses native physiology produces. That’s the receptor doing the direct fat-cell work (insulin efficiency, adipose thermogenesis), and it is mostly online before the appetite arm (GLP-1R) has climbed. Even at 1 mg, retatrutide is a GIP-dominant drug; its GLP-1R functional potency is lower than native GLP-1, and the glucagon arm climbs proportionally with dose.

Second, the lean and obese columns sit close. The per-mg exposure shift between phenotypes is real but modest. The larger phenotype difference is downstream: the same engagement produces a measurably stronger cardiovascular response in lean cohorts — higher resting heart-rate sensitivity, sharper β-OHB rise, faster onset of skin sensitivity and chills. Lean, sensitive, South Asian, or tirzepatide-transition users typically start at 0.3-1 mg with 4+ week holds, not because the receptor engagement is different at the same dose, but because the body responds more loudly to the same engagement.

Glucagon-mediated effects are threshold-dependent. At lower doses the signal is more liver-facing: hepatic fat handling, glucose output, and energy-expenditure pressure. As exposure rises, glucagon-driven peripheral effects emerge: resting heart-rate elevation, chills, insomnia, and a more catabolic feel. Skin sensitivity (dysesthesia) climbs with dose too, but it rides the GLP-1 arm rather than glucagon.

The dose decision is therefore not just "how much weight loss." It is how quickly the user pushes GIP, GLP-1, and glucagon engagement at once.

But mobilized fat still needs to be burned. That makes endogenous NAD+ recycling essential; supplemental NAD+ is the intervention this protocol builds on that requirement.

In a deficit, cells lean heavily on β-oxidation—the pathway that converts fat to ATP. This pathway spends NAD+ every cycle.² When demand outruns availability or recycling, fat can be mobilized faster than it is comfortably converted to usable energy.³ Fatigue sets in, cravings return, and progress stalls.

Retatrutide concentrates this demand in the liver. Its glucagon receptor activation increases hepatic fat oxidation, while the liver is also a major hub for NAD+ recycling and nicotinamide clearance. The liver-fat and metabolite studies carry the retatrutide side of that chain; the claim that injectable NAD+ corrects the resulting fatigue remains the protocol synthesis.¹¹

Maintaining NAD+ keeps the fat-burn → ATP chain from becoming the weak link. What that buys is better tolerance of the deficit retatrutide already created, at the same appetite suppression.

Preventing the Reta Driven Metabolic Wall

A subset of GLP-1 users hit a "wall" around months 3-6: energy crashes, exercise tolerance drops, progress feels stuck. The mechanism below is real and fairly well understood, but it does not hit everyone equally. It concentrates in users who start with a vulnerability: marginal thyroid, subclinical mitochondrial dysfunction, a prior chronic-fatigue history, a micronutrient-thin diet, or disrupted sleep. Most users never hit the wall; the ones who do tend to carry one of those.

Retatrutide mobilizes stored fat through its triple-receptor mechanism. That fat still has to be converted to ATP through beta-oxidation, the pathway that breaks fat into usable energy. Every turn of beta-oxidation hands electrons to NAD+, converting it to NADH; the cell then regenerates NAD+ by passing those electrons down the electron transport chain at Complex I. What limits the cycle is not only the size of the NAD+ pool but the ratio of NAD+ to NADH: there has to be oxidized NAD+ free to accept the next round of electrons.⁸

The ratio spiral:

1. Caloric deficit raises fat-oxidation demand; beta-oxidation runs at high capacity
2. If Complex I throughput cannot clear NADH at the same rate, NAD+/NADH recycling becomes the bottleneck⁸
3. NADH builds up faster than it clears, and the NAD+/NADH ratio falls
4. The low ratio quiets sirtuins and mimics a low-oxygen state in normal oxygen, a "pseudohypoxic" pattern⁸
5. Fat is mobilized but not cleanly converted to ATP: the wired-but-underpowered feeling, and progress stalls

Competing demands for NAD+

The NAD+ pool serves four masters simultaneously—and they all compete for the same finite resource:

When energy production dominates the pool—as it does during aggressive metabolic protocols—the other systems get rationed. Recovery slows, stress adaptation weakens, and the "wall" materializes. The inflammation arm is worth understanding because it consumes rather than uses NAD+: CD38 is an enzyme on immune cells that degrades NAD+ outright, and its activity rises with inflammatory load and with the accumulation of senescent cells.⁴ ⁵ That is a draw on the same pool, not a share of it.

