What it is

Tirzepatide is a dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist developed by Eli Lilly. Unlike semaglutide, which targets only the GLP-1 receptor, tirzepatide activates both the GIP and GLP-1 pathways simultaneously. GIP is a hormone that also plays a role in insulin secretion and, separately, may influence fat storage and energy expenditure through adipose tissue receptors. The dual mechanism is the basis for why tirzepatide has shown larger weight reductions in trials than GLP-1-only agents in head-to-head comparisons.

FDA and approval status

Zepbound (tirzepatide) is FDA-approved for chronic weight management in adults with obesity (BMI 30+) or overweight (BMI 27+) with at least one weight-related health condition. Mounjaro (tirzepatide) is FDA-approved for type 2 diabetes management. Both are prescription drugs requiring evaluation by a licensed clinician and dispensing through a licensed pharmacy.

What the evidence shows

The SURMOUNT trial program is the primary evidence base for tirzepatide in weight management. SURMOUNT-1 (Jastreboff et al., 2022, New England Journal of Medicine) enrolled 2,539 adults with obesity or overweight and no diabetes. At 72 weeks, participants on 15 mg tirzepatide weekly achieved a mean weight reduction of 20.9% versus 3.1% on placebo. At the 5 mg and 10 mg doses, reductions were 15.0% and 19.5% respectively. These are the largest mean weight reductions seen in a pharmaceutical weight management trial with agents of this class to date.

SURMOUNT-2 examined participants with type 2 diabetes and found weight reductions of approximately 15.7% at the 15 mg dose. Head-to-head comparisons with semaglutide in the SURMOUNT-5 trial (published 2025) showed tirzepatide achieved greater mean weight loss than semaglutide 2.4 mg in the same population. These are trial-level findings and do not constitute a guarantee of outcome for any individual.

Dosing note for informational context only: SURMOUNT-1 used doses of 5 mg, 10 mg, and 15 mg weekly with a dose-escalation schedule. Any prescription dosing is determined by your prescribing clinician, not by this guide.

What it is

Retatrutide is an investigational triple receptor agonist developed by Eli Lilly that activates GIP, GLP-1, and glucagon receptors simultaneously. Adding glucagon receptor activity to the GIP/GLP-1 dual mechanism is theorized to increase energy expenditure alongside appetite suppression, which is the basis for interest in this compound as a potential next-generation weight management drug. It is currently in Phase 3 clinical trials. It is not FDA-approved and is not commercially available.

FDA and approval status

Retatrutide is not FDA-approved for any indication. It is an investigational new drug (IND) in clinical development. As of mid-2026, it is in Phase 3 trials. It is not available for prescription, not available through telehealth providers, and not available from research peptide vendors. It cannot be legally obtained outside of a clinical trial.

What the evidence shows

A Phase 2 trial (Jastreboff et al., 2023, New England Journal of Medicine) enrolled 338 adults with obesity. At 24 weeks, participants on the highest dose (12 mg weekly) achieved a mean weight reduction of approximately 17.5%. At 48 weeks, weight loss continued, with the 12 mg group approaching 24% mean reduction. These Phase 2 findings are preliminary. Phase 2 results establish biological activity and inform dose selection for Phase 3 but do not constitute an established evidence base in the way that Phase 3 RCTs do. Phase 3 results are needed before a full assessment of efficacy and safety is possible.

What it is

Cagrilintide is a long-acting amylin analogue developed by Novo Nordisk. Amylin is a hormone co-secreted with insulin by pancreatic beta cells that contributes to satiety signaling through the central nervous system. The endogenous amylin analogue pramlintide is FDA-approved as an adjunct to insulin therapy in type 1 and type 2 diabetes, but cagrilintide is not pramlintide — it is a newer, longer-acting analogue designed for once-weekly dosing. It is primarily being studied in combination with semaglutide (as the fixed-dose combination "CagriSema") rather than as a standalone agent.

FDA and approval status

Cagrilintide is not FDA-approved for any indication, including as a standalone agent or in combination. The CagriSema combination (cagrilintide plus semaglutide) is in Phase 3 trials as of 2026. It is an investigational compound. It cannot be legally obtained outside of a clinical trial and is not available through commercial telehealth providers or research vendors.

What the evidence shows

The SCALE NEXT Phase 3 trial program is evaluating CagriSema (2.4 mg cagrilintide plus 2.4 mg semaglutide once weekly) in adults with obesity. Phase 2 results for CagriSema (Lau et al., 2021, The Lancet) showed that the combination produced greater weight loss than either agent alone in a 32-week trial. The combination arm at the highest doses achieved approximately 17.1% mean weight reduction versus 9.0% for cagrilintide alone and 15.2% for semaglutide alone, though these are Phase 2 findings in small populations. Phase 3 data is required to confirm the magnitude of effect and characterize the safety profile.

What it is

AOD-9604 is a synthetic peptide fragment comprising amino acids 177 through 191 of the human growth hormone (hGH) sequence. It was originally developed by Monash University and licensed to Metabolic Pharmaceuticals as an anti-obesity drug candidate. The hypothesis behind its development was that this C-terminal fragment of hGH might preserve the lipolytic properties of growth hormone (stimulating fat breakdown) while avoiding the diabetogenic effects (insulin resistance, glucose elevation) associated with full-length hGH. It received GRAS (Generally Recognized as Safe) status from the US FDA as a food ingredient in 2014, which is distinct from drug approval.

