Mazdutide reduced weight in U.S. phase 2 trial, with tolerability trade-offs

What happened

A phase 2 trial conducted at 24 U.S. centers found that once-weekly mazdutide produced greater weight reduction than placebo in adults with obesity or overweight who did not have type 2 diabetes. The peer-reviewed results were published August 21 in The Lancet Diabetes & Endocrinology.

Mazdutide is a synthetic peptide modeled on oxyntomodulin, a gut hormone that can activate both the glucagon-like peptide-1, or GLP-1, receptor and the glucagon receptor. The dual mechanism distinguishes it from medicines that target GLP-1 alone, but whether glucagon-receptor activity delivers better clinical outcomes remains unsettled.

The trial offers the first substantial randomized assessment of mazdutide across doses as high as 16 mg in a U.S. population. It also exposes an important development trade-off: larger weight changes at higher doses accompanied more treatment discontinuations related to adverse events.

How the trial worked

Investigators enrolled 179 adults between November 17, 2023, and July 9, 2025. Eligible participants were 18 to 75 years old and had either a body-mass index of at least 30 or a BMI from 27 to below 30 plus a weight-related condition. People with type 2 diabetes were excluded.

Participants were randomly assigned under double-blind conditions to placebo or one of three mazdutide regimens: a lower-dose arm that used 3 mg through week 32 before increasing to 6 mg, a 10-mg arm or a 16-mg arm. Treatment continued for 48 weeks. The primary endpoint was percentage change in body weight at week 32, analyzed using an efficacy estimand intended to estimate effects under specified assumptions about treatment interruption and missing data.

At week 32, estimated mean weight changes were reductions of 7.3% in the lower-dose group, 15.6% with 10 mg and 18.1% with 16 mg, compared with 0.9% on placebo. The estimated differences from placebo ranged from 6.5 to 17.2 percentage points, with all primary comparisons meeting the study’s statistical-significance threshold. The researchers reported further weight reductions through week 48.

Safety complicates the dose response

The most common adverse events associated with mazdutide involved the gastrointestinal system and were generally classified as mild or moderate. That description does not mean they were inconsequential: adverse events led 20% of participants assigned to 16 mg to stop treatment, the highest discontinuation proportion among the study groups. Gastrointestinal disorders accounted for most discontinuations at that dose.

The finding makes retention and tolerability central to interpreting the highest-dose result. An efficacy estimand can answer a legitimate question about biological effect under its prespecified assumptions, but it does not by itself show what average outcomes would look like when every randomized participant’s treatment experience—including discontinuation—is treated as part of effectiveness.

What remains unknown

Each study arm contained only 32 to 51 participants. That is adequate for detecting a dose-related weight signal but too small to characterize uncommon harms, cardiovascular outcomes or safety during years of use. The trial had no active comparator, so it cannot establish whether mazdutide is more effective or better tolerated than an approved obesity medicine.

The lower-dose group also changed from 3 mg to 6 mg after the primary endpoint, complicating interpretation of its 48-week trajectory. Participants did not have diabetes, and the U.S.-only sample does not resolve how results might differ across broader populations or clinical settings. Eli Lilly funded the study, and several authors were company employees or shareholders.

The practical conclusion is therefore limited. Mazdutide demonstrated substantial, dose-dependent weight reduction in a controlled phase 2 setting, supporting further clinical development. The trial does not establish long-term health benefits, cardiovascular risk reduction, superiority over existing therapies or a favorable benefit-risk profile for routine U.S. use.