Maintaining the NAD+ floor

NAD+ support keeps all four systems from competing against a shrinking floor:

• Energy production runs without exhausting other pathways
• DNA repair continues in the background
• Sirtuin-driven adaptation stays active
• The depletion spiral never gains momentum

This is the logic behind the combination: retatrutide creates the deficit and mobilizes fat; NAD+ helps preserve the capacity to oxidize it. The biochemistry here is established: beta-oxidation requires NAD+. One nuance matters. Because the bottleneck is the NAD+/NADH ratio, supplying NAD+ helps most when the clearance side (Complex I throughput) is intact; where mitochondrial throughput is itself impaired, adding more substrate alone can push the ratio the wrong way, and the next layer is the mito-stack (SS-31 to restore Complex I) rather than more NAD+.⁸ What has not been tested in a controlled trial is whether supplementing NAD+ during GLP-1 therapy specifically prevents the fatigue wall. The mechanistic case is strong; the clinical proof is still emerging.

For deeper understanding of NAD+ mechanisms, including the CD38/senescent cell loop that drives age-related depletion, see the complete NAD+ guide.

What NAD+ support does

NAD+ is a capacity layer. It changes how well the machinery handles the throughput retatrutide creates, which shows up as fatigue, recovery, and craving pressure rather than as faster scale movement. Receptor potency and appetite suppression are unchanged by it.

Dosing

Retatrutide 0.3-4mg total weekly depending on starting weight and metabolic health, each dose held 4+ weeks before titration.¹² NAD+ 50-100 mg every other day or 50-200 mg 2-3×/week; IM preferred; SubQ runs 50-100 mg per dose split into injections of 50 mg or less. Oral NR 300-500 mg or NMN 250-500 mg daily as the maintenance layer.

The peptide reconstitution calculator gives the exact injection volume for any reconstitution concentration. For preparation instructions, see the reconstitution guide.

The injectable NAD+ range above is a loading-phase convention, and as of 2026 its lower end has a controlled human anchor: a small double-blind trial (45 people, nine arms) administered 100 mg NAD+ by IM, IV, and SC over three consecutive days and found the injections tolerated. That trial deferred its blood-NAD+ measurement, and it speaks to tolerability rather than to how much reaches tissue — the 200 mg end of the range is still convention. The range applies when there is reason to expect a depleted baseline — age 50+, recovering from chronic illness or a post-viral state, prolonged caloric deficit, chronic stress, or symptomatic fatigue at protocol start. After 4-8 weeks of loading, the dose typically steps down to 2× weekly or transitions to oral precursors for ongoing support. Users without depletion markers can skip the loading phase and operate on oral precursors from the start.

The non-injectable route. Oral precursors — nicotinamide riboside (NR) at 300-500 mg daily or nicotinamide mononucleotide (NMN) at 250-500 mg daily — raise NAD+ levels more gradually than injections. NR has the cleaner human pharmacokinetic evidence base; NMN remains a reasonable oral option. They are not the same as injectable NAD+, but they are legitimate maintenance support. See the NAD+ guide for a full comparison of repletion strategies.

Weekly Schedule (Example)

The pattern flexes to whatever retatrutide frequency the schedule runs on. Consistency matters more than the specific day.

Timeline: What to Expect

Weeks 1-4

• Adaptation — Appetite suppression begins within 48-72 hours
• Early signals — Reduced snacking, flatter glucose curves, 2-4 lb loss (some water/glycogen)
• Side effects — Mild nausea possible; smaller protein-first meals help
• Energy — May fluctuate initially; NAD+ is used to support the oxidation side of the deficit

Weeks 5-8

• Steady progress — Fat loss stabilizes at 1-2 lb/week
• Appetite — Becomes mechanical rather than emotional
• Energy — Often steadier when NAD+ support, protein, hydration, and sleep are all in place
• Challenge — May need reminders to eat enough protein

Weeks 9-12

• Consolidation — Scale progress may slow; body composition keeps improving
• Measurements — Waist circumference drops, clothes fit differently
• Metabolic state — Hunger control consistent for most users, energy stable
• Decision point — Continue, maintain, or advance to Intermediate

Lifestyle Foundation

This protocol works on top of, not instead of, basic metabolic hygiene.

