Incretin & Metabolic Receptor Agonists

A long-acting copy of the gut hormone GLP-1 that turns up the body's own fullness and blood sugar signals, FDA-approved for diabetes, obesity, heart and kidney risk, and fatty liver disease.

Overview

Semaglutide is a modified version of GLP-1, a hormone the gut releases after meals to help control blood sugar and signal fullness. Natural GLP-1 lasts only minutes; semaglutide carries a fatty side chain that lets it ride on albumin in the blood, stretching its half-life to about a week^[2]. It is sold as a weekly injection (Ozempic, Wegovy) and as a daily tablet^[1,2]. It is one of the most heavily studied drugs of the past decade.

In the 68-week STEP 1 trial, adults without diabetes lost an average of 14.9% of body weight versus 2.4% on placebo^[3]. The 17,604-person SELECT trial found 20% fewer heart attacks, strokes and cardiovascular deaths in people with heart disease and excess weight^[4], and a 2025 phase 3 trial showed improvement in fatty liver inflammation^[5]. A higher 7.2 mg injection was approved in March 2026^[6,9].

Mechanism of Action

Semaglutide shares 94% of its sequence with human GLP-1 and selectively activates the GLP-1 receptor^[2]. In the pancreas, that receptor boosts insulin release and dampens glucagon, but only when blood sugar is elevated (a glucose-dependent effect). It also slightly delays stomach emptying after meals^[2]. GLP-1 receptors sit in brain regions that regulate appetite, and the weight-loss label describes the drug as lowering body weight mainly by reducing hunger and calorie intake rather than by burning more energy^[1]. How it lowers kidney and cardiovascular risk is not fully established; the Ozempic label states the kidney mechanism is unknown^[2].

Two chemical changes make the molecule last. A swap at position 8 blocks the enzyme DPP-4, which chops up natural GLP-1 within minutes. A C18 fatty acid attached through a spacer at position 26 makes more than 99% of the drug bind to albumin, shielding it from the kidneys and from breakdown^[2]. The result is an elimination half-life of about one week, and the drug stays in circulation for roughly five weeks after the last injection^[2].

What the Research Shows

• STEP 1 RCT, NEJM 2021 (n=1,961 adults without diabetes, 68 weeks): weight fell 14.9% vs 2.4% on placebo (P<0.001). 50.5% vs 4.9% lost at least 15% of body weight. GI side effects led 4.5% vs 0.8% to stop treatment^[3].
• SELECT cardiovascular outcomes RCT, NEJM 2023 (n=17,604 with heart disease and BMI 27 or higher, no diabetes, mean follow-up 39.8 months): heart attack, stroke or cardiovascular death in 6.5% vs 8.0% (HR 0.80, 95% CI 0.72 to 0.90, P<0.001)^[4].
• SUSTAIN 6 and FLOW outcome trials in type 2 diabetes (n=3,297 and n=3,533): major cardiovascular events 6.6% vs 8.9% (HR 0.74), and a 24% lower risk of the composite of serious kidney decline, kidney failure or cardiovascular death (HR 0.76, P=0.0003)^[2].
• ESSENCE phase 3 RCT in MASH, NEJM 2025 (first 800 of 1,197 patients with stage 2 or 3 liver fibrosis, 72 weeks): steatohepatitis resolved without fibrosis worsening in 62.9% vs 34.3%, and fibrosis improved in 36.8% vs 22.4% (both P<0.001). The trial continues to 240 weeks for clinical outcomes^[5].
• STEP UP RCT, 2025 (n=1,407, 72 weeks): the 7.2 mg weekly injection produced 18.7% vs 3.9% weight loss on placebo, with about 31% losing a quarter or more of body weight^[6,9].
• OASIS 4 RCT, oral 25 mg (n=307, 64 weeks): weight fell 13.6% vs 2.2% on placebo (P<0.001); GI events in 74.0% vs 42.2%^[10].

• Rats and mice, lifetime studies: semaglutide caused thyroid C-cell tumors at clinically relevant exposures. Whether this applies to humans is unknown, which is the basis of the boxed warning^[1].

Open Questions

• Whether the MASH biopsy improvements translate into fewer cases of cirrhosis, liver failure or death is still being tested in ESSENCE^[5].
• The pivotal trials were funded by the manufacturer^[3,4].
• Weight and risk-factor benefits depend on continued use; very long-term outcomes beyond about four years of treatment are limited.
• The human relevance of the rodent thyroid tumor finding is still unresolved^[1].
• Compounded or research-labelled semaglutide has not been evaluated for purity, potency or safety by the FDA^[7].

Regulatory Status

FDA-approved as Ozempic (type 2 diabetes, cardiovascular and kidney risk reduction), Wegovy injection and tablet (weight management and cardiovascular risk; MASH with fibrosis on accelerated approval), and Rybelsus^[1,2]. FDA declared the semaglutide shortage resolved in February 2025 and its enforcement discretion for mass compounding has ended^[7]. Not prohibited in sport, but included in the WADA 2026 Monitoring Program^[8].

Related Compounds

A once-weekly peptide that activates two gut hormone receptors, GIP and GLP-1, at the same time; FDA-approved for type 2 diabetes, obesity, and sleep apnea in adults with obesity.

Overview

Tirzepatide is a single synthetic peptide built on the backbone of GIP, a gut hormone released after meals, and tuned so it also activates the GLP-1 receptor^[1,3]. A fatty acid chain lets it bind albumin in the blood, giving it a half-life of about five to six days^[1]. It is marketed as Mounjaro for type 2 diabetes and as Zepbound for weight management and obstructive sleep apnea^[1,2].

In the 72-week SURMOUNT-1 trial, adults without diabetes lost 15.0% to 20.9% of body weight across the three tested strengths, versus 3.1% on placebo^[4]. In a 2025 head-to-head trial it produced more weight loss than semaglutide (20.2% vs 13.7%)^[5]. A large cardiovascular outcomes trial against dulaglutide showed it was at least as protective, but not clearly better^[8].

Mechanism of Action

GIP and GLP-1 are incretins: hormones released by the gut after eating that amplify insulin release when blood sugar is rising^[3]. The label states that tirzepatide selectively binds and activates both the GIP and GLP-1 receptors^[1]. In early human studies it lowered fasting glucose in people with type 2 diabetes by about 43 to 49 mg/dL more than placebo over four weeks and reduced body weight in healthy volunteers^[3]. GLP-1 receptor signaling also reduces appetite and slows stomach emptying, while the precise contribution of the GIP side to weight loss in humans is still being worked out. Which receptor accounts for which effect has not been cleanly separated in clinical trials.

Structurally, tirzepatide is based on the GIP sequence, with two unusual amino acids (aminoisobutyric acid at positions 2 and 13) that resist enzyme breakdown^[1]. A 20-carbon fatty diacid is attached to the lysine at position 20 through a linker. That chain makes about 99% of the drug bind to albumin, which slows clearance and supports once-weekly use^[1]. The molecular weight is about 4,814 daltons, and the elimination half-life is roughly five to six days^[1].

