Mazdutide vs Retatrutide.

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.

Retatrutide (development code LY3437943) is an investigational once-weekly injectable peptide developed by Eli Lilly for the treatment of obesity and related cardiometabolic disease. It is a single synthetic peptide engineered to act as a "triple G" agonist, simultaneously stimulating three nutrient-hormone receptors: the glucagon-like peptide-1 (GLP-1) receptor, the glucose-dependent insulinotropic polypeptide (GIP) receptor, and the glucagon receptor. This distinguishes it from the single agonist semaglutide (GLP-1) and the dual agonist tirzepatide (GIP/GLP-1), both already approved.

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.

Retatrutide is a balanced agonist at three receptors, each contributing a distinct metabolic effect. GLP-1 receptor agonism enhances glucose-dependent insulin secretion, slows gastric emptying, and acts centrally to reduce appetite and food intake. GIP receptor agonism further modulates insulin response and appears to improve nutrient handling and tolerability. The defining addition is glucagon receptor agonism, which raises hepatic glucose output and, importantly, increases energy expenditure and promotes hepatic lipid oxidation/mobilization. The combination is intended to layer glucagon-driven increases in energy expenditure and reductions in liver fat on top of the appetite suppression and glycemic benefits of incretin (GLP-1/GIP) signaling. Because glucagon agonism can raise hepatic glucose production and resting heart rate, the receptor balance and dose are designed to keep net effects metabolically favorable.

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.

Human evidence comes from a completed Phase 2 program and emerging Phase 3 data, so this is no longer animal-only, though long-term outcome and safety data remain immature. In the 48-week Phase 2 obesity trial (Jastreboff et al., NEJM 2023), adults with obesity/overweight without diabetes had least-squares mean weight reductions of roughly -17.1%, -22.8%, and -24.2% across higher dose groups versus -2.1% with placebo. A parallel Phase 2 trial in type 2 diabetes (Rosenstock et al., Lancet 2023) showed substantial reductions in HbA1c and body weight. A Phase 2a trial in metabolic dysfunction-associated steatotic liver disease (Nature Medicine 2024) reported large relative reductions in liver fat, with the majority of higher-dose participants reaching liver fat below the steatosis threshold. In May 2026 Lilly reported topline Phase 3 results (TRIUMPH-1, ~2,339 adults), with the highest dose producing about 28.3% mean weight loss at 80 weeks; full peer-reviewed Phase 3 publications and the broader TRIUMPH cardiovascular/diabetes outcome trials were still pending at that time.

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.

In trials the most common adverse events were gastrointestinal (nausea, vomiting, diarrhea, constipation), dose-related, mostly mild to moderate, and concentrated during dose escalation; using a lower starting dose partially mitigated them. A mechanistically important signal is a dose-dependent increase in heart rate, which in the Phase 2 obesity trial peaked around 24 weeks before declining; glucagon receptor agonism also raises hepatic glucose output, requiring monitoring. Phase 3 topline data showed dose-dependent discontinuation due to adverse events. Because retatrutide is investigational, its long-term safety, cardiovascular outcomes, and effects in broad real-world populations are not yet established. Compounded, "research-use-only," or gray-market retatrutide is not quality-controlled and carries additional, unquantified risks.

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.

As of mid-2026 retatrutide is investigational and not approved by the FDA, EMA, MHRA, or any other regulator for any indication; it remains in Phase 3 development (the TRIUMPH program) by Eli Lilly. It is not a dietary supplement and any product sold as "research-use-only" retatrutide is unapproved.