Appetite & satiety signalling
One of 6 mechanistic pathways to 🔥 Lose fat · 22 options
Incretin and amylin receptors in the hypothalamus and brainstem set how much food it takes to feel done, and how fast the stomach empties. Engage them and intake falls without willpower being involved. This is the most clinically developed pathway in the whole Vault — and the least interesting one if your intake is already low.
High fasting insulin with a normal glucose is the classic pre-diabetic picture, and it means appetite is being driven hormonally rather than by willpower. That is the strongest argument for this pathway. If insulin is genuinely low and you still can't stop eating, the driver is behavioural or psychological and no incretin will fix it.
Fasting InsulinHbA1c (Hemoglobin A1c)C-Peptide, Serum📉 Insulin Resistance Deep Dive covers these in one panel →
What engages this pathway
Ordered by how directly each one acts on the mechanism above — never by how much trial evidence exists. Each links to its full breakdown with dosing, half-life and vendor.
💉 Retatrutide
Triple GLP-1/GIP/glucagon agonism — the glucagon arm adds hepatic fat oxidation and energy expenditure on top of appetite suppression, which is why its phase-2 numbers outrun the duals. The only one here arguing on two pathways at once.
💉 Tirzepatide
Dual GIP/GLP-1. GIP appears to improve the tolerability ceiling, so more people reach a dose that actually suppresses intake rather than quitting at nausea.
💉 Semaglutide
The reference GLP-1. Slows gastric emptying and raises satiety centrally; the fat loss is almost entirely downstream of eating less.
💉 Survodutide
GLP-1/glucagon dual. Same theoretical advantage as retatrutide's glucagon arm — expenditure plus appetite — without the GIP component.
💉 Mazdutide
GLP-1/glucagon dual developed largely in Chinese trials; mechanistically parallel to survodutide.
💉 Pemvidutide
GLP-1/glucagon tuned deliberately toward liver-fat reduction and lean-mass preservation rather than maximum scale weight loss.
💉 Orforglipron
Oral non-peptide GLP-1 — the mechanism is unchanged, the delivery is the innovation. Matters if needles are your adherence problem.
💉 Ecnoglutide
Long-acting GLP-1 analog engineered for weekly dosing with a cAMP-biased signalling profile.
💉 Amycretin
Single molecule hitting both GLP-1 and amylin receptors. Early human data looks strong, but it is early — the trial base is thin next to the duals.
💉 Cagrilintide
Long-acting amylin analog. Amylin slows gastric emptying and signals satiety through a route GLP-1 doesn't use, which is the argument for stacking it rather than replacing.
💉 Eloralintide
Selective amylin-receptor agonist. The selectivity argument is that you get satiety with less of the nausea that comes from broad calcitonin-family activity — plausible, and not yet settled in humans.
💉 Pramlintide
The original amylin analog, approved alongside insulin. Proof the amylin pathway moves intake in humans; short half-life makes it fiddly.
💉 Liraglutide
Daily GLP-1. Superseded on convenience, not on mechanism.
💉 Dulaglutide
Weekly GLP-1 built for glycaemic control; weight loss is real but a smaller effect than the newer agents.
💉 Exenatide
The first-generation GLP-1, derived from Gila monster venom. Historically important, mechanistically identical, clinically outclassed.
💉 Metatrutide
Marketed as a triple-agonist analog. Treat the identity and purity as the open question here, not the pathway.
💉 Tesofensine
Triple monoamine reuptake inhibition — dopamine, noradrenaline, serotonin. Appetite suppression via a completely different route to the incretins, with the blood-pressure and mood consequences you'd predict from that mechanism.
💉 Ondansetron
A 5-HT3 antagonist used for nausea. The extrapolation: it makes GLP-1 titration tolerable, which indirectly makes fat loss possible. It is not a fat-loss agent itself.
🧬 Glucomannan
Konjac fibre that gels in the stomach — mechanical satiety with no receptor pharmacology at all. The cheapest version of this pathway.
🧬 Psyllium Husk
Viscous soluble fibre. Slows gastric emptying and blunts the post-meal glucose curve; modest, real, and it stacks with everything.
🧬 Gymnema Sylvestre
Gymnemic acids transiently block sweet-taste receptors on the tongue and possibly in the gut. The prediction is reduced sweet-seeking rather than reduced total intake.
🧬 GLP-1 Support Stack
Formulated around the side-effect profile of GLP-1 use — constipation, muscle loss, micronutrient gaps. Supportive, not causal.
The other 5 routes to lose fat
Pick the pathway that matches where you are actually stuck. An appetite drug does nothing for someone who already undereats.
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Frequently asked questions
Incretin and amylin receptors in the hypothalamus and brainstem set how much food it takes to feel done, and how fast the stomach empties. Engage them and intake falls without willpower being involved. This is the most clinically developed pathway in the whole Vault — and the least interesting one if your intake is already low.
22 options are mapped to this pathway in the Vault, including Retatrutide, Tirzepatide, Semaglutide, Survodutide. They are grouped by the mechanism they act through rather than ranked by how much trial evidence exists — 16 carry clinical validation and 6 are mechanistic predictions.
High fasting insulin with a normal glucose is the classic pre-diabetic picture, and it means appetite is being driven hormonally rather than by willpower. That is the strongest argument for this pathway. If insulin is genuinely low and you still can't stop eating, the driver is behavioural or psychological and no incretin will fix it. The markers worth checking are Fasting Insulin, HbA1c (Hemoglobin A1c), C-Peptide, Serum.
Unproven is not the same as ineffective. Of the 22 options on this pathway, 16 have clinical validation and 6 are graded theoretical — meaning the mechanism is sound but the specific human trial has not been run, which is true of a great deal of what works in this space. Nothing on this page is ordered by evidence tier, because sorting by trial count would bury the compounds you came looking for.