What the Research Shows

• SURMOUNT-1 RCT, NEJM 2022 (n=2,539 adults without diabetes, 72 weeks): weight changed by -15.0%, -19.5% and -20.9% on the three doses vs -3.1% on placebo (P<0.001). At the top dose, 57% lost at least 20% of body weight vs 3% on placebo^[4].
• SURMOUNT-5 head-to-head RCT, NEJM 2025 (n=751, 72 weeks, open-label): weight fell 20.2% with tirzepatide vs 13.7% with semaglutide (P<0.001); waist shrank 18.4 vs 13.0 cm^[5].
• SURMOUNT-OSA, two RCTs, NEJM 2024 (adults with obesity and moderate-to-severe sleep apnea, 52 weeks): breathing interruptions per hour fell by 20.0 and 23.8 events more than placebo, from baselines near 50 per hour (P<0.001)^[6].
• SURMOUNT-4 withdrawal RCT, JAMA 2024 (n=670 after a 36-week lead-in with 20.9% weight loss): over the next 52 weeks, those switched to placebo regained 14.0% while those who continued lost a further 5.5%^[7].
• SURPASS-CVOT, NEJM 2025 (n=13,299 with type 2 diabetes and heart disease, vs dulaglutide): heart attack, stroke or cardiovascular death in 12.2% vs 13.1% (HR 0.92, 95.3% CI 0.83 to 1.01). Noninferior (P=0.003), not superior (P=0.09)^[8].

• Rats, lifetime studies: tirzepatide caused thyroid C-cell tumors. Human relevance is unknown and is the basis for the boxed warning^[1].

Open Questions

• No placebo-controlled trial has yet shown that tirzepatide reduces heart attacks or deaths in people with obesity but without diabetes.
• Weight returns substantially after stopping, so lifetime-use questions about cost, safety and muscle and bone health remain open^[7].
• Exactly how much the GIP receptor contributes, versus GLP-1 alone, is still debated.
• Most pivotal trials were sponsored by the manufacturer^[4,5,8].

Regulatory Status

FDA-approved as Mounjaro (type 2 diabetes in adults and children 10 and older; cardiovascular risk reduction added August 2026) and Zepbound (weight management; obstructive sleep apnea with obesity)^[1,2]. FDA declared the tirzepatide shortage resolved in December 2024 and enforcement discretion for mass compounding has ended^[9]. Not prohibited in sport; added to the WADA Monitoring Program for 2026^[10].

Related Compounds

An investigational once-weekly peptide from Boehringer Ingelheim that activates both the GLP-1 and glucagon receptors, studied for obesity and fatty liver disease, with phase 3 results reported in 2026.

Overview

Survodutide (BI 456906) is a lab-made peptide that switches on two receptors: GLP-1, which curbs appetite, and glucagon, which acts mainly on the liver and energy use^[1]. A C18 fatty acid chain lets it last long enough for weekly injection^[1]. Its developer has positioned it for both obesity and MASH, the inflammatory form of fatty liver disease, and it holds FDA Breakthrough Therapy designation for MASH^[7].

In the phase 3 SYNCHRONIZE-1 trial, adults with obesity lost 12.2% to 13.0% of body weight over 76 weeks versus 5.4% on placebo when everyone randomized was counted^[5]. A companion trial in people with fatty liver found large drops in liver fat^[6]. Gastrointestinal side effects were frequent, and about one in five stopped treatment because of them^[7].

Mechanism of Action

In laboratory and mouse studies, survodutide activated both the glucagon receptor (GCGR) and the GLP-1 receptor, and in mice it produced more weight loss than the highest effective doses of semaglutide^[1]. The authors attributed the extra effect to two levers: reduced food intake and increased energy expenditure^[1]. A 2026 mouse study clarified where the appetite effect starts. Labeled survodutide reached the circumventricular organs, brain areas with a leaky blood-brain barrier, and switched on appetite-related neurons through GLP-1 receptors, because glucagon receptors are barely present there. A glucagon-only agonist lowered weight in mice without reducing food intake^[2].

The glucagon receptor is concentrated in the liver, where its activation promotes fat breakdown and energy use. This is the rationale for testing survodutide in MASH and MASLD, and liver fat fell sharply in human trials^[4,6]. Glucagon also raises blood sugar, so the GLP-1 side has to balance it; in a 2026 diabetes trial HbA1c still fell, by up to 1.21 points^[8]. How much of the human weight loss comes from higher energy burn rather than eating less has not been directly measured in the published trials.

What the Research Shows

• Phase 2 dose-finding RCT, 2024 (n=387 without diabetes, 46 weeks): planned-treatment weight loss of 6.2% to 14.9% across four strengths vs 2.8% on placebo. Only 60.4% completed the trial, and GI adverse events affected 75% vs 42%^[3].
• Phase 2 MASH biopsy RCT, NEJM 2024 (n=293 with MASH and fibrosis stage 1 to 3, 48 weeks): MASH improved without fibrosis worsening in 43% to 62% vs 14% on placebo (P<0.001); fibrosis improved by one stage or more in 34% to 36% vs 22%^[4].
• SYNCHRONIZE-1 phase 3 RCT, NEJM 2026 (n=725 with obesity, no diabetes, 76 weeks): weight changed -12.2% and -13.0% vs -5.4% on placebo; at least 5% loss in about 72% vs 46.3% (P<0.001). Up to 16.6% loss if everyone stayed on treatment^[5,7].
• SYNCHRONIZE-MASLD phase 3 RCT, Nat Med 2026 (n=216 with obesity and fatty liver, 48 weeks): at least a 30% liver fat drop in 68.5% vs 28.6% (all randomized) and weight -8.7% vs -1.4% (P<0.0001). Liver fat normalized in 61.0% vs 5.7% of those who stayed on treatment^[6,7].
• SYNCHRONIZE-2 phase 3 RCT, topline October 2026 (n=755 with obesity and type 2 diabetes, 76 weeks): weight loss up to 13.1% vs 3.1%; HbA1c fell up to 1.21 points from 7.4% vs 0.03. Not yet peer-reviewed^[8].

• Mice, diet-induced obesity: greater weight loss than maximally effective semaglutide, driven by both lower food intake and higher energy expenditure; GLP-1 receptor knockout mice confirmed dual-receptor engagement^[1].
• Mice, brain mapping: survodutide reached circumventricular organs and activated appetite-regulating nuclei without broadly crossing the blood-brain barrier^[2].

• Receptor assays: in vitro testing confirmed agonist activity at both the human glucagon and GLP-1 receptors, the basis for its dual-agonist design^[1].

Open Questions

• Whether liver fat and biopsy improvements lead to fewer cases of cirrhosis, liver failure or liver-related death; the LIVERAGE outcome trials are ongoing^[7].
• Cardiovascular effects, including heart rate and long-term heart outcomes, await the SYNCHRONIZE-CVOT trial^[8].
• High discontinuation rates may limit real-world benefit^[5,7].
• All trials were funded by the developer, and no regulatory filing timeline for obesity has been announced^[3,7].

Regulatory Status

Investigational and not approved by any regulator as of October 2026. For MASH it holds FDA Fast Track (2021) and Breakthrough Therapy (2024) designations, EMA PRIME status (2023) and China NMPA Breakthrough designation (2024)^[7]. As an unapproved substance it falls under WADA's S0 category, prohibited at all times^[9].