When Progress Stalls

Dose escalation runs gradual and methodical in this protocol. When weight loss plateaus, the order of checks runs:

1. Protein, steps, hydration, electrolytes, and the carbohydrate floor come first. A plateau with fatigue is often under-fueling, not a retatrutide-dose problem.
2. Active nausea, constipation, resting heart rate, chills, skin sensitivity, insomnia, or appetite collapse marks a body that has not caught up to the current dose — the signal against a step up.
3. A dose that has been quiet for 4+ weeks is the point where a small step beats jumping dose bands.
4. When fatigue is the main limiter, the NAD+ lever moves first — toward 200 mg per dose, better route or dilution, or a steady NR/NMN base — before retatrutide climbs.
5. The new pattern holds 4+ weeks before any further titration.

Managing Side Effects

Monitoring

What Comes Next

After 12 weeks, two paths:

Maintenance: retatrutide drops to the lowest effective dose, often 0.5-2 mg/week. NAD+ can move to 100-250 mg total weekly during training blocks, high stress, or fatigue-prone periods. Oral NR/NMN carries the daily maintenance layer.

Progress to Intermediate: the next layer adds L-Carnitine and MOTS-c for fat-oxidation capacity, with Tesamorelin in reach where lean-mass preservation or visceral-fat focus becomes central. See Retatrutide Recomp Protocol.

Contraindications

Retatrutide:

• Personal or family history of medullary thyroid carcinoma or MEN2 syndrome
• Active pancreatitis
• Pregnancy or breastfeeding
• Severe GI motility disorders
• Pre-existing atrial fibrillation, structural heart disease, or sustained tachycardia without medical oversight

NAD+ supplementation:

• Active cancer (NAD+ supports cellular metabolism in every cell, including malignant ones)
• Severe hepatic or renal impairment
• Concurrent chemotherapy (some regimens work by depleting NAD+; supplementation may interfere)
• Heart failure, significant arrhythmia, or recent cardiac events — injectable or IV NAD+ can stress the cardiovascular system; use medical oversight or oral NR/NMN instead

A history of cancer, gallbladder disease, or diabetic retinopathy, and concurrent glucose-lowering medications or anticoagulants that may need adjustment, are the profiles that warrant clinical oversight before starting.

Retatrutide Clinical Trial Results

Retatrutide has produced unusually large weight-loss outcomes in clinical trials. The landmark NEJM 2023 study (Jastreboff et al.) reported:

Reading the arms. 1 mg is the real low-dose Phase 2 arm in non-diabetic obesity; 4 mg is mid-range, where glucagon thresholds begin to matter; 8 mg captures most of the 12 mg effect; 12 mg is the top of the Phase 2 range, with a higher side-effect burden.

The 1 mg arm matters because of where it lands on the receptor map. At 1 mg, GIPR is the dominant modeled engagement axis, held continuously instead of in native meal-time pulses. The measured 8.7% weight loss is the integrated output of all three receptors rather than a GIPR figure, and it is a real efficacy result at a dose most protocols treat as a titration rung. No other compound in the GLP-1 family has direct sub-label-floor evidence at this magnitude.

The placebo-adjusted dose-response saturates between 8 and 12 mg. Beyond 8 mg, the additional weight loss is small relative to the side-effect cost. This beginner protocol uses conservative doses (0.3-4 mg weekly) to prioritize tolerability while still producing meaningful appetite and metabolic effects. The outcome depends heavily on starting weight, metabolic health, dose discipline, protein intake, and training.

