Fat Loss & Metabolic

SLU-PP-332 is a synthetic agonist of all three estrogen-related receptors (ERRα, β and γ), strongest at ERRα, and the best-known "exercise mimetic" research compound. In mice it switched on an aerobic exercise gene program, increased oxidative muscle fibers and improved endurance. In obese mice it raised energy expenditure and fat oxidation, reduced fat mass and improved glucose tolerance. It has never been tested in humans.

SLU-PP-915 is a pan-ERR agonist from the lab that made slu-pp-332. It is a chemically distinct thiophene boronic acid and, unlike SLU-PP-332, it is orally bioavailable. In mice it improved aerobic exercise performance as much as SLU-PP-332 did and protected the heart in a heart-failure model. It has never been tested in humans.

Sobetirome (GC-1) is a thyroid hormone receptor β-preferring agonist studied for lipid disorders and metabolic disease. It reduced fat mass and stimulated subcutaneous white-fat browning in mice, but separate rodent studies found impaired glucose control at lower doses. No published human study demonstrates weight loss from sobetirome.

Bromantane is a lipophilic adamantane stimulant-anxiolytic developed in the Soviet Union and marketed in Russia as Ladasten for asthenic disorders. A 30-person, single-blind placebo trial reported faster and greater symptom relief, while a 728-patient uncontrolled program reported improvement from day 3; neither result has been independently replicated. Its best-supported mechanism is not direct receptor agonism or dopamine transporter blockade, but altered expression of dopamine-synthesis enzymes in animals.

Mirabegron is an approved overactive-bladder drug that activates β3 adrenergic receptors. Small human metabolic studies found higher brown-fat activity and energy expenditure, and two uncontrolled studies found improved glucose measures. Neither chronic study produced significant weight or fat loss.

Phenylpiracetam is a Soviet-era piracetam analog with a phenyl ring on the pyrrolidone, developed in 1983 and prescribed in Russia as Phenotropil. Modern work identifies the dopamine transporter as its only significant molecular target, and the two enantiomers do different things. It was the first nootropic banned in sport, in 1998. Its human evidence is substantial but almost entirely Russian and non-randomized: a matched 400-patient stroke-rehabilitation study, a 56-patient comparison against piracetam and a 1170-patient observational program.

Tesofensine is not a GLP-1 anything. It is a triple monoamine reuptake inhibitor - it blocks the transporters for norepinephrine, dopamine and serotonin - originally developed for Parkinson's and Alzheimer's disease, where trials failed but participants lost weight. That observation led to a phase 2 obesity trial in 203 patients: 24 weeks at 0.5 mg gave 9.2% weight loss against 2.0% on placebo, with heart rate up 7.4 beats per minute. It never reached phase 3 for obesity. That trial also carries a Lancet expression of concern, issued in 2013 over under-reporting of adverse effects and never withdrawn. A newer formulation combining tesofensine with metoprolol has been tested in hypothalamic obesity, a condition with almost no other options, giving 6.3% more weight loss than placebo in 21 patients.

ATX-304, formerly O304, is a pan-AMPK activator from Betagenon developed as a type 2 diabetes drug and exercise mimetic. In a phase IIa trial in people with type 2 diabetes already on metformin, it lowered fasting glucose and insulin resistance and improved microvascular perfusion. In a 2026 phase 1b trial in 23 adults with obesity and prediabetes, 400 mg a day for 8 weeks was reported to lower liver fat, visceral fat and triglycerides and to raise resting metabolic rate, with minimal weight loss; so far that trial exists only as a poster abstract and a company press release. Newer mouse work extends it to fatty liver and kidney injury. The developer's patents describe a milled sodium salt: in volunteers, about a quarter of the dose in enteric capsules matched the blood levels of the original suspension, and rabbit work suggests both the salt and the milled capsule formulation contribute.

BAM15 is a mitochondrial uncoupler. It lets protons leak back into mitochondria so fuel is burned without making ATP, and unlike older uncouplers it does not depolarize the cell's outer membrane. In obese mice it reduced fat mass and improved insulin sensitivity without changing food intake, lean mass or body temperature. It has not been tested in humans.