Related Compounds

An investigational once-weekly peptide from Eli Lilly that activates three hormone receptors (GIP, GLP-1 and glucagon), producing the largest average weight loss yet seen in phase 3 obesity trials.

Overview

Retatrutide (LY3437943) is a single peptide designed to activate three receptors at once: GLP-1 and GIP, the two gut hormones behind tirzepatide, plus the glucagon receptor, which acts mainly on the liver and energy use^[1]. It is injected weekly and remains investigational. It is not approved anywhere^[7,8].

In the 80-week TRIUMPH-1 trial of 2,339 adults with obesity, average weight loss reached 25.0% at the highest strength versus 3.9% on placebo, counting everyone randomized^[5]. A diabetes trial (TRIUMPH-2) showed smaller losses of up to 18.8%^[6]. A trial in people with heart disease found no significant difference in cardiovascular events, though it was not designed to test that^[8]. Lilly expects to file with the FDA in the first quarter of 2027^[8].

Mechanism of Action

Retatrutide was engineered as one molecule with agonist activity at the glucagon, GIP and GLP-1 receptors, moving from discovery to early human proof of concept in 2022^[1]. The GLP-1 component reduces appetite and improves insulin release after meals. GIP is a second incretin hormone that also enhances insulin release. The glucagon component is the new ingredient: in the liver it promotes fat breakdown and energy use. That likely explains why liver fat fell by more than 80% at the higher strengths in a phase 2 substudy, with 86% of participants on the top strength reaching normal liver fat by 24 weeks^[4]. Glucagon by itself raises blood sugar, but the incretin components more than offset this; HbA1c fell by up to 2.0 points in phase 2 diabetes testing^[3].

Activating three receptors also brings trade-offs. Heart rate rose in a dose-dependent way in phase 2, peaking around 24 weeks^[2]. Abnormal skin sensations (dysesthesia) emerged as a distinctive side effect in phase 3, affecting about 12% on the higher strengths versus about 1% on placebo^[7]. How much of the extra weight loss over dual agonists comes from increased energy expenditure rather than reduced eating has not been directly measured in humans. The relative weighting of activity at each receptor is described in the discovery paper but its clinical consequences are still being worked out^[1].

What the Research Shows

• Phase 2 obesity RCT, NEJM 2023 (n=338, 48 weeks): weight fell 8.7% to 24.2% across strengths vs 2.1% on placebo; at the top strength, 83% lost at least 15% of body weight^[2].
• Phase 2 type 2 diabetes RCT, Lancet 2023 (n=281, 36 weeks): HbA1c fell up to 2.02 points at 24 weeks vs 0.01 on placebo and 1.41 on dulaglutide; weight fell up to 16.9% vs 3.0% on placebo^[3].
• Phase 2a liver fat substudy, Nat Med 2024 (n=98 with at least 10% liver fat): liver fat fell 81.4% and 82.4% on the two highest strengths vs +0.3% on placebo at 24 weeks (P<0.001)^[4].
• TRIUMPH-1 phase 3 RCT, NEJM 2026 (n=2,339 with obesity, no diabetes, 80 weeks): weight changed -17.6%, -23.7% and -25.0% vs -3.9% on placebo (P<0.001). In the sleep apnea subgroup (n=243), breathing interruptions fell by about 22 to 24 events per hour more than placebo; knee pain scores also improved in the osteoarthritis subgroup (n=574)^[5].
• TRIUMPH-2 phase 3 RCT, Lancet 2026 (n=1,152 with obesity and type 2 diabetes, 80 weeks): weight changed -11.9%, -16.8% and -18.8% vs -5.1% on placebo (P<0.0001)^[6].
• TRIUMPH-3 phase 3 RCT, topline July 2026 (n=1,949 with BMI 35 or higher and heart disease, 80 weeks): weight loss up to 22.6% vs 3.2%. Cardiovascular events did not differ significantly (MACE-5 HR 0.82, 95% CI 0.55 to 1.22). Not yet peer-reviewed^[8].

• Rodent obesity models (discovery program): the triple agonist reduced body weight and improved glucose control in preclinical testing that preceded human trials^[1].

• Receptor assays: in vitro testing established agonist activity at the human glucagon, GIP and GLP-1 receptors^[1].

Open Questions

• Whether the large weight loss translates into fewer heart attacks, strokes or deaths; TRIUMPH-3 was too small to tell^[8].
• Long-term effects of sustained glucagon receptor activation on heart rate, muscle, bone and the liver beyond two years.
• How much weight returns after stopping, and what happens with long-term maintenance.
• All trials are sponsor-funded, and FDA review has not yet begun^[5,6,8].

Regulatory Status

Not approved by the FDA or any other regulator as of October 2026; Lilly states it plans to submit to the FDA in the first quarter of 2027 for obesity, with knee osteoarthritis pain and sleep apnea also targeted^[8]. As an unapproved substance it falls under WADA's S0 category, prohibited at all times^[9].

Related Compounds

Two weight-loss peptides, one approved and one still experimental, sold mixed in one vial; both act on the GLP-1 and GIP receptors, and the pairing has never been studied.

Overview

This is a market product category, not a drug any company has developed or tested. It combines tirzepatide, approved as Mounjaro and Zepbound^[2,3], with retatrutide, an investigational Eli Lilly drug available legally only in Lilly's trials^[4]. Tirzepatide activates the GIP and GLP-1 receptors^[5]. Retatrutide activates those same two receptors plus the glucagon receptor^[6]. The mix therefore puts two molecules on the same two targets, with retatrutide's glucagon activity as the only distinct addition.

Each drug has strong evidence on its own. Tirzepatide produced 15.0% to 20.9% average weight loss over 72 weeks in SURMOUNT-1^[7], and retatrutide 17.6% to 25.0% over 80 weeks in TRIUMPH-1^[8]. We found no study of the two together. Lilly is comparing them head to head (NCT06662383)^[1], and the Zepbound label states that combining tirzepatide with any GLP-1 receptor agonist is not recommended^[2].

Mechanism of Action

Both molecules are long-acting peptides designed at Lilly. Tirzepatide is built on the GIP hormone sequence and engineered to also activate the GLP-1 receptor^[5]. Retatrutide was engineered as a single molecule with activity at the glucagon, GIP and GLP-1 receptors^[6]. GLP-1 receptor activation reduces appetite, slows stomach emptying and boosts insulin release when blood sugar is high, and GIP adds a second insulin-releasing signal^[2,5]. Glucagon receptor activation, unique to retatrutide in this pairing, acts mainly on the liver to promote fat breakdown and energy use^[6].

Because the two drugs overlap at the GLP-1 and GIP receptors, a combination would be expected to behave largely like a higher total amount of incretin activity, plus the glucagon activity from the retatrutide portion. In each drug's own trials, gastrointestinal side effects rose with strength^[2,9], so stacking two agonists on the same receptors would be expected to stack those effects too. This is reasoning from pharmacology, not data. Nobody has measured how the two molecules share receptors, whether one blunts the other, or how the changed glucagon-to-incretin balance affects blood sugar, heart rate or muscle.

