Mazdutide, a dual GLP-1/glucagon agonist, significantly reduces body weight and HbA1c in Chinese adults with obesity/T2D

Despite advances in Type 2 Diabetes (T2D) management, a significant unmet need persists for therapies that effectively control hyperglycemia while also addressing comorbid obesity and broader metabolic dysfunction. Current standard-of-care often falls short in achieving comprehensive metabolic improvements. Glucagon-like peptide-1 receptor (GLP-1R) agonists are effective, but dual agonism targeting both GLP-1R and glucagon receptor (GCGR) offers a promising strategy to leverage complementary metabolic pathways, potentially leading to superior weight loss and glycemic control by enhancing energy expenditure and insulin sensitivity.

This systematic review and meta-analysis synthesized data from 9 randomized controlled trials (RCTs), encompassing N=2292 predominantly Chinese adults with overweight/obesity and/or T2D. The studies compared once-weekly subcutaneous injections of mazdutide 3 mg, 4 mg, or 6 mg against placebo or an active comparator, dulaglutide. Co-primary outcomes were percent change in body weight and change in HbA1c. Secondary outcomes included waist circumference, lipid profiles, liver enzymes, and uric acid levels, alongside safety assessments. Random-effects models were used for pooled mean differences, and GRADE assessed the certainty of evidence.

Mazdutide demonstrated dose-dependent efficacy across both populations. In overweight/obesity without diabetes, mazdutide significantly reduced body weight compared to placebo: -6.56% for 3 mg, -9.92% for 4 mg, and -11.1% for 6 mg (very low COE due to heterogeneity). In patients with T2D, mazdutide 4 mg and 6 mg not only reduced body weight and HbA1c versus placebo (moderate COE) but also outperformed dulaglutide for both outcomes. Specifically, mazdutide 6 mg showed superior reductions in HbA1c and body weight compared to dulaglutide. Beyond glycemic and weight control, mazdutide also improved several secondary metabolic markers, including waist circumference, lipid profiles, liver enzymes, and uric acid levels. Gastrointestinal adverse events were more frequently reported with mazdutide, but serious adverse events and treatment discontinuation rates were comparable to those of the comparators. This suggests a favorable safety profile despite the increased GI side effects.

Mazdutide 6 mg achieved the largest body weight reduction of -11.1% in overweight/obesity without diabetes, highlighting its potent impact on adiposity.