FDA and regulatory status

AOD-9604 is not FDA-approved as a drug for weight loss or any other therapeutic indication. Its GRAS status applies only to its use as a food additive ingredient, not as a pharmaceutical or injectable compound. Drug development as an obesity treatment was discontinued after Phase 2b and Phase 3 human trials did not demonstrate statistically significant superiority over placebo for weight loss at endpoints studied. It is sold as a research compound for laboratory use only.

What the evidence shows

Early preclinical work in obese rodent models (Heffernan et al., 2001) showed reductions in fat mass with AOD-9604 without affecting insulin sensitivity or IGF-1 levels. These animal findings drove significant commercial interest and clinical development. Human trials (Heffernan et al., 2001; Phase 2 trials conducted by Metabolic Pharmaceuticals) were less convincing. Phase 2b and 3 trials in human subjects did not demonstrate weight loss outcomes sufficient to support drug approval, which is why development was discontinued. The gap between preclinical promise and human trial results is the central fact about AOD-9604 that its popularity in research communities tends to obscure.

What it is

MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) is a peptide encoded within mitochondrial DNA rather than nuclear DNA, placing it in a category of compounds called mitochondria-derived peptides (MDPs). It was first described by Lee et al. in 2015. Its proposed mechanism involves activation of AMPK (AMP-activated protein kinase), a cellular energy sensor that plays roles in glucose metabolism, fat oxidation, and mitochondrial biogenesis. The interest in MOTS-c for fat loss stems from its studied effects on metabolic function in preclinical models, particularly around insulin sensitivity and fat metabolism, rather than appetite suppression.

FDA and regulatory status

MOTS-c is not FDA-approved for any human therapeutic use. There are no approved drugs containing MOTS-c. It is an emerging research compound with a relatively short published history (first described 2015) compared to the GLP-1 class compounds discussed in Group 1. It is sold as a research chemical for laboratory use only.

What the evidence shows

Preclinical work in mouse models has shown that MOTS-c administration can reduce fat accumulation, improve insulin sensitivity, and increase exercise endurance, with some findings suggesting effects on brown adipose tissue activity. The 2015 Lee et al. paper demonstrated that MOTS-c injection in mice on high-fat diets reduced adiposity. Subsequent studies have explored age-related metabolic decline, with MOTS-c levels found to decrease with age in humans in observational data.

A small number of early human studies are emerging, primarily in the context of aging and insulin resistance rather than weight loss specifically. Human pharmacokinetic data is limited. There are no published RCTs examining MOTS-c for weight loss outcomes in humans. The mechanism is scientifically interesting; the human evidence for fat loss is not yet present in the published literature.

What it is

5-Amino-1MQ (5-amino-1-methylquinolinium) is a small molecule that functions as an inhibitor of NNMT (nicotinamide N-methyltransferase), an enzyme expressed in adipose tissue that regulates NAD+ metabolism and is linked to fat cell differentiation and energy expenditure. It is technically not a peptide by structure, though it is sold in the peptide research market due to its metabolic research interest. NNMT inhibition is theorized to increase NAD+ availability in fat tissue, which may influence fat storage and metabolic rate in preclinical models. It is one of the newer and less-studied entries in this guide.

FDA and regulatory status

5-Amino-1MQ is not FDA-approved for any human use. It is an early-stage research compound with a limited published research history. It is sold as a research chemical for laboratory use only. There are no clinical trials registered for 5-Amino-1MQ in major trial registries as of mid-2026.

What the evidence shows

The primary published evidence base for 5-Amino-1MQ comes from a 2021 study by Neelakantan et al. published in Cell Chemical Biology, which examined NNMT inhibition in mouse models fed a high-fat diet. Mice receiving the compound showed reduced fat mass and improved metabolic markers compared to untreated controls. This is a single preclinical study from one research group. There is no published human pharmacokinetic data, no clinical safety data, and no human efficacy data in the peer-reviewed literature as of this writing. The compound has attracted attention in biohacking communities well ahead of the evidence warranting that attention.

What it is

Tesamorelin is a synthetic analogue of growth hormone-releasing hormone (GHRH) developed as Egrifta by Theratechnologies. Unlike most compounds in this guide, tesamorelin does have an FDA-approved indication: it is approved for the reduction of excess visceral abdominal fat in adults with HIV-associated lipodystrophy, a specific fat redistribution condition associated with antiretroviral therapy. Its relevance to the general weight loss discussion comes from its studied effects on visceral fat in HIV-positive populations, which some researchers and clinicians have explored in other fat redistribution contexts, though those uses are off-label.

FDA and regulatory status

Tesamorelin (Egrifta SV) has a narrow FDA approval specifically for reducing excess visceral adipose tissue in adults with HIV-associated lipodystrophy. It is not FDA-approved for weight loss in the general population, for obesity management, or for fat reduction in people without HIV-associated lipodystrophy. When sold by research peptide vendors, it is sold as a research compound for laboratory use, outside of its narrow approved indication. The FDA-approved version (Egrifta) is a prescription drug dispensed through licensed pharmacies under physician supervision.

What the evidence shows

The approval basis for tesamorelin comes from the LADI (Lipodystrophy in AIDS) trials. Falutz et al. (2010, New England Journal of Medicine) enrolled 412 HIV-positive adults with lipodystrophy and abdominal fat excess. After 26 weeks, tesamorelin reduced visceral adipose tissue by approximately 15.2% versus an increase in the placebo group. GH and IGF-1 levels increased. These findings are specific to HIV-associated fat redistribution and were conducted in a population with a distinct pathophysiology. The applicability of these results to fat loss in healthy adults without this condition is not established in published literature and would represent an off-label use.