What the Research Shows

• No human studies of the combination have been published, and we found no registered trial testing the two together.
• Head-to-head trial, registered (NCT06662383): compares retatrutide with tirzepatide in adults with obesity; it tests one against the other, not both at once^[1].
• Component evidence, tirzepatide, SURMOUNT-1 RCT 2022 (n=2,539 without diabetes, 72 weeks): weight changed -15.0% to -20.9% vs -3.1% on placebo (P<0.001)^[7].
• Component evidence, retatrutide, TRIUMPH-1 and TRIUMPH-2 RCTs 2026 (n=2,339 and 1,152, 80 weeks): weight changed up to -25.0% vs -3.9% on placebo without diabetes^[8], and up to -18.8% vs -5.1% with type 2 diabetes^[9].

• No animal studies of the combination have been published.
• Rats, lifetime studies (tirzepatide alone): thyroid C-cell tumors, the basis of the label's boxed warning; relevance to humans is unknown^[2].

Open Questions

• Whether combining adds anything over a higher strength of either drug alone.
• How two peptides competing for the same GLP-1 and GIP receptors share them, and whether one reduces the other's effect.
• How the combination affects heart rate, blood pressure, blood sugar and muscle compared with each drug alone.
• Whether the head-to-head trial will show one drug is simply better, which may matter more than combining them^[1].

Regulatory Status

Tirzepatide is FDA-approved as Mounjaro and Zepbound, and FDA has ended enforcement discretion for mass compounding of it^[2,3,10]. Retatrutide is not approved anywhere and is legally available only in Lilly's clinical trials^[4]; no regulator has evaluated the combination. As an unapproved substance, retatrutide falls under WADA's S0 category, prohibited at all times^[11].

Related Compounds

An experimental obesity pill from a small U.S. company, claimed to act on four metabolic hormone receptors at once; all results so far come from the company's own announcements.

Overview

Bioglutide is the brand name Biomed Industries, a private company in San Jose, California, uses for NA-931, an experimental pill for obesity^[4,5]. The company describes it as an orally active small molecule that activates four receptors: IGF-1, GLP-1, GIP and glucagon^[5]. Despite a name that echoes peptide drugs such as semaglutide, the company calls it a small molecule, and no chemical structure has been published. In March 2024 the company described the same compound as a triple agonist, without glucagon^[4].

The main human evidence is a registered phase 2 trial (NCT06564753) of about 125 adults with obesity or overweight^[3,1]. The company reports up to 13.8% average weight loss over 13 weeks at the highest strength, with the placebo-adjusted figure given as 12.4% in one release and 11.9% in another^[1,2]. A phase 3 program has been announced but, as of June 2026, not started^[5].

Mechanism of Action

Three of the four claimed targets are the same receptors used by approved and late-stage injectable peptides. Tirzepatide activates GLP-1 and GIP receptors, which reduce appetite, slow stomach emptying and boost insulin release when blood sugar is high^[6]. Retatrutide adds the glucagon receptor, which acts mainly on the liver to promote fat breakdown and energy use^[7]. Biomed's distinctive addition is the IGF-1 receptor, the target of insulin-like growth factor 1. The company says this component preserves muscle during weight loss and helps regulate glucagon release^[8]. It reports that no muscle loss was seen in phase 2, but has not released body-composition measurements or the method used^[1,2].

None of this has been independently confirmed. No receptor-binding data, potency figures at each target, pharmacokinetics or chemical structure have been published, so the four-receptor claim cannot be checked from outside the company^[5]. The description itself shifted from a triple IGF-1/GLP-1/GIP agonist in March 2024 to a quadruple agonist by October 2024^[4,8]. The side effects reported most often, nausea and diarrhea, fit what GLP-1 activity would be expected to cause^[1].

What the Research Shows

• Phase 1 trial (NCT06615700), company release 2024 (n not reported, 28 days plus a 12-week open-label extension): up to 6.8% weight loss at 28 days, reported as 5.1% beyond placebo (P<0.001), though the same release also cites 6.4%; up to 12.7% in the uncontrolled extension. Mild nausea in 8.3% at the top strength^[8].
• Phase 2 RCT (NCT06564753), presented at ADA, ENDO and EASD 2025 (n=125, 13 weeks, double-blind, placebo-controlled): up to 13.8% weight loss from baseline at the highest strength; placebo-adjusted figures of 12.4%^[1] and 11.9%^[2] appear in different releases. In an exploratory analysis, up to 72% of treated participants vs 1.9% on placebo lost at least 12%^[2]. The registry lists 126 participants^[3].
• Independent analyst review, 2025: noted no confidence intervals, P values or baseline characteristics in the presented data, a 12% threshold not among the listed secondary endpoints, and diarrhea in 8.1% vs 3.2% on placebo^[9].
• Planned trials: a phase 2 trial of NA-931 with tirzepatide (NCT06732245, 224 planned, not yet recruiting as of March 2026)^[10] and a 68-week phase 3 trial (BIOCOMBO-1, about 466 planned) testing NA-931 alone and with oral semaglutide^[5].

• Unnamed animal obesity model (company release, 2024): body weight down by up to 26%, plasma glucose by up to 23% and triglycerides by up to 34%, with muscle mass reported as preserved. The species, design and methods were not disclosed and no paper has been published^[4].

Open Questions

• The chemical structure, potency at each of the four claimed receptors, and how the body absorbs and clears the drug have not been published.
• Whether the 13-week results survive peer review, and why the placebo-adjusted figure differs between company releases^[1,2].
• Whether any muscle is actually preserved; no body-composition data have been shown.
• Whether the announced phase 3 and combination trials will start and report^[10,5].

Regulatory Status

Not approved by the FDA or any other regulator; NA-931 is an investigational drug in company-sponsored trials^[3,10]. The company has announced a global phase 3 program but said in June 2026 that enrollment would begin after regulatory and operational preparations^[5]. As an unapproved substance it falls under WADA's S0 category, prohibited at all times^[11].

Related Compounds

A once-weekly peptide that activates both the GLP-1 and glucagon receptors, approved in China for obesity and type 2 diabetes but still investigational in the United States.

Overview

Mazdutide (also coded IBI362 or LY3305677) is a dual agonist: one peptide that switches on both the GLP-1 receptor, which curbs appetite and helps control blood sugar, and the glucagon receptor, which acts mainly on the liver and energy use^[1]. Eli Lilly discovered it and licensed rights in China to Innovent Biologics^[2]. China's NMPA approved it for chronic weight management in June 2025 and for type 2 diabetes in September 2025^[1,3].

In the 48-week GLORY-1 trial in Chinese adults, weight fell 11.0% and 14.0% on two strengths versus a 0.3% gain on placebo^[4]. A higher-strength trial (GLORY-2) reported a 16.65% loss over 60 weeks^[5], and a smaller US phase 2 trial sponsored by Lilly reported up to 18.1% at 32 weeks^[8]. Nearly all phase 3 data so far come from Chinese populations.

