Mazdutide cut weight by 18% at its top dose in a first US obesity trial

Mazdutide, a drug that activates both the glucagon and the GLP-1 receptor, reduced bodyweight by 18.1% at its highest dose over 32 weeks in its first randomised trial run in the United States, against 0.9% on placebo [s1]. The result puts a glucagon-based dual agonist in the same weight-loss range as the leading approved drugs, but it comes from a phase 2 trial of 179 people, and gastrointestinal side-effects drove one in five participants off the top dose [s1].

Mazdutide is already approved in China, where it was cleared in 2025 on the strength of trials in Chinese adults [s2]. This trial is the first to test it in a US population and the first to push the dose as high as 16 mg [s1].

The trial

The study was a randomised, double-blind, placebo-controlled phase 2 trial at 24 US centres [s1]. It enrolled adults aged 18 to 75 without type 2 diabetes who had a body-mass index of 30 kg/m² or higher, or 27 to under 30 kg/m² with at least one weight-related condition [s1]. Between 17 November 2023 and 9 July 2025, 179 participants were randomly assigned in a 3:2:3:3 ratio to placebo or mazdutide at 3–6 mg, 10 mg or 16 mg, taken once weekly for 48 weeks [s1]. The 3–6 mg group held at 3 mg from week 4 to week 32 before moving up to 6 mg, so the trial could look at both as possible maintenance doses [s1]. Of the 179, 32 were assigned to 3–6 mg, 48 to 10 mg, 51 to 16 mg and 48 to placebo; mean age was 47.7 years and 118 (66%) were female [s1]. The primary endpoint was the percentage change in bodyweight from baseline to 32 weeks [s1].

What it showed

At 32 weeks, the least-squares mean change in bodyweight was −7.3% on 3–6 mg, −15.6% on 10 mg and −18.1% on 16 mg, compared with −0.9% on placebo [s1]. The treatment differences versus placebo ranged from −6.5% to −17.2%, all statistically significant [s1]. Weight was still falling at the end of the primary period: the trial reported additional reductions by 48 weeks [s1].

The cost side was, as with the whole drug class, gastrointestinal. The most common adverse events were gastrointestinal and mostly mild to moderate, but discontinuation of treatment because of adverse events was most frequent on the 16 mg dose, at 20%, driven mainly by gastrointestinal problems [s1]. That is the practical tension a dose-ranging trial exists to expose: the dose that lost the most weight was also the one people were most likely to abandon.

How the doses compare with China

The Chinese phase 3 trial that supported approval there, GLORY-1, used lower doses and produced smaller weight loss. Among 610 participants, bodyweight fell 10.09% on 4 mg and 12.55% on 6 mg at 32 weeks, against a 0.45% gain on placebo, and 73.9% and 82.0% of the two dose groups lost at least 5% of bodyweight, versus 10.5% on placebo [s2]. The US trial's larger effect tracks its higher doses, which is what a dose-response result should look like, but it also means the 18.1% figure belongs to a dose whose tolerability is the open question [s1].

What it does and does not establish

This is a mid-stage trial, and its limits are the usual ones for the stage. It is small, at 179 participants; its primary readout is at 32 weeks; and it was funded by the manufacturer, Eli Lilly [s1]. It had no active comparator, so it cannot say whether mazdutide beats, matches or trails tirzepatide or semaglutide — the comparison a prescriber would actually want [s1]. Cross-drug rankings for obesity treatments come instead from network meta-analyses that pool separate trials, an indirect method with its own uncertainties [s3].

What is genuinely different about mazdutide is the glucagon component. Most approved weight-loss drugs act on GLP-1 alone or with the related hormone GIP; adding glucagon-receptor activity is the feature its developers are betting on to differentiate it [s1]. Whether that translates into any advantage over existing drugs — in weight, in metabolic measures, or in effects on the liver — is not something a placebo-controlled phase 2 trial can answer.

What to watch

The questions that matter now are whether the weight loss holds and deepens past a year, whether the 16 mg dose can be made tolerable enough to keep people on it, and how mazdutide performs when tested directly against the drugs already on the market. Those answers require larger and longer trials than this one.

This article describes results from randomised trials and is informational only. It is not medical advice and does not recommend any drug or dose. Mazdutide is not approved in the United States.

Sources

• [s1] Hsia SH, Bays HE, Billings LK, Weideman AMK, Mather KJ, Coskun T, Haupt A, Thomas MK, Tham LS, Calderon B, Ni W, De Araujo OFG, Efficacy and safety of mazdutide in adults with obesity or overweight: a US-based, multicentre, phase 2, randomised, placebo-controlled clinical trial, The Lancet Diabetes & Endocrinology, published online 2026-08-21.
• [s2] Ji L, Jiang H, Bi Y, et al., Once-Weekly Mazdutide in Chinese Adults with Obesity or Overweight (GLORY-1), The New England Journal of Medicine, 2025;392:2215-2225, published online 2025-05-25.
• [s3] Comparative effects of drugs for adults with overweight or obesity: systematic review and network meta-analysis, The BMJ, 2026;394:e372161, published online 2026-07-08.