MOTS-c is a 16-amino-acid peptide encoded in mitochondrial DNA, not in the cell nucleus. In mice, injections prevented diet-induced obesity and insulin resistance and improved running capacity at every age tested. In people, exercise raises the body's own MOTS-c, but no trial has given MOTS-c to humans, and measurements of it in blood disagree between methods.

5-Amino-1MQ is a small-molecule inhibitor of nicotinamide N-methyltransferase (NNMT), an enzyme that is more active in the fat and liver of obese mice. In obese mice, injections reduced body weight and fat without lowering food intake. In old mice they improved muscle repair and grip strength. No study has given it to people, and nearly all of the published work comes from one group linked to the company developing it.

AOD-9604 is a synthetic copy of the last fifteen amino acids of growth hormone, with a tyrosine stuck on the front. The idea, worked out at Monash University in the 1990s, is that this is the part of growth hormone that burns fat, separated from the parts that raise IGF-1 and blood sugar. In obese mice it reduced weight gain and fat mass and raised fat oxidation and energy expenditure; none of these studies measured IGF-1, so the separation the molecule is named for has not actually been demonstrated. It was developed for obesity by Metabolic Pharmaceuticals and abandoned. No trial of AOD-9604 in humans for weight, fat or anything else appears in the published literature — the human evidence for it is adipose tissue in a dish.

Cagrilintide is a long-acting analog of amylin, the pancreatic hormone co-secreted with insulin that signals meal-related satiety. It works on its own - the phase 2 trial gave up to 10.8% weight loss at 4.5 mg over 26 weeks, beating daily liraglutide 3.0 mg at 9.0% - but it is being developed primarily as half of CagriSema, a fixed combination with semaglutide. That combination gave 20.4% weight loss at 68 weeks against 3.0% on placebo in REDEFINE 1, and 13.7% against 3.4% in people with type 2 diabetes. The interest in amylin is that it suppresses appetite by a different route from GLP-1, so the two add up rather than overlap - and in eloralintide's phase 2 trial the amylin mechanism alone reached 20%.

Eloralintide is a selective amylin receptor agonist - selective being the operative word, since amylin signals through receptor complexes built on the calcitonin receptor and earlier analogs hit both. Its phase 2 trial is the reason the amylin class is now taken seriously on its own: 48 weeks of once-weekly dosing produced mean weight reductions of 18% at 6 mg and 20% at 9 mg, against 0.4% on placebo. That is semaglutide territory, reached without touching the GLP-1 receptor at all. The adverse-effect profile is also different rather than simply lighter: nausea peaked at 64% in one dose group, and fatigue - which is not a prominent incretin effect - reached 43-46% at the higher doses. There is no phase 3 data, and no cardiovascular or long-term evidence of any kind.

Exenatide is the original GLP-1 receptor agonist, and it came out of a lizard. Exendin-4 was isolated from the venom of the Gila monster, Heloderma suspectum, and turned out to be a full agonist at the human GLP-1 receptor that resists the enzyme which destroys the human hormone. It reached the market in 2005 as twice-daily Byetta and later as weekly Bydureon, and everything that followed - liraglutide, semaglutide, tirzepatide - descends from the idea it proved. By modern standards it is weak: roughly 1% of body weight lost, and its cardiovascular outcome trial, EXSCEL, missed superiority at a hazard ratio of 0.91 with a confidence interval touching 1.00. Its most interesting current life is outside diabetes, and that story ended badly too: a promising phase 2 result in Parkinson's disease was followed by a clean negative phase 3.

HGH fragment 176-191 is the C-terminal tail of human growth hormone, synthesized on its own. It is the peptide behind AOD-9604, which is this same fragment with a tyrosine added, and the two share a literature. In obese mice, chronic treatment cut cumulative weight gain and fat mass, and it suppressed fat synthesis as strongly as the intact hormone, and the AOD-coded analog raised lipolytic activity in fat tissue from obese rodents and from humans in a dish. No study in this literature measured IGF-1, and no trial has ever given the peptide to a person: everything known about it comes from mice, rats and isolated cells.