Mechanism of Action

Mazdutide is a long-acting synthetic peptide that activates both the GLP-1 receptor and the glucagon receptor^[1]. The natural gut hormone oxyntomodulin also hits both receptors, and dual agonists like mazdutide are built around that idea. The GLP-1 side lowers appetite, slows stomach emptying, and boosts insulin release when blood sugar is high. The glucagon side acts largely on the liver, where it promotes fat burning and the use of stored energy. That liver action is one reason trials track liver fat: in GLORY-1, participants with high baseline liver fat saw reductions of roughly 66% to 80% versus about 5% on placebo^[2]. Glucagon also raises blood sugar, so the GLP-1 component has to offset that effect.

The balance between the two receptors matters. Too much glucagon activity could worsen blood sugar or raise heart rate, and too little would make it behave like an ordinary GLP-1 drug. In type 2 diabetes trials, HbA1c still fell by about 1.6 to 2.2 percentage points, suggesting the GLP-1 effect dominated for glucose control^[6,7]. Exactly how much of the extra weight loss comes from increased energy expenditure in humans, as opposed to reduced eating, has not been directly measured in the published phase 3 trials^[4,5].

What the Research Shows

• GLORY-1 phase 3 RCT, NEJM 2025 (n=610 Chinese adults with overweight or obesity, 48 weeks): weight changed -11.0% and -14.0% on the lower and higher trial strengths vs +0.3% on placebo; 49.5% on the higher strength lost at least 15%. Discontinuation for adverse events was 0.5% to 1.5%^[4].
• GLORY-2 phase 3 RCT, JAMA 2026 (n=462 Chinese adults with BMI 30 or higher, 60 weeks, highest trial strength): weight fell 16.65% vs 1.50% on placebo (P<.001). Vomiting 53.1% vs 1.3%, nausea 46.9% vs 3.2%^[5].
• DREAMS-1 phase 3 RCT, Nature 2026 (n=320 with type 2 diabetes, 24 weeks): HbA1c fell 1.57 and 2.15 points vs 0.14 on placebo; weight fell 5.6% and 7.8% vs 1.3% (P<0.0001)^[6].
• DREAMS-2 phase 3 RCT, Nature 2026 (n=731 with type 2 diabetes on metformin, 28 weeks, vs dulaglutide): HbA1c -1.61 and -1.66 vs -1.36; weight -6.6% and -8.5% vs -2.8%^[7,3].
• US phase 2 RCT, Lancet Diabetes Endocrinol 2026 (n=179, 32-week primary endpoint): weight changed -7.3%, -15.6% and -18.1% across three strengths vs -0.9% on placebo; 20% stopped for adverse events at the highest strength. Funded by Eli Lilly^[8].
• DREAMS-3 head-to-head vs semaglutide 1 mg (n=349 Chinese adults with diabetes and obesity, 32 weeks, company-reported): weight -10.3% vs -6.0%, HbA1c -2.03 vs -1.84 points. Not yet peer-reviewed^[11].

• Published phase 3 reports and the approval review focus on human data; detailed animal pharmacology and toxicology for mazdutide are largely held by the developers and not summarized in the sources reviewed here^[1].

Open Questions

• Whether results in Chinese adults (mean age about 34 in GLORY-2) carry over to older, heavier or more diverse populations^[5,8].
• Effects on heart attacks, strokes, kidney disease and death have not been studied.
• How much the glucagon component adds beyond GLP-1 alone, and whether it raises heart rate or affects muscle and bone over years.
• Whether and when Lilly will run phase 3 trials and file outside China.

Regulatory Status

Approved by China's NMPA for chronic weight management (June 2025) and glycemic control in type 2 diabetes (September 2025); a higher-strength application was accepted for NMPA review in November 2025^[1,3,9]. Not approved by the FDA or EMA; US development is at phase 2^[8]. It is not named in the WADA 2026 Monitoring Program, which lists only semaglutide and tirzepatide among this class^[10].

Related Compounds

A long-acting copy of amylin, a fullness hormone released alongside insulin, being developed with semaglutide as a once-weekly weight-loss combination now under FDA review.

Overview

Cagrilintide is a lab-made, long-acting version of amylin, a hormone the pancreas releases together with insulin after meals. Novo Nordisk developed it for once-weekly injection and has tested it both alone and paired with semaglutide, the GLP-1 drug behind Wegovy and Ozempic. The pairing is called CagriSema^[4,6]. It is one of the most thoroughly studied compounds in this section that is still not approved.

In the 68-week REDEFINE 1 trial of 3,417 adults with obesity, CagriSema produced an average weight loss of 20.4% versus 3.0% on placebo^[2]. Cagrilintide on its own produced about 6 to 11% weight loss over 26 weeks in a phase 2 trial^[4]. Novo Nordisk submitted CagriSema to the FDA in December 2025^[1].

Mechanism of Action

Natural amylin is co-secreted with insulin and acts on the brain to promote fullness and on the gut to slow stomach emptying, but it lasts only minutes in the blood. Cagrilintide is an amylin analogue engineered to last far longer: in a phase 1b trial its elimination half-life was 159 to 195 hours, roughly a week, which is what makes once-weekly injection possible^[6]. Its appetite-suppressing effect is separate from the GLP-1 pathway, which is why it was tested alongside semaglutide. In the phase 1b study, adding cagrilintide to semaglutide produced 6 to 7 percentage points more weight loss than semaglutide with placebo over 20 weeks^[6].

The combination also appears to add to glucose control. In a 32-week phase 2 trial in type 2 diabetes, HbA1c fell 2.2 points with CagriSema, 1.8 with semaglutide and 0.9 with cagrilintide alone; weight fell 15.6%, 5.1% and 8.1% respectively^[5]. In the larger REIMAGINE 2 trial the HbA1c edge of CagriSema over semaglutide was small (0.16 points), though statistically significant^[8]. Exactly how much of the weight effect comes from appetite versus slowed digestion in people has not been separated out in the trials.

What the Research Shows

• Phase 3 RCT, REDEFINE 1, NEJM 2025 (n=3,417 adults with overweight or obesity, no diabetes, 68 weeks): body weight fell 20.4% with CagriSema vs 3.0% with placebo, a 17.3-point difference (P<0.001). Gastrointestinal adverse events occurred in 79.6% vs 39.9%^[2].
• Phase 3 RCT, REDEFINE 2, NEJM 2025 (n=1,206 adults with obesity and type 2 diabetes, 68 weeks): weight fell 13.7% vs 3.4% on placebo. HbA1c of 6.5% or lower was reached by 73.5% vs 15.9%^[3].
• Phase 2 dose-finding RCT, Lancet 2021 (n=706 on cagrilintide alone, 99 liraglutide, 101 placebo, 26 weeks): weight loss of 6.0% to 10.8% across cagrilintide doses vs 3.0% on placebo (P<0.001 for each dose); the top dose beat liraglutide 3.0 mg (10.8% vs 9.0%, P=0.03)^[4].
• Phase 2 RCT in type 2 diabetes, Lancet 2023 (n=92, 32 weeks): CagriSema lowered weight 15.6% vs 5.1% with semaglutide alone and 8.1% with cagrilintide alone (both P<0.0001); no severe hypoglycemia^[5].
• Phase 3 RCT, REIMAGINE 3, Lancet 2026 (n=274 adults with type 2 diabetes on basal insulin, 40 weeks): HbA1c fell 2.33 points vs 0.66 on placebo (P<0.0001), with overall weight reductions of 10 to 12%^[9].
• Secondary analysis of REDEFINE 1, Hypertension 2026: systolic blood pressure fell 10.9 vs 2.8 mm Hg on placebo, and 39.6% of those taking blood-pressure drugs reduced or stopped them vs 18.8%^[7].