Current Status & Availability

Retatrutide (development code: LY3437943) is not FDA approved. Phase 3 topline readouts include the obesity-plus-osteoarthritis trial (December 11, 2025: 28.7% average weight loss at 12 mg over 68 weeks)⁷ and the pivotal obesity trial (May 21, 2026: 28.3% at 12 mg over 80 weeks).¹⁰ The current held registry inventory contains nine Phase 3 trials; the 2025 design paper describes the original four-trial registrational core.⁶

Key regulatory milestones:

• Phase 2 results published in NEJM (2023)
• Phase 3 topline results reported for the obesity-plus-osteoarthritis trial on December 11, 2025 (28.7% mean weight loss at 12 mg / 68 weeks)⁷ and the pivotal obesity trial on May 21, 2026 (28.3% at 12 mg / 80 weeks)¹⁰
• FDA approval window: still pending the full Phase 3 package and regulatory review

Current non-trial access is research or grey-market, not an approved prescription pathway.

FAQ

What starting-dose ranges are used in beginner retatrutide protocols?

The usual modeled entry is 0.5 mg per week by subcutaneous injection; 1 mg remains the lowest chronic arm directly measured in the Phase 2 obesity trial. Lean, sensitive, South Asian, bodybuilding-cut, or tirzepatide-transition users typically belong closer to 0.5 mg; further down at 0.3 mg for the lean South Asian phenotype with high cardiac sensitivity.

Each dose holds at least 4 weeks before the next step, and active nausea, constipation, resting-HR elevation, chills, skin sensitivity, insomnia, or appetite collapse marks a body not yet caught up to the current dose — the signal against titrating through it.¹² See the retatrutide dosing calculator for the full ladder.

What weight-loss outcomes have been observed with retatrutide?

Phase 2 means at 48 weeks (non-diabetic obesity):

Phase 3 obesity-plus-osteoarthritis trial (68 weeks): 28.7% mean at 12 mg.⁷

These are averages, not ceilings. Trial responder distributions show meaningful spread — about 1 in 5 participants on the 12 mg arm in Phase 2 lost ≥30%; some lost much less. A 12-week beginner protocol using 0.3-4 mg is a different exposure window than the 48- or 68-week trials. Early losses often include water and glycogen; sustained fat loss depends on starting weight, metabolic health, dose discipline, protein intake, and training.

How does retatrutide compare to semaglutide (Ozempic)?

Retatrutide is a triple agonist; semaglutide is GLP-1-only. The pharmacology gap is wider than the receptor count suggests. Retatrutide is a full GLP-1R agonist with lower functional potency than native GLP-1; semaglutide is a different molecule and dose scale, which makes "softer" the wrong word for the difference.

Its GIP arm — absent in semaglutide entirely — engages adipose thermogenesis directly. Its glucagon arm actively mobilizes liver fat, while semaglutide reduces liver fat passively as a downstream consequence of weight loss. The structural difference shows up most clearly at sub-trial-floor doses: at 1 mg, retatrutide’s GIP and GLP-1 arms are both already in the working range, and the glucagon arm has no analog in semaglutide at any dose.

Is retatrutide FDA approved?

Retatrutide is not FDA approved. Phase 3 topline data include the obesity-plus-osteoarthritis trial (28.7% mean weight loss at 12 mg over 68 weeks)⁷ and the pivotal obesity trial (28.3% at 12 mg over 80 weeks).¹⁰ Additional Phase 3 trials are continuing, and any approval depends on the full Phase 3 package and regulatory review. Current non-trial access is research or grey-market, not an approved prescription pathway.

Why combine retatrutide with NAD+?

NAD+ supports the beta-oxidation pathway that converts mobilized fat into ATP. When retatrutide creates a deficit, stored fat still has to be burned efficiently. During significant caloric restriction, training, or rapid weight loss, NAD+ demand can rise faster than recycling keeps up. Injectable NAD+ is usually dosed 50-200 mg IM 2-3×/week for active support; SubQ runs 50-100 mg per dose, split into injections of 50 mg or less, if irritation is managed; above 100 mg use IM.

How do oral NMN and NR compare with each other, and with injectable NAD+?

Less differently than the marketing on either suggests, and the mg numbers are not comparable across routes at all.

