Despite advances in type 2 diabetes (T2D) management, unmet needs remain for therapies that effectively control hyperglycaemia while addressing comorbid metabolic disorders1,2. Here we assessed the efficacy and safety of the dual glucagon receptor (GCGR)/glucagon-like peptide-1 receptor (GLP-1R) agonist mazdutide monotherapy versus placebo in Chinese adults with T2D controlled inadequately with diet and exercise alone. In this phase 3 trial, 320 participants (mean glycated haemoglobin A1c (HbA1c) of 8.24%, body mass index of 28.2 kg m−2 and diabetes duration of 1.9 years) were randomized 1:1:1 to receive weekly subcutaneous injections of mazdutide (4 mg or 6 mg) or placebo for 24 weeks, followed by a 24-week extended mazdutide treatment. At week 24, mazdutide significantly reduced HbA1c versus placebo (primary endpoint): −1.57% with mazdutide 4 mg and −2.15% with mazdutide 6 mg, versus −0.14% with placebo, with treatment differences of −1.43% and −2.02% (both P < 0.0001). Weight loss from baseline at week 24 occurred with −5.61% (4 mg) and −7.81% (6 mg) versus −1.26% (placebo) (both P < 0.0001). Furthermore, more participants with mazdutide achieved HbA1c < 7.0%, weight loss ≥ 5% (all P < 0.0001) and composite endpoints (HbA1c < 7.0% and weight loss ≥ 5%) versus placebo (P = 0.0006 for 4 mg; P < 0.0001 for 6 mg) at week 24. The most common adverse events—diarrhoea, decreased appetite and nausea—were consistent with GLP-1R agonists. These results establish mazdutide monotherapy as an effective intervention providing clinically meaningful glycaemic control and weight reduction alongside a favourable safety profile in this population.