• Animal and laboratory studies were run by the developer during early development, but the evidence base that matters here is the large human trial program summarized above; no animal findings are needed to interpret it.

Open Questions

• No cardiovascular outcomes trial has reported, so effects on heart attacks, strokes and deaths are unknown.
• Whether the weight comes back after stopping has not been reported for CagriSema.
• Head-to-head results against tirzepatide had not appeared in a peer-reviewed journal at the time of writing, so how CagriSema compares with the strongest approved option is unsettled.
• Nearly all trials were designed and funded by the manufacturer^[2,3,4,5].

Regulatory Status

Not approved by the FDA or EMA. Novo Nordisk submitted a New Drug Application for CagriSema (cagrilintide plus semaglutide) to the FDA in December 2025, with a review expected in 2026^[1]. Cagrilintide is not named on the WADA 2026 list, but as an unapproved drug it falls under the S0 "non-approved substances" category, prohibited at all times^[10].

Related Compounds

A small signaling peptide encoded in mitochondrial DNA that improves metabolism and exercise capacity in mice; whether giving it to people does anything useful has not been tested in published trials.

Overview

MOTS-c is a 16-amino-acid peptide discovered in 2015, unusual because its code sits inside the mitochondria's own DNA (within the 12S rRNA gene) rather than in the cell nucleus^[1]. It acts mainly on skeletal muscle and appears to help cells cope with metabolic stress. In mice it prevented diet-induced obesity and age-related insulin resistance^[1], and it improved running capacity in old mice^[3].

In people, exercise raises MOTS-c levels in muscle and blood^[3], and a MOTS-c gene variant common in Northeast Asia is linked to higher type 2 diabetes rates in inactive men^[4]. No peer-reviewed trial of MOTS-c itself in humans has been published. An FDA advisory committee narrowly voted in July 2026 to recommend it for compounding, against FDA staff advice^[8].

Mechanism of Action

In the original Cell Metabolism study, MOTS-c inhibited the folate cycle and the linked pathway that builds purines (DNA and RNA building blocks). That metabolic bottleneck activated AMPK, a cellular fuel sensor that increases glucose uptake and fat burning when energy is scarce^[1]. Skeletal muscle was the main target tissue, and the peptide improved insulin sensitivity in mice^[1]. This is why MOTS-c is often called an "exercise mimetic": AMPK is one of the same switches that exercise flips.

A 2018 follow-up showed that when cells are starved of glucose or under oxidative stress, MOTS-c moves into the nucleus in an AMPK-dependent way and regulates many nuclear genes, including antioxidant-response genes controlled by NRF2^[2]. This made it one of the first known mitochondrial-encoded molecules that directly influences nuclear gene expression. A natural variant (K14Q) found in Northeast Asians produced a less effective peptide that lost its weight and glucose benefits in male mice, linking structure to function^[4]. How MOTS-c gets into cells and whether it has a specific receptor remain unclear.

What the Research Shows

• Exercise study, Nature Communications 2021 (n=10 sedentary young men, single bout): skeletal muscle MOTS-c rose about 11.9-fold after exercise (P=0.0098) and blood levels rose about 1.5 to 1.6-fold, returning to baseline after 4 hours of rest^[3].
• Genetic meta-analysis, Aging 2021 (n=27,527 across three Japanese and multiethnic cohorts): men carrying the m.1382A>C variant, which alters MOTS-c, had higher type 2 diabetes prevalence; the link appeared only in the least physically active men and not in women^[4].
• Phase 1b RCT of the analog CB4211, 2021 company report (n=20 obese adults with fatty liver, 4 weeks): ALT fell 21% vs rose 4% on placebo, and glucose fell 6% vs 0%; liver fat fell similarly in both groups (about 5 points). Results were announced by the company and not published in a peer-reviewed journal^[5].

• Mice, diet-induced obesity and aging: MOTS-c prevented high-fat-diet obesity and insulin resistance as well as age-dependent insulin resistance^[1].
• Old mice (22 months), 2 weeks: treated mice ran about twice as long and 2.16 times as far on a treadmill as untreated old mice, outperforming untreated middle-aged mice^[3].
• Very old mice, treatment started at about 23.5 months: improved grip strength, stride and walking tests and reduced fat mass; median lifespan rose about 6.4%, but the overall survival difference was not statistically significant (P=0.23)^[3].
• High-fat-fed male mice: normal MOTS-c reduced weight and improved glucose tolerance, while the K14Q variant did not; female mice showed no effect^[4].

• Cultured cells under glucose restriction: MOTS-c translocated to the nucleus and regulated stress-response genes, interacting with NRF2^[2].
• Insulin-sensitivity assays: the K14Q variant produced less insulin sensitization than normal MOTS-c^[4].

Open Questions

• Whether MOTS-c given by injection reaches muscle and changes metabolism in humans has not been shown in any published controlled trial.
• Most foundational work comes from one research group and its collaborators^[1,2,3,4].
• The lifespan signal in mice was not statistically significant and needs larger studies^[3].
• CB4211 results were never peer-reviewed, and the analog differs from the MOTS-c sequence^[5].

Regulatory Status

Not approved anywhere. It was placed in the FDA's Category 2 for compounding before the nomination was withdrawn^[6]; at the July 23, 2026 Pharmacy Compounding Advisory Committee meeting, members voted 7-5 (2 abstentions) to recommend adding it to the 503A bulks list, a nonbinding vote that FDA staff had opposed, and it had not been added at the time of writing^[7,8]. WADA names MOTS-c as a prohibited AMPK activator under S4 metabolic modulators^[9].

Related Compounds

A small, modified piece of the growth hormone molecule once developed as an obesity pill; it looked safe in human trials, but evidence that it causes meaningful weight loss was never published.

Overview

AOD-9604 is a 16-amino-acid fragment copied from the tail end of human growth hormone (residues 177 to 191, with an extra tyrosine added). The idea was to keep growth hormone's fat-burning effect while leaving out its effects on growth, blood sugar and IGF-1^[1,3]. An Australian company, Metabolic Pharmaceuticals, developed it as an oral obesity treatment and had phase 2 trials under way by 2002^[5].

In obese mice and rats it reduced weight gain and increased fat breakdown without the blood sugar problems seen with whole growth hormone^[1,2,3]. In people, a 2013 paper pooling six randomized trials reported a safety profile "indistinguishable from placebo" but did not report weight-loss results^[4]. It never reached approval, and the FDA has flagged gaps in its safety information^[7].

