Mazdutide is the first dual GLP-1 and glucagon receptor agonist approved for obesity. Innovent Biologics and Eli Lilly developed it under the code IBI362, and China’s National Medical Products Administration approved it for chronic weight management in June 2025. The drug is interesting because it doesn’t just suppress appetite the way semaglutide does. It also burns more energy by activating the glucagon receptor, a mechanism that newer obesity drugs are starting to chase.<\/p>\n
The compound is a synthetic analog of oxyntomodulin, a gut hormone humans produce naturally after eating. Oxyntomodulin hits two receptors at once: GLP-1 (which reduces hunger and improves blood sugar) and glucagon (which raises metabolic rate and mobilizes fat). Mazdutide takes that natural hormone, stabilizes it with a fatty acid side chain so it lasts a week in the body, and tunes the receptor ratio for safety. The result is a once-weekly injection that produced 18% mean weight loss in the GLORY-1 phase 3 trial at 48 weeks.<\/p>\n
This article walks through the receptor biology, the trial evidence, and why the dual mechanism matters compared to GLP-1 monotherapy or GLP-1\/GIP dual agonists like tirzepatide.<\/p>\n
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Mazdutide is a once-weekly injectable peptide that activates two gut hormone receptors at the same time.<\/strong> Innovent Biologics developed it in China, with Eli Lilly licensing the global rights outside Greater China. It is the first approved drug in its class, the GLP-1\/glucagon dual receptor agonist family.<\/p>\n Quick Answer: Mazdutide activates both GLP-1 and glucagon receptors, mimicking the natural gut hormone oxyntomodulin<\/p>\n The molecule is a structural analog of oxyntomodulin, a 37 amino acid peptide that the L cells of the small intestine release after a meal. Native oxyntomodulin only lasts a few minutes in circulation. Mazdutide includes a C18 fatty diacid side chain attached at position 20, which lets it bind albumin in the blood and resist degradation. This is the same engineering trick semaglutide uses for its weekly half-life.<\/p>\n The drug entered phase 3 trials in 2022 and reported results across the GLORY (obesity) and DREAMS (diabetes) programs. The FDA has not yet approved it. Eli Lilly is running global phase 3 studies for a potential US filing, though no timeline has been confirmed.<\/p>\n GLP-1 receptor activation reduces food intake by signaling fullness to the brain and slowing how fast the stomach empties.<\/strong> This is the same primary mechanism that drives weight loss with semaglutide (Wegovy\u00ae) and the GLP-1 half of tirzepatide.<\/p>\n When mazdutide binds GLP-1 receptors in the hypothalamus and brainstem, it activates neurons that signal satiety. People feel full sooner, eat less per meal, and report less interest in food between meals. In the GLORY-1 trial, participants on 6 mg mazdutide reduced daily energy intake by roughly 400 to 600 calories without conscious dieting effort.<\/p>\n GLP-1 receptors in the pancreas also stimulate glucose-dependent insulin release. That’s why mazdutide lowers HbA1c in people with type 2 diabetes. The receptor in the stomach slows gastric emptying, which contributes to early satiety and to the nausea side effect that most patients feel for the first few weeks.<\/p>\n Glucagon receptor activation increases energy expenditure and fat oxidation, two effects that GLP-1 alone does not produce.<\/strong> This is the unique selling point of the dual agonist class.<\/p>\n Glucagon is best known as the hormone that raises blood sugar when you fast. In low, sustained doses, though, it also tells the liver to break down fat stores and tells brown adipose tissue to burn more calories as heat. Phase 1 and 2 studies of mazdutide showed resting energy expenditure rose 5 to 10% in dosed participants compared with placebo. Over months, that adds up to thousands of extra calories burned.<\/p>\n The trick is balancing the two receptors. Pure glucagon would spike blood sugar. Pure GLP-1 leaves energy expenditure flat. Mazdutide’s receptor activation ratio favors GLP-1 enough to lower glucose, while keeping glucagon activity strong enough to add the metabolic boost. In GLORY-1, HbA1c still fell despite the glucagon component.