ITPP is a synthetic phosphate derivative of inositol that gets inside red blood cells and makes hemoglobin let go of its oxygen more readily, so more oxygen reaches tissue that is short of it. It was developed as a cancer drug, to relieve tumor hypoxia, and has been through one phase Ib trial in 28 patients that established a maximum tolerated intravenous dose. Its reputation as a performance drug rests on a single 2009 mouse study in which it raised maximal exercise capacity by up to 57%; nothing like that has been tested in people, and anti-doping laboratories screen urine for it.

JBSNF-000088 (6-methoxynicotinamide) is an experimental inhibitor of nicotinamide N-methyltransferase (NNMT). Oral treatment reduced weight gain and improved glucose handling in diet-induced obese mice, but it did not reduce weight in two genetic obesity models. Its published evidence is preclinical; no human dose, efficacy or safety has been established.

Mazdutide is a glucagon/GLP-1 dual agonist built on oxyntomodulin, a natural gut peptide that hits both receptors. It was licensed from Eli Lilly to Innovent Biologics and developed almost entirely in China, which makes its trial program unusual: every efficacy result comes from Chinese participants, who start from a lower mean body weight than the Western obesity trials. GLORY-1 gave 14.01% weight loss at 6 mg over 48 weeks against a 0.30% gain on placebo, and GLORY-2, at 9 mg over 60 weeks, gave 16.65% against a 1.50% loss. Those are tirzepatide-class numbers. The caveat is the population: whether they transfer to a heavier, more metabolically damaged Western cohort has not been tested, and a head-to-head against semaglutide is only now running.

Mitochonic Acid 5 (MA-5) is a synthetic indole compound studied for mitochondrial disease. It binds mitofilin/MIC60, a protein involved in organizing the inner mitochondrial membrane. Human development has reached phase I safety testing; clinical benefit remains unproven.

MK-677 (ibutamoren) is an orally active drug that mimics ghrelin at the GHS-R1a receptor, making the pituitary release more of the body's own growth hormone in its normal pulses. It reliably raises growth hormone and IGF-1: 25 mg daily restored IGF-1 in older adults to young-adult levels within four weeks, and a two-year randomized trial found about 1.1 kg more fat-free mass at 12 months than placebo. What it has never shown is a benefit that people can feel: the same trial found no change in strength, walking, stair climbing or quality of life, and trials in hip-fracture recovery and Alzheimer's disease were negative. It consistently raises fasting glucose, HbA1c and appetite, and it was never approved for any human use.

Myricetin is a flavonol found in berries, vegetables, tea and wine. It is studied for glucose regulation, mitochondrial function and neuroprotection, but the evidence for the isolated molecule remains preclinical. Small human trials have used blends containing myricetin; none separates its contribution from the other ingredients.

Fish oil supplies the two long-chain marine omega-3 fatty acids EPA and DHA. Its best-established effect is on triglycerides: high-quality evidence puts the reduction at roughly 15%, dose-dependently, and prescription formulations at 4 g a day are licensed drugs for severe hypertriglyceridemia. What it does not do is what most people buy it for. A Cochrane review of 79 trials in 112,059 people found little or no effect of EPA and DHA on all-cause mortality, cardiovascular mortality or cardiovascular events, and the three largest modern supplement trials — VITAL, ASCEND and STRENGTH — were all null.

Orforglipron is the first GLP-1 receptor agonist that is not a peptide. That matters for a practical reason: a small molecule can be made by ordinary chemical synthesis rather than fermentation, and swallowed as a normal tablet with no food or water restrictions - unlike oral semaglutide, which needs an absorption enhancer and an empty stomach. In ATTAIN-1, 72 weeks of 36 mg daily gave a mean 11.2% weight loss against 2.1% on placebo; in ATTAIN-2, in people with obesity and type 2 diabetes, 9.6% against 2.5%. That places it below injected semaglutide and well below tirzepatide on weight, and roughly where oral semaglutide sits - while being far easier to take and, in principle, far easier to manufacture at scale.