Mechanism of Action

AOD-9604 is based on the C-terminal region of growth hormone, which earlier work linked to growth hormone's effects on fat. Unlike intact growth hormone, it did not compete for the growth hormone receptor and did not make cells proliferate in laboratory tests^[1]. In obese mice, two weeks of treatment increased fat oxidation and plasma glycerol (a marker of fat breakdown) and reduced weight gain, without causing high blood sugar or lowering insulin secretion as whole growth hormone did^[1]. In obese Zucker rats given the fragment by mouth for 19 days, weight gain was cut by more than half and fat tissue showed higher lipolytic activity, with no loss of insulin sensitivity^[3].

How it produces these effects is not settled. Both growth hormone and AOD-9604 raised levels of beta-3 adrenergic receptors in the fat of obese mice, and the long-term weight effect disappeared in mice lacking that receptor. Yet the authors concluded that neither compound acts directly on the receptor, and AOD-9604 still raised fat oxidation acutely in the knockout mice^[2]. No specific receptor for AOD-9604 has been identified in the studies reviewed here. In human trials it did not raise IGF-1, consistent with the claim that it avoids growth hormone's growth-promoting signaling^[4].

What the Research Shows

• Pooled safety report of six RCTs, 2013 (about 893 healthy or obese adults; single intravenous or oral exposures up to 24 weeks of daily oral treatment): no effect on serum IGF-1, no worsening of oral glucose tolerance, and no anti-AOD-9604 antibodies detected. No withdrawal or serious adverse event was attributed to the drug^[4].
• Largest trials within that report (n=300 over 12 weeks; n=502 randomized over 24 weeks): adverse events were common in all groups (88.9% and 78.7% overall), mainly headache, infections and diarrhea, and were similar between drug and placebo. Weight-loss results were not reported^[4].
• Authorship and funding: the safety paper was sponsored by the developer, and the efficacy outcomes of these trials have not appeared in peer-reviewed literature indexed in PubMed^[4,5].

• Obese (ob/ob) mice, 14 days: reduced body weight gain, increased fat oxidation and lipolysis; unlike whole growth hormone, no hyperglycemia or reduced insulin secretion^[1].
• Obese mice and beta-3 receptor knockout mice, 14 days: reduced body weight and fat in obese mice; the chronic weight and lipolysis effects were absent in knockout mice^[2].
• Obese Zucker rats, 19 days oral: weight gain 15.8 g vs 35.6 g in controls, with increased fat-tissue lipolysis and preserved insulin sensitivity^[3].
• Rabbit knee osteoarthritis model (n=32), 4 to 7 weeks: joint injections of AOD-9604 improved cartilage scores and shortened lameness compared with saline, and worked better combined with hyaluronic acid; a single small study^[6].

• Cell proliferation assays: unlike growth hormone, AOD-9604 did not stimulate cell proliferation and did not compete for the growth hormone receptor^[1].

Open Questions

• Whether AOD-9604 produces clinically meaningful weight loss in humans: the efficacy results of the 12-week and 24-week trials were not published.
• The human trials tested an oral form; injected products in circulation today have no published controlled human data.
• Its molecular target remains unidentified^[2].
• The joint and cartilage claims rest on a single rabbit study^[6].

Regulatory Status

Never approved by the FDA or any major regulator. It was nominated for use in compounding and placed in the FDA's Category 2 (significant safety concerns) before the nomination was withdrawn; it was not among the peptides reviewed at the July 2026 Pharmacy Compounding Advisory Committee meeting, so it has no clear compounding pathway^[7,10]. WADA names AOD-9604 as a prohibited growth hormone fragment under S2, and anti-doping labs have developed tests for it^[8,9].

Related Compounds

A lab-made small molecule, not a peptide, that switches on estrogen-related receptors (ERRs) in muscle; in mice it mimicked parts of endurance exercise, but it has never been tested in humans.

Overview

SLU-PP-332 is a synthetic small molecule, not a peptide, first described in 2023 by an academic group led by Cyrielle Billon and colleagues^[1]. It activates all three estrogen-related receptors (ERR alpha, beta and gamma), with the strongest effect on ERR alpha^[1]. Despite the name, these receptors do not respond to estrogen; they are master switches for genes that build mitochondria and burn fat. It is sometimes described online as a PPAR-delta agonist, but the published work identifies it as an ERR agonist^[1,2].

In mice, it increased oxidative (endurance-type) muscle fibers and running endurance^[1], reduced fat gain and improved insulin sensitivity in obese animals^[2], and protected the heart and aging kidney in disease models^[3,4]. Anti-doping laboratories have already characterized how it is broken down, anticipating misuse^[6]. No human data exist.

Mechanism of Action

ERRs are nuclear receptors: proteins inside the cell that bind DNA and turn on sets of genes. They help control energy metabolism, including genes for mitochondrial function and fatty acid oxidation. SLU-PP-332 was identified as a pan-ERR agonist with the highest potency at ERR alpha and drug-like properties suitable for animal studies^[1]. In a skeletal muscle cell line it increased mitochondrial function and cellular respiration. In mice it switched on an acute aerobic-exercise gene program that depended on ERR alpha, and the endurance benefit was lost without ERR alpha activation^[1].

In obese mice, the compound increased whole-body energy expenditure and fatty acid oxidation and reduced fat accumulation, which the authors described as mimicking the metabolic benefits of exercise^[2]. In the heart, the effects ran mainly through ERR gamma, boosting fatty acid metabolism and mitochondrial capacity in a heart-failure model^[3]. These receptors also influence many other tissues, and it is not yet clear which effects would matter, or be safe, in humans. The broad, multi-receptor activity is a strength in mice but makes side effects harder to predict.

What the Research Shows

• No human studies of SLU-PP-332 have been published. All evidence comes from cells and mice^[1,2,3,4].

• Mice, exercise capacity: increased type IIa oxidative muscle fibers and enhanced running endurance, an effect that depended on ERR alpha^[1].
• Diet-induced obese and ob/ob mice: increased energy expenditure and fatty acid oxidation, decreased fat mass accumulation, and improved insulin sensitivity^[2].
• Mice, pressure-overload heart failure (6 weeks): SLU-PP-332 and a related agonist improved ejection fraction, reduced fibrosis and increased survival, without changing heart muscle thickening^[3].
• Aged mice (21 months), 8 weeks: reversed age-related increases in urine albumin, loss of kidney filtering cells, mitochondrial dysfunction and inflammatory signals, similar to lifelong calorie restriction^[4].

• Skeletal muscle cell line: increased mitochondrial function and cellular respiration^[1].
• In vitro metabolism studies: anti-doping chemists mapped its breakdown products to build detection methods^[6].

Open Questions

• Whether SLU-PP-332 is absorbed, reaches muscle, or has any effect in humans.
• Long-term effects of activating all three ERRs at once, in the heart, kidney, muscle and other tissues^[3,4].
• Nearly all studies come from the same academic group and its collaborators^[1,2,3,5].
• Whether the newer compounds in the series replace it in future development^[5].

Regulatory Status

Not approved anywhere and not in clinical trials based on published records. WADA's 2026 list does not name it, but as an unapproved substance it falls under S0 (non-approved substances), prohibited at all times; anti-doping labs have developed detection methods^[6,7].

Related Compounds

A compounded injection of nutrients (methionine, inositol, choline, often with B12 or carnitine), not a peptide, marketed for fat loss and liver support without studies of the blend itself.