<\/p>\n Mazdutide is mechanistically closer to retatrutide than to semaglutide or tirzepatide, but it’s the only one currently approved in its class.<\/strong> Here’s the receptor breakdown:<\/p>\n Semaglutide hits one receptor: GLP-1. Tirzepatide hits two: GLP-1 and GIP (glucose-dependent insulinotropic polypeptide). Mazdutide also hits two, but the second is glucagon instead of GIP. Retatrutide, which Eli Lilly is developing for obesity, hits all three (GLP-1, GIP, and glucagon).<\/p>\n The clinical translation is roughly this. STEP 1 semaglutide produced 14.9% weight loss at 68 weeks. SURMOUNT-1 tirzepatide produced 20.9% at 72 weeks. GLORY-1 mazdutide produced 18% at 48 weeks. The trials aren’t head-to-head, populations differ (GLORY-1 enrolled Chinese adults), and timelines vary. But mazdutide is clearly in the same league as the top GLP-1 drugs.<\/p>\n The glucagon mechanism could also matter for liver disease. Glucagon receptor activation reduces hepatic fat directly, which is why mazdutide is being studied for MASH (metabolic dysfunction-associated steatohepatitis).<\/p>\n GLORY-1 was the key phase 3 study supporting China’s approval.<\/strong> Ji et al. published the results in NEJM in 2025. The trial enrolled 610 Chinese adults with obesity or overweight plus a weight-related comorbidity, all without diabetes.<\/p>\n Participants were randomized to mazdutide 4 mg, mazdutide 6 mg, or placebo, once weekly for 48 weeks. The primary endpoint was percent change in body weight. At the 6 mg dose, mean weight loss was 14.4% from baseline versus 0.3% in the placebo arm. The full 48-week analysis with completers showed roughly 18% mean weight loss at the top dose.<\/p>\n Secondary endpoints all moved in the right direction. Waist circumference dropped by an average of 12 cm at the 6 mg dose. Systolic blood pressure fell 6 to 7 mmHg. Triglycerides dropped 25%. LDL cholesterol fell modestly. The most common side effect was nausea, reported by about 30% of participants and mostly during dose escalation.<\/p>\n GLORY-2, an ongoing trial in Chinese adults with obesity plus comorbidities, is reading out next. Global phase 3 trials are running through 2026.<\/p>\n Mazdutide lowers HbA1c in people with type 2 diabetes by 1.4 to 1.8 percentage points, depending on dose, based on the DREAMS-1 and DREAMS-2 phase 3 trials.<\/strong> That puts it in the same range as semaglutide 1 mg weekly.<\/p>\n DREAMS-1 enrolled adults with type 2 diabetes inadequately controlled on lifestyle alone. At 24 weeks, HbA1c dropped 1.6 percentage points at the 4 mg dose versus 0.1 in placebo. Mean weight loss was about 6.7% in the same arm. DREAMS-2 added mazdutide to metformin and showed similar HbA1c reductions plus additional weight loss.<\/p>\n The glucagon component does not appear to worsen diabetes control in practice. This was a theoretical concern early on, since glucagon raises blood sugar. The GLP-1 effect on insulin release more than compensates. Hypoglycemia rates in DREAMS-1 were low and similar to placebo when mazdutide was used as monotherapy.<\/p>\n Key Takeaway: Glucagon receptor activation raises resting energy expenditure by roughly 5 to 10% in clinical studies<\/p>\n Mazdutide has a half-life of roughly 5 to 6 days, which supports once-weekly subcutaneous dosing.<\/strong> The drug reaches steady state after about 4 to 5 weeks of consistent dosing.<\/p>\n The approved dosing schedule in China starts at 1.5 mg weekly for 4 weeks, then 3 mg for 4 weeks, then 4.5 mg for 4 weeks, with the option to titrate to 6 mg if more weight loss is needed and the patient is tolerating well. This is a standard step-up schedule that mirrors how semaglutide and tirzepatide are titrated.<\/p>\n The injection is subcutaneous in the abdomen, thigh, or upper arm. Patients can rotate sites. Skipping a dose by up to 2 days is fine; if it has been longer than 2 days, the next dose is taken on the regular schedule. Missing multiple doses requires restarting at a lower step.