Start with the comparison that actually breaks: injected and oral doses cannot be compared milligram for milligram. What transfers between routes is the vitamin-B3 equivalent — one pyridine ring per molecule, preserved through every conversion step — and by that measure 100 mg of injected NAD+ carries about as much substrate as 38-96 mg of oral NR. A single 250 mg NMN capsule carries roughly five times that. The case for injecting rests on speciation and the acute concentration wave rather than on substrate quantity, because injection skips the gut-and-liver first pass that converts oral precursors almost entirely to nicotinamide before they reach circulation.

Between the two orals: NR is the more direct cellular substrate, and NMN reaches cells largely by converting to NR after absorption — the parent NMN does not rise in plasma. NR carries more human pharmacokinetic and trial data; NMN carries more consumer-supplement volume and has its own functional results, including muscle improvements at 250 mg daily over 12 weeks in older men and skeletal-muscle insulin sensitivity in prediabetic women. There is no definitive oral head-to-head. Dose, duration, and cohort matter more than which precursor is chosen.

One caveat that applies to every "NAD+ level" claim: NR, NMN, and NAD+ all stay inside cells, leaving plasma to show only nicotinamide and its methylated products. Plasma-NAD+ studies measure the wrong pool; whole-blood or tissue measurement is the meaningful instrument. See the NAD+ guide for the full route-and-precursor matrix.

When are retatrutide effects typically observed?

Appetite suppression often begins within 48-72 hours of the first injection as the GIP and GLP-1 pathways engage. Measurable weight change in the first 4 weeks often includes water and glycogen. The 12-week window is a practical evaluation block: long enough to assess appetite control, energy, training output, side effects, and whether the current dose is doing enough.

Limitations

The biochemistry is settled: beta-oxidation spends NAD+, retatrutide increases beta-oxidation, and demand rises. The step after that is where the evidence stops — no controlled trial has tested whether supplementing NAD+ prevents the fatigue wall in a GLP-1 user. Response also splits by person: some never hit a wall, and some hit one while fully supplemented.

Two claims commonly attached to NAD+ do not survive checking, and both change what a reader should expect. The "50-80% decline by age 60" figure comes from plasma studies whose results span no age effect to near-total loss; whole-blood NAD+ is stable with age across seven cohorts. Decline is tissue-specific and appears under load rather than on a birthday. And blood is the wrong instrument for the question: NR, NMN, and NAD+ all act inside cells, which leaves a plasma reading tracking breakdown products rather than the pool.

The practical consequence: judge this layer by fatigue, training output, and recovery. An NAD+ blood test will not answer it. Precursor trials run 8 to 12 weeks, and outcomes past that window are unmeasured.

Related Topics

• Retatrutide Guide — complete retatrutide overview
• Retatrutide Dosing Calculator — reconstitution math for 10/12/24mg vials
• Retatrutide vs. Tirzepatide — head-to-head mechanism and weight-loss differential
• Retatrutide Recomp Protocol — advanced dual-axis protocol
• GLP-1 Hub — broader GLP-1 family coverage
• Why GLP-1 Medications Make You Tired — broader GLP-1 fatigue guide covering all compounds
• GLP-1 Compounds Tool — interactive comparison with trial data on weight loss and body composition
• NAD+ Guide — why NAD+ matters for metabolic function
• MOTS-c Guide — Next-level addition: MOTS-c for fat oxidation capacity
• Mito Stack — full SS-31 + MOTS-c + NAD+ stack for mitochondrial support during GLP-1 protocols

References

¹ Jastreboff AM, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity. NEJM 2023. NEJM 2023 retatrutide trial
² Yoshino J, et al. NAD+ Intermediates: The Biology and Therapeutic Potential. Cell Metabolism 2021. NAD+ intermediates: The biology and therapeutic potential
³ Covarrubias AJ, et al. NAD+ metabolism and its roles in cellular processes during ageing. Nature Reviews Molecular Cell Biology 2020.
⁴ Covarrubias AJ, et al. Senescent cells promote tissue NAD+ decline during ageing. Nature Metabolism 2020. Senescent cells promote tissue NAD+ decline with ageing
⁵ Camacho-Pereira J, et al. CD38 dictates age-related NAD decline and mitochondrial dysfunction. Cell Metabolism 2016.