Retatrutide is an experimental once-weekly injected peptide from Eli Lilly that activates three hormone receptors: GIP, GLP-1 and glucagon. In a 48-week phase 2 trial in adults with obesity, the 12 mg dose lowered body weight by 24.2%, against 2.1% on placebo. The first phase 3 trial, in type 2 diabetes, confirmed large falls in HbA1c and weight. It is not approved; in the cited literature its phase 3 obesity trials are still under way.

SANA is a nitroalkene derivative of salicylate, the parent of aspirin, developed for obesity and type 2 diabetes. In obese mice it reduced weight, liver fat and insulin resistance by raising creatine-dependent energy expenditure in fat tissue. MVD1 is the name its first human trial ran under. That trial was a small, 15-day phase 1 study, which reported good tolerability and early effects on body weight and glucose.

Semaglutide is the GLP-1 receptor agonist that turned obesity into a treatable condition in mainstream medicine. In STEP 1, 68 weeks of 2.4 mg weekly produced a mean 14.9% weight loss against 2.4% on placebo, with half of participants losing 15% or more. In SELECT, 17,604 people with obesity and established cardiovascular disease but no diabetes had a 20% reduction in major cardiovascular events over the trial - the result that moved it from a weight drug to a cardiovascular one. The costs are real and well documented: gastrointestinal effects in most people, about 4.5% discontinuing for them in STEP 1, and weight regain when it stops. A year after withdrawal in the STEP 1 extension, participants had regained two-thirds of what they lost.

Somatropin is recombinant human growth hormone — the 191-amino-acid protein itself, which is what "HGH 191AA" on a vial means. It is a long-approved prescription medicine for growth hormone deficiency and several causes of short stature. Outside those uses, the evidence is much less flattering than its reputation. In healthy older adults, a meta-analysis of 18 study populations found about 2.1 kg more lean mass and 2.1 kg less fat, no weight change, no improvement in bone density, and significantly more soft-tissue swelling, joint pain, carpal tunnel syndrome, gynecomastia and new diabetes — concluding it cannot be recommended as an anti-aging therapy. In young athletes the pattern repeats: lean mass up 2.1 kg, strength and exercise capacity not improved, and more swelling and fatigue.

Survodutide activates the glucagon receptor as well as the GLP-1 receptor. Adding glucagon agonism to an incretin is counterintuitive - glucagon raises blood sugar - but it also raises energy expenditure and acts directly on the liver, and in a weight-losing context the GLP-1 arm covers the glycemic downside. The phase 2 obesity trial gave 14.9% weight loss at 4.8 mg over 46 weeks against 2.8% on placebo. The more striking result is hepatic: in a phase 2 trial in MASH, 48 weeks improved histological steatohepatitis without worsening fibrosis in 47-62% of participants against 14% on placebo, and a phase 3 trial in MASLD found 84.2% achieved a 30% or greater reduction in liver fat against 24.3%. The tolerability cost is high: vomiting in 41% against 4% on placebo in the MASH trial.

Tesamorelin (Egrifta) is a synthetic version of growth hormone-releasing hormone (GHRH). It makes the pituitary release more of the body's own growth hormone. It is approved to reduce excess abdominal fat in people with HIV. In two phase 3 trials, daily injections cut visceral (deep abdominal) fat by about 15% more than placebo over 26 weeks while leaving fat under the skin alone, and it also lowered liver fat. The fat returns once treatment stops. One trial in older adults reported better executive function, but a later trial in people with HIV found no clear cognitive benefit.

Tirzepatide is a once-weekly injected peptide that activates two gut-hormone receptors, GIP and GLP-1. It is approved for type 2 diabetes and, as Zepbound, for chronic weight management. In a 72-week trial in adults with obesity, the top dose lowered body weight by 20.9%, against 3.1% on placebo. In a head-to-head trial it caused more weight loss than semaglutide (20.2% vs 13.7%). Most side effects are gastrointestinal, and the weight comes back when treatment stops.