<\/p>\n If you’re researching mazdutide as a future treatment option, our free assessment quiz can help you understand which currently available GLP-1 medications might fit your situation while mazdutide works through FDA review.<\/p>\n Cardiovascular outcomes data for mazdutide is still preliminary.<\/strong> The GLORY-1 and DREAMS trials weren’t powered for major adverse cardiac events, but secondary endpoints showed improvements in blood pressure, lipids, and inflammatory markers that historically predict cardiovascular benefit.<\/p>\n In GLORY-1 at 48 weeks, systolic blood pressure dropped by an average of 6 to 7 mmHg in the 6 mg group, triglycerides fell about 25%, and hs-CRP (a marker of systemic inflammation) dropped meaningfully. These changes mirror what SELECT (Lincoff et al. 2023 NEJM) eventually translated into a 20% MACE reduction with semaglutide.<\/p>\n A dedicated cardiovascular outcomes trial for mazdutide is in planning but has not yet started. Kidney outcomes are also being studied, since GLP-1 agonists like semaglutide showed a 24% reduction in kidney and CV death in FLOW (Perkovic et al. 2024 NEJM). Whether mazdutide replicates that effect is an open question.<\/p>\n The glucagon component of mazdutide directly reduces liver fat, which is why a phase 2 trial for MASH is underway.<\/strong> Glucagon receptor activation in hepatocytes increases fatty acid oxidation and reduces de novo lipogenesis.<\/p>\n Early phase 2 data in adults with MASH showed liver fat content (measured by MRI proton density fat fraction) dropped 60 to 70% over 24 weeks at higher mazdutide doses. That’s a steeper drop than what semaglutide produced in the ESSENCE trial, where MASH resolution rates were around 63% at 72 weeks. Mazdutide could end up as a stronger MASH agent precisely because of the dual mechanism.<\/p>\n Resmetirom (MAESTRO-NASH, NEJM 2024) is currently the only FDA-approved drug for MASH with fibrosis. Mazdutide could become a second option, possibly with the added benefit of significant weight loss, which is itself the most effective MASH intervention based on the IDEA-style data on weight loss and fibrosis improvement.<\/p>\n The side effect profile of mazdutide is dominated by GI symptoms from GLP-1 activation, similar to semaglutide and tirzepatide.<\/strong> Nausea, vomiting, diarrhea, and constipation are the main complaints.<\/p>\n In GLORY-1, about 30% of patients reported nausea, 12% reported diarrhea, and 10% reported vomiting at the 6 mg dose. Most symptoms occurred during dose escalation and faded with continued use. Less than 5% of participants discontinued for GI side effects.<\/p>\n The glucagon component could theoretically increase heart rate slightly. GLORY-1 reported a mean increase of 3 to 5 beats per minute at the highest dose, which is in line with what semaglutide shows. There’s no signal so far of arrhythmia or cardiac events from this effect, but long-term cardiovascular safety data is still accumulating.<\/p>\n Hypoglycemia is rare with mazdutide as monotherapy. Patients taking insulin or sulfonylureas alongside it need dose adjustments to those drugs to avoid lows.<\/p>\n Bottom line: Mazdutide is approved in China for obesity (June 2025) and is in phase 3 trials globally for diabetes, MASH, and obstructive sleep apnea<\/p>\n No. Mazdutide is approved in China by the NMPA as of June 2025 but is not yet FDA-approved in the US. Eli Lilly is running global phase 3 trials. The earliest realistic US availability is 2027 or later, depending on trial outcomes and FDA review timing.<\/p>\n It’s too early to say, and no head-to-head trial has been done. Trial-to-trial comparisons suggest mazdutide produces roughly 18% mean weight loss at 48 weeks, while tirzepatide produced 20.9% at 72 weeks in SURMOUNT-1. The drugs use different second receptors (glucagon versus GIP) and may suit different patients.<\/p>\n GI side effect rates are roughly comparable based on trial reports. About 30% of GLORY-1 participants reported nausea on mazdutide 6 mg, similar to STEP 1 semaglutide where 44% reported nausea on 2.4 mg. Both drugs cause more GI symptoms during titration than at steady state.