⁶ Giblin K, Kaplan LM, Somers VK, et al. Retatrutide for the treatment of obesity, obstructive sleep apnea, and knee osteoarthritis: Rationale and design of the TRIUMPH registrational clinical trials. Diabetes Obes Metab. Published online October 15, 2025: 10.1111/dom.70209 — design of the original four-trial registrational core (~5,800 participants). Later ClinicalTrials.gov registrations expand the program beyond those four trials.

⁷ Eli Lilly press release, December 11, 2025. "Lilly’s triple agonist, retatrutide, delivered weight loss of up to an average of 71.2 lbs along with substantial relief from osteoarthritis in first successful Phase 3 trial." investor.lilly.com — primary announcement of TRIUMPH-4 topline results. The 28.7% mean weight-loss figure at 12mg is consistent with the Lilly-announced 71.2 lb absolute figure at typical cohort starting weight.

⁸ NAD+/NADH ratio and pseudohypoxia — Gomes AP, et al. "Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging." Cell 2013;155:1624-1638. A falling NAD+/NADH ratio suppresses sirtuin activity and stabilizes HIF-1α, mimicking hypoxia in normal oxygen. The paper establishes the age-related NAD+/pseudohypoxia mechanism; it does not establish a caloric-deficit → T3 → Complex I chain. 10.1016/j.cell.2013.11.037

⁹ Receptor-engagement model — Rosenstock 2023/NCT04867785 supplies arm-level steady-state serum anchors; Coskun 2022 Figure 1 and Table S2 supply receptor cAMP potency and efficacy; the corpus derives the retatrutide albumin/free-fraction conversion. Body-weight scaling borrows Schneck and Urva’s tirzepatide PopPK structure, which fixed BW^0.8 from Wang & Prueksaritanont’s generic therapeutic-protein allometry rather than estimating it from tirzepatide data. Retatrutide has no published PopPK covariate model. The dose-by-dose table is therefore a model reconstruction, not a table printed in any one paper: Coskun 2022; Rosenstock 2023; Schneck 2024; Wang 2010.

¹⁰ Eli Lilly press release, May 21, 2026. TRIUMPH-1 topline: 2,339 randomized participants; 12 mg produced 28.3% mean weight loss at week 80 under the efficacy estimand. TRIUMPH-1 announcement

¹¹ Retatrutide hepatic oxidation chain — Sanyal AJ, et al. Nature Medicine 2024 measured liver-fat and β-hydroxybutyrate changes: 10.1038/s41591-024-03018-2. Pearson MJ, et al. Retatrutide and Lipid and Metabolite Profiles in Participants With Obesity With or Without Type 2 Diabetes. Journal of Clinical Endocrinology & Metabolism. 2026: 10.1210/clinem/dgag201. Together they carry increased hepatic FAO demand; neither tests injectable NAD+ as the intervention.

¹³ Pooled 4 mg and 8 mg figures — Jastreboff 2023 ran two arms at each of those doses, differing only in starting dose and therefore escalation speed. Per-arm results: 4 mg = −16.3% (start 2 mg) and −17.8% (start 4 mg); 8 mg = −21.7% (start 2 mg) and −23.9% (start 4 mg). The table above averages each pair. That pooling is worth knowing about here, because the 8 mg pair is also the program’s cleanest escalation-speed contrast: same destination dose, and the faster ladder carried 36.9% peak gastrointestinal burden against 16.7% on the slower one, still 17.0% at week 48 versus single digits. The faster route bought about 2 points more weight loss for roughly double the peak GI burden — which is the reason this protocol holds each step 4+ weeks rather than climbing to a destination quickly.

¹² Slow-titration evidence — Nauck MA, Punov V, Kang YM, Lim S. Diabetes, Obesity and Metabolism. 2026;28:4232-4242: 10.1111/dom.70613. Nausea tolerance tracked escalation duration (r²=0.834) and step count (r²=0.764); within tirzepatide, full escalation shifted nausea and vomiting ED50 by about fivefold. This supplies the logic for 4+ week holds and smaller steps.