Mazdutide: a glucagon-GLP-1 dual agonist reaches 18% weight loss in phase 2

Design

phase 2, randomised, double-blind, placebo-controlled, 24 US centres

Population

179 adults aged 18–75 with BMI ≥30, or ≥27 with a weight-related comorbidity, without type 2 diabetes

Primary outcome

percentage change in bodyweight from baseline to 32 weeks

Effect

−18.1% (SE 1.0) with 16 mg, −15.6% (0.7) with 10 mg, −7.3% (0.9) with 3–6 mg, versus −0.9% (0.8) with placebo

Mazdutide adds glucagon receptor agonism to GLP-1, a different pairing from the GLP-1/GIP combination that tirzepatide uses. This US phase 2 trial randomised 179 adults with obesity, or overweight with a weight-related comorbidity, and without type 2 diabetes, to placebo or one of three mazdutide arms for 48 weeks. The primary endpoint was percentage weight change at 32 weeks.

At 32 weeks the least-squares mean change was −7.3% on 3–6 mg, −15.6% on 10 mg and −18.1% on 16 mg, against −0.9% on placebo. Weight continued to fall to 48 weeks. That places the top dose alongside the most effective agents in the class, in a population without diabetes, where weight responses are typically larger than they will be in your clinic.

The tolerability signal deserves equal attention. Adverse events were mainly gastrointestinal and mostly mild to moderate, but 20% of the 16 mg group discontinued treatment because of them. A dose that a fifth of a trial population cannot stay on is not a dose most patients will reach outside a trial. The 10 mg arm gave −15.6% with less attrition, and that is the more informative number for practice.

• This is phase 2 in 179 people — dose-finding, not a licensing dataset.
• Participants did not have type 2 diabetes; expect smaller weight responses in those who do.
• Record baseline gastrointestinal tolerance before escalating anyone on any incretin — the discontinuations here clustered at the top dose.
• Mazdutide is not approved by CDSCO and is not available in India; it is developed in partnership for the Chinese market, where regulatory filings are further ahead.
• There is no cardiovascular outcome data for this agent.

Why it matters

The weight-loss ceiling in this class keeps moving, and a glucagon component raises a different set of questions — energy expenditure, hepatic fat, and whether the gastrointestinal burden is worse.

Don't overread it

Phase 2 dose-finding in 179 people establishes a dose range, not a place in therapy.

The statistics, in plain English

The treatment differences versus placebo ran from −6.5% to −17.2%, all with p<0.0001. Those p values are not the interesting part — with placebo losing under 1%, almost any real drug effect would clear significance here. What matters is the size of the separation and whether it holds in a larger, longer trial with a harder endpoint. A 20% discontinuation rate at 16 mg also means the 18.1% figure comes from an efficacy estimand, which estimates what would have happened had people stayed on treatment, rather than what happened to everyone randomised.

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