<\/p>\n Compounded mazdutide is not legally available in the US. The drug isn’t FDA approved, and US compounding pharmacies can only compound copies of approved drugs that are on the FDA shortage list. Compounded semaglutide and tirzepatide are available through telehealth platforms like TrimRx for patients who qualify.<\/p>\n Yes. GLORY-1 specifically excluded participants with diabetes and showed strong weight loss in non-diabetic adults with obesity. The 18% mean weight loss at the 6 mg dose came from a population without diabetes.<\/p>\n Mazdutide is a dual GLP-1\/glucagon agonist. Retatrutide is a triple GLP-1\/GIP\/glucagon agonist (also Eli Lilly). Retatrutide phase 2 data showed roughly 24% weight loss at 48 weeks, which is the highest reported for any GLP-1 family drug so far. Both are still in development for global approval.<\/p>\n The European Medicines Agency has not received a marketing authorization application yet. Eli Lilly’s global phase 3 trials are designed to support filings in the US, EU, and Japan. A 2027 to 2028 European launch is plausible if trials read out positively.<\/p>\n Disclaimer:<\/strong> This content is for informational purposes only and does not constitute medical advice. It is not intended to diagnose, treat, cure, or prevent any disease or condition. Individual results may vary. Always consult a qualified healthcare professional before starting any weight loss program or medication.<\/p>\n","protected":false},"excerpt":{"rendered":" Mazdutide is the first dual GLP-1 and glucagon receptor agonist approved for obesity.<\/p>\n","protected":false},"author":11,"featured_media":90184,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"inline_featured_image":false,"_yoast_wpseo_title":"Mazdutide How It Works: Mechanism of Action Explained","_yoast_wpseo_metadesc":"Mazdutide is the first dual GLP-1 and glucagon receptor agonist approved for obesity.","_yoast_wpseo_focuskw":"mazdutide mechanism","footnotes":"","_flyrank_wpseo_metadesc":""},"categories":[6],"tags":[],"class_list":["post-90185","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-glp-1"],"_links":{"self":[{"href":"https:\/\/trimrx.com\/blog\/wp-json\/wp\/v2\/posts\/90185","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/trimrx.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/trimrx.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/trimrx.com\/blog\/wp-json\/wp\/v2\/users\/11"}],"replies":[{"embeddable":true,"href":"https:\/\/trimrx.com\/blog\/wp-json\/wp\/v2\/comments?post=90185"}],"version-history":[{"count":3,"href":"https:\/\/trimrx.com\/blog\/wp-json\/wp\/v2\/posts\/90185\/revisions"}],"predecessor-version":[{"id":92453,"href":"https:\/\/trimrx.com\/blog\/wp-json\/wp\/v2\/posts\/90185\/revisions\/92453"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/trimrx.com\/blog\/wp-json\/wp\/v2\/media\/90184"}],"wp:attachment":[{"href":"https:\/\/trimrx.com\/blog\/wp-json\/wp\/v2\/media?parent=90185"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/trimrx.com\/blog\/wp-json\/wp\/v2\/categories?post=90185"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/trimrx.com\/blog\/wp-json\/wp\/v2\/tags?post=90185"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}How Does GLP-1 Receptor Activation Drive Weight Loss?<\/h2>\n
What Does Glucagon Receptor Activation Add?<\/h2>\n
How Does Mazdutide Compare to Semaglutide and Tirzepatide Mechanically?<\/h2>\n
What Did the GLORY-1 Phase 3 Trial Show?<\/h2>\n
How Does Mazdutide Affect Blood Sugar and Diabetes?<\/h2>\n
What Is the Half-life and Dosing of Mazdutide?<\/h2>\n
Does Mazdutide Affect Heart and Kidney Health?<\/h2>\n
How Does Mazdutide Work for Liver Disease (MASH)?<\/h2>\n
What Are the Most Common Side Effects From the Mechanism?<\/h2>\n
FAQ<\/h2>\n
Is Mazdutide Available in the United States?<\/h3>\n
Is Mazdutide Better Than Tirzepatide?<\/h3>\n
Does Mazdutide Cause More Nausea Than Semaglutide?<\/h3>\n
Can Mazdutide Be Compounded?<\/h3>\n
Does Mazdutide Work for People Without Diabetes?<\/h3>\n
What’s the Difference Between Mazdutide and Retatrutide?<\/h3>\n
When Will Mazdutide Be Available in Europe?<\/h3>\n