Overview

Lipo-C is a market name for a compounded injectable blend of so-called lipotropic nutrients: the amino acid methionine, inositol and choline, often with vitamin B12, other B vitamins or L-carnitine. It is a product category, not a single molecule and not a peptide, and recipes vary by maker. The idea comes from nutrition science: choline is needed to move fat out of the liver, and people deprived of it can develop liver dysfunction^[1].

That logic covers deficiency, not supplementation. No controlled trial has tested the injectable blend for weight loss, fat loss or liver health. Component evidence is mixed: carnitine produced about 1.3 kg of extra weight loss in a meta-analysis^[3], inositol improved insulin measures in women with polycystic ovary syndrome^[4], and B12 does not improve performance or energy in people with adequate levels^[2].

Mechanism of Action

Each component has a known biological job. Choline is needed to make phosphatidylcholine, a membrane building block that is essential for exporting fat from the liver; it is also used to make the neurotransmitter acetylcholine and serves as a source of methyl groups^[1]. Methionine, an essential amino acid, feeds into the same methyl-group pathways as choline and folate^[1]. Inositol acts inside cells as part of insulin signaling, which is the rationale for its study in insulin-resistant conditions such as polycystic ovary syndrome^[4]. L-carnitine shuttles long-chain fatty acids into mitochondria to be burned for energy^[3].

The marketing leap is from "required for" to "more is better." Choline deficiency in controlled feeding studies caused liver dysfunction in about two thirds of volunteers, which reversed when choline was restored^[1]. That shows the body needs adequate choline, not that extra choline drains fat in people who already get enough. Similarly, B12 helps only when someone is deficient^[2]. No study has measured whether injecting these nutrients together changes fat metabolism, and possible interactions between components have not been examined.

What the Research Shows

• Injectable blend: no published randomized or controlled trials of the methionine, inositol and choline combination were identified.
• Choline depletion study, 2007 (per NIH ODS) (n=57 adults, up to 42 days on a very low choline diet): 37 developed liver dysfunction, which normalized when choline was restored. In a 15-person pilot of IV-fed patients, extra choline resolved fatty liver^[1].
• Carnitine meta-analysis, 2016 (per NIH ODS) (9 RCTs, n=911): carnitine users lost about 1.33 kg more than placebo^[3].
• Myo-inositol meta-analysis, Endocr Connect 2017 (9 RCTs, n=496 women with polycystic ovary syndrome): fasting insulin and HOMA insulin resistance fell, with high heterogeneity; weight was not an outcome^[4].
• Vitamin B12: supplementation does not appear to improve athletic performance or endurance in people with sufficient B12 status^[2].

• No animal studies of the injectable blend were identified.

Open Questions

• Whether the blend does anything beyond correcting deficiency has never been tested.
• How components interact when injected together, including any effect on homocysteine from extra methionine, is unstudied.
• Whether injection offers any advantage over food or oral supplements for these nutrients is unknown^[2].
• Formulations vary widely between compounders, so results from one product would not apply to another^[5].

Regulatory Status

Lipo-C is not an FDA-approved drug; it is prepared by compounding pharmacies. On FDA's 503A list (updated May 2026), choline chloride is in Category 1 (under evaluation), while methionine and plain inositol are not listed as nominated bulk substances^[5].

Related Compounds

A small drug-like molecule, not a peptide, that blocks an enzyme called NNMT; it reduced fat gain and improved metabolism in obese mice but has never been tested in people.

Overview

5-Amino-1MQ (5-amino-1-methylquinolinium) is a small synthetic molecule, not a peptide. It is included here because it is often discussed alongside metabolic peptides. It blocks nicotinamide N-methyltransferase (NNMT), an enzyme that is more abundant in the fat tissue and liver of obese and diabetic mice and whose suppression protected mice from diet-induced obesity^[2]. Its developers designed this family of methylquinolinium inhibitors as possible anti-obesity drugs^[1].

In diet-induced obese mice, 5-amino-1MQ and related compounds reduced body weight, fat mass and fat-cell size and lowered cholesterol without reducing food intake^[1]. A 28-day mouse study also reported better glucose tolerance and less fatty liver^[3]. No human studies of any kind have been published.

Mechanism of Action

NNMT attaches a methyl group from S-adenosylmethionine (SAM, the body's main methyl donor) to nicotinamide, a form of vitamin B3, producing 1-methylnicotinamide (1-MNA). Because nicotinamide is also the raw material the cell recycles into NAD+, high NNMT activity may drain both SAM and NAD+^[2]. In the 2014 Nature study, knocking down NNMT in fat and liver raised SAM and NAD+ in fat tissue, increased the activity of polyamine-processing enzymes, and protected mice from diet-induced obesity^[2]. The authors linked NNMT to histone methylation and SIRT1 signaling.

5-Amino-1MQ belongs to a series of methylquinolinium compounds screened as NNMT inhibitors. In laboratory tests these compounds crossed cell membranes well and did not inhibit related methyltransferases or NAD+ recycling enzymes^[1]. In cultured fat cells they lowered 1-MNA, raised NAD+ and SAM, and suppressed fat synthesis^[1]. Whether the same chain of events happens in human fat tissue, and which of these changes matters most for the weight effect, has not been established.

What the Research Shows

• No human studies of 5-amino-1MQ have been published. The only data come from cultured cells and mice^[1,3,4].

• Diet-induced obese mice: a potent methylquinolinium NNMT inhibitor reduced body weight and white fat mass, shrank fat cells and lowered total cholesterol, without changing food intake or causing observable adverse effects^[1].
• Diet-induced obese mice, 28 days: 5-amino-1MQ limited weight and fat gain in a dose-dependent way, improved glucose tolerance and insulin sensitivity, reduced fatty liver and normalized ALT and AST; the compound reached fat, muscle and liver^[3].
• Obese mice on a reduced-calorie diet: combining NNMT inhibition with diet normalized body composition and added metabolic benefits beyond diet alone^[6], and produced a distinct gut microbiome profile^[5].
• Aged mice (22 to 24 months): an NNMT inhibitor from the same research program gave about 40% greater grip strength than sedentary controls, vs about 20% with exercise alone and 60% with both^[4].
• NNMT knockdown mice: genetically lowering NNMT in fat and liver protected against diet-induced obesity, supporting NNMT as a target^[2].

• Cultured adipocytes: methylquinolinium NNMT inhibitors lowered 1-MNA, raised NAD+ and SAM, and suppressed lipogenesis^[1].

Open Questions

• Whether 5-amino-1MQ has any effect on body weight or metabolism in humans.
• Nearly all studies come from one research group and its collaborators, and independent replication is limited^[1,3,4,5].
• How quality and identity of unregulated products compare with the research compound is unknown.
• Whether NNMT inhibition is safe over months or years, given NNMT's role in methylation^[2].

Regulatory Status

Not approved by the FDA or any major regulator, and it has not entered published clinical trials. It does not appear on the FDA's Category 2 compounding list or among the withdrawn peptide nominations, and it has no recognized compounding pathway^[7]. It is not named on the WADA 2026 list, but as an unapproved substance it falls under S0, prohibited at all times^[8].

Related Compounds