Mazdutide vs AOD-9604.

Mazdutide (IBI362, originally LY3305677) is an investigational once-weekly injectable dual agonist of the GLP-1 and glucagon receptors, based on a mammalian oxyntomodulin analog. It is being developed by Innovent Biologics under a license from Eli Lilly, primarily for obesity and type 2 diabetes and with additional metabolic indications under study. It is furthest advanced in China, where it has progressed through Phase 3 trials, but it is not an approved medicine in the United States or Europe. Like other dual agonists, it is designed to pair appetite and glucose control with added energy expenditure.

AOD-9604 ("Advanced Obesity Drug 9604") is a synthetic 16-amino-acid peptide corresponding to the C-terminal lipolytic region of human growth hormone (hGH), residues 177–191, with an added tyrosine at the N-terminus. It was engineered in the 1990s by researchers at Monash University and developed by the Australian biotech Metabolic Pharmaceuticals as an orally-investigated anti-obesity agent. The design goal was to isolate hGH's fat-mobilizing activity while leaving out the growth-promoting, IGF-1-stimulating actions of the full hormone.

Mazdutide derives from oxyntomodulin, a natural gut hormone that engages both the GLP-1 and glucagon receptors. GLP-1 activation drives appetite suppression, delayed gastric emptying, and glucose-dependent insulin release, while glucagon-receptor activation is thought to increase energy expenditure and reduce hepatic fat. The combined signaling is intended to produce weight loss alongside improvements in lipids, blood pressure, liver enzymes and other metabolic markers. Structural modifications extend its half-life to allow weekly subcutaneous administration.

In rodent models, AOD-9604 reproduces the lipolytic (fat-breakdown) and fat-oxidation–promoting effects of full-length growth hormone without binding the GH receptor and without raising IGF-1. Mechanistic work in obese and beta-3-adrenergic-receptor knockout mice indicated its effect on fat metabolism is associated with modulation of beta-3 adrenergic receptor activity and increased lipolysis and fat oxidation rather than classic GH-receptor signaling. Because it does not engage the GH receptor, it was hypothesized to avoid the insulin-resistance and tissue-growth liabilities of GH itself. Importantly, the cleanly receptor-independent, IGF-1-sparing profile is best characterized in animal and in-vitro work, not firmly established in humans.

A randomised, double-blind, placebo-controlled Phase 2 trial in 248 Chinese adults with overweight or obesity, published in Nature Communications (2023), tested mazdutide 3 mg, 4.5 mg and 6 mg over 24 weeks. Mean body-weight reductions reached roughly 11% at the 6 mg dose versus about 3% with placebo, with dose-dependent effects. Participants also showed improvements in waist circumference, blood pressure, blood lipids, liver transaminases and serum uric acid. Earlier Phase 1b studies in Chinese adults with overweight/obesity and with type 2 diabetes supported tolerability and metabolic benefit at higher doses. Phase 3 obesity and diabetes programs (the GLORY series) have since been conducted in China, and GLORY-1, a randomised placebo-controlled Phase 3 trial of once-weekly mazdutide in Chinese adults with obesity or overweight, was published in the New England Journal of Medicine in 2025. A further Phase 2 randomised controlled trial in Chinese adults with a body mass index of at least 30 and without diabetes was reported in Med, and mazdutide has been included in network meta-analyses of glucagon receptor agonists that pool metabolic outcomes across compounds. Evidence outside Chinese populations and long-term outcome data remain limited. The trials are sponsor-run, of moderate size, and almost entirely single-country, so generalisability to other ancestries, body-composition distributions and background diets is untested. There is no cardiovascular outcome trial for mazdutide, no published head-to-head randomised comparison with semaglutide or tirzepatide, and no multi-year durability or weight-regain dataset. By contrast, semaglutide and tirzepatide each have global multi-thousand-participant Phase 3 programs and regulatory approval in the United States and Europe, and semaglutide additionally has dedicated cardiovascular outcome data, which places mazdutide an evidence tier behind them despite broadly similar reported weight reductions. Regulatory acceptance in one country also does not substitute for the outcome evidence that has not yet been generated.

Preclinical evidence is the strongest part of the AOD-9604 record: chronic dosing reduced body-weight gain and increased fat oxidation in obese mice (Heffernan et al., Int J Obes, 2001; PMID 11673763). It progressed into human obesity trials in the early-mid 2000s; a 12-week randomized study reported only a modest separation from placebo (on the order of ~1–2 kg), and development was halted around 2007 after a larger ~24-week trial failed to show meaningful weight-loss efficacy, particularly once diet and exercise were standardized. No peer-reviewed pivotal trial demonstrates clinically useful weight loss, and there is no robust human evidence for the commonly marketed claims around cartilage, joint, or tendon repair: those rest on limited preclinical/early work. In short, the human data are negative-to-thin for obesity and largely absent for other indications.

Across trials, the most common adverse events were gastrointestinal, including nausea, diarrhoea and decreased appetite, typical of GLP-1-based agents and generally most pronounced during dose escalation. Overall tolerability was described as favorable in the Phase 2 study, but as an investigational drug its full safety profile, including uncommon and long-term risks, is not yet established. Glucagon-receptor activation warrants monitoring of parameters such as heart rate and hepatic markers in ongoing studies. Documented class considerations for incretin-based agents include gallbladder and biliary events, reported pancreatitis, delayed gastric emptying with implications for sedation and anaesthesia, loss of lean mass in parallel with fat loss, and rodent thyroid C-cell findings that shaped labelling for several approved GLP-1 drugs. A trial adequate to characterise these requires scheduled laboratory chemistry, vital-sign monitoring, pregnancy prevention requirements, protocol-defined dose-reduction and stopping rules, and independent adjudication of serious events, none of which exists outside a regulated study. Mazdutide is not approved or commercially supplied in the United States or Europe, so material sold there as mazdutide comes from unregulated research-chemical or compounding channels with no verified identity, potency, purity or sterility, no stability data, and no route for reporting harm. Peptide products from such channels have been associated with mislabelling and contamination, which makes any observed effect, benign or adverse, difficult to attribute to the intended molecule.

Across the obesity trials, AOD-9604 was generally reported as well tolerated with a clean short-term safety signal, which is part of why it was later nominated for compounding review; however, these data come from time-limited studies and do not establish long-term safety. There is no established safety profile for chronic use, for injectable research-grade ("gray market") product, or for the unindicated cosmetic, joint, and anti-aging uses now marketed online. Purity, identity, and contamination of non-pharmaceutical material are real concerns, underscored by published forensic identification of illicit AOD9604 preparations (Drug Testing and Analysis, 2014; PMID 24976118). No dosing or administration guidance is provided here.

Mazdutide is investigational and not approved by the FDA or EMA. Its development is most advanced in China, where a regulatory filing for obesity/overweight has been pursued following Phase 3 results. Any use outside an authorized clinical trial is unapproved.

AOD-9604 is not approved by the FDA (or any major regulator) for any therapeutic use; its obesity development program was discontinued, and it remains investigational/research-use-only. The FDA has evaluated it among nominated bulk drug substances for pharmacy compounding under section 503A and has flagged peptide candidates of this type as raising significant safety questions; it is also prohibited in sport and tested for by anti-doping authorities under the WADA framework.