Mazdutide

Mazdutide is a first-in-class once-weekly dual agonist of both glucagon-like peptide-1 (GLP-1) and glucagon receptors, designed as a long-acting synthetic oxyntomodulin analog. It has been approved in China for chronic weight management in adults with obesity or overweight and is being investigated for type 2 diabetes treatment. Through its dual mechanism, mazdutide promotes insulin secretion and appetite suppression via GLP-1 receptor activation while increasing energy expenditure, enhancing fatty acid oxidation, and reducing liver fat through glucagon receptor activation. Phase 3 clinical trials have demonstrated superior efficacy compared to existing GLP-1 agonists, achieving up to 14% body weight reduction at 48 weeks, exceptional liver fat reduction (up to 80.2%), and multiple cardiometabolic benefits including improvements in blood glucose, lipids, blood pressure, and liver enzymes.

Weight Loss and Body Composition

• Achieved mean body weight reductions of -11.00% (4 mg dose) and -14.01% (6 mg dose) at 48 weeks in the Phase 3 GLORY-1 trial, compared to 0.30% with placebo ^[1]
• At 48 weeks, 35.7% of participants on 4 mg and 49.5% on 6 mg achieved ≥15% weight reduction, versus only 2.0% with placebo ^[1]
• Higher doses (9 mg) produced 18.6% placebo-adjusted mean weight reduction after 48 weeks ^[2]
• Ultra-high doses (16 mg) in Phase 1 trials achieved remarkable -20.0% to -21.0% weight reduction at 20 weeks ^[3]
• Significant reductions in waist circumference observed across multiple trials ^[4][5]

Liver Health and MASLD/MASH

• Demonstrated exceptional liver fat reduction with mean relative reductions of -63.3% (4 mg) and -73.2% (6 mg) compared to 8.2% increase with placebo in participants with baseline liver fat content ≥5% ^[6]
• Among participants with baseline liver fat ≥10%, mazdutide 6 mg achieved an 80.2% mean relative reduction in liver fat content ^[6]
• 95.5% of participants on 6 mg achieved ≥30% liver fat reduction, and 77.3% reached normalization of liver fat content (<5%) by week 48 ^[6]
• Significant improvements in liver enzymes (ALT, AST) observed across multiple studies ^[4][5]
• Phase 3 GLORY-3 trial ongoing to compare mazdutide vs semaglutide specifically for metabolic dysfunction-associated fatty liver disease (MAFLD) ^[7]

Glycemic Control (Type 2 Diabetes)

• HbA1c reductions ranging from -1.41% to -1.67% with mazdutide (3-6 mg doses) compared to minimal change with placebo in Phase 2 diabetes trial ^[8]
• Superior to dulaglutide 1.5 mg, achieving HbA1c reductions of -1.46% to -2.23% versus -1.98% with dulaglutide in Phase 1b trial ^[9]
• Phase 3 DREAMS-2 trial demonstrated superiority over high-dose dulaglutide for glycemic control in type 2 diabetes patients ^[10]
• Improved insulin sensitivity and beta-cell function through GLP-1 receptor-mediated enhancement of insulin secretion ^[11]

Cardiovascular and Metabolic Benefits

• Significant reductions in systolic blood pressure (mean difference -7.57 mmHg) and diastolic blood pressure (-2.98 mmHg) compared to placebo in meta-analysis ^[12]
• Improvements in blood lipid profiles including total cholesterol, LDL-C, and triglycerides ^[4][5][10]
• Reduction in serum uric acid levels, beneficial for patients with hyperuricemia ^[5]
• Multiple cardiometabolic benefits including improved cardiovascular risk markers ^[10]

Energy Metabolism

• Increased energy expenditure through glucagon receptor activation, promoting greater caloric burn ^[11]
• Enhanced fatty acid oxidation and lipolysis, facilitating fat mobilization and utilization ^[11]
• Dual receptor activation provides synergistic metabolic effects beyond GLP-1 monotherapy ^[9]

Cognitive Function (Preclinical)

• Preclinical studies show mazdutide significantly improved cognitive performance in diabetic mice compared to dulaglutide
• Improvements in neuronal structure, brain tissue integrity, and hippocampal synaptic plasticity in animal models
• Multi-omics analyses identified neuroprotective pathways, enhanced energy metabolism in brain tissue, and improved synaptic plasticity

Overall Safety Profile

Mazdutide has demonstrated a favorable safety profile across multiple clinical trials with no serious adverse events reported in Phase 1b studies . All treatment-emergent adverse events (TEAEs) were mild to moderate in severity, and no participants discontinued due to adverse events in early-phase trials . The medication was generally well-tolerated with a safety profile consistent with the GLP-1 receptor agonist class ^[1][2][8][9].

Common Adverse Effects

Gastrointestinal symptoms represent the most frequently reported adverse effects, including nausea, diarrhea, vomiting, abdominal distension, and decreased appetite ^[1][2]. These events were predominantly mild to moderate in severity and occurred primarily during dose escalation periods . The incidence of gastrointestinal adverse events increased with higher doses, with nausea reported in up to 62.5% of participants in high-dose cohorts versus 37.5% in low-dose cohorts . Importantly, the frequency of these events declined over time during up-titration . Other common adverse events included upper respiratory tract infection and urinary tract infection .

Hypoglycemia Risk

The risk of hypoglycemia was low across clinical trials . Only mild, asymptomatic hypoglycemic events were reported, with no severe hypoglycemia observed . In one Phase 1b study, one participant receiving mazdutide 9 mg and one receiving placebo reported mild hypoglycemia . This low incidence is consistent with the glucose-dependent mechanism of GLP-1 receptor agonists.

Cardiovascular Safety

Three participants receiving mazdutide reported mild and asymptomatic cardiac disorders detected by electrocardiogram in Phase 1b trials . However, the incidence of serious adverse events was low and comparable to placebo across studies ^[2][8]. The medication demonstrated cardiovascular benefits including reductions in blood pressure, which may contribute to long-term cardiovascular risk reduction ^{[4][5][10][12]}.

Liver Safety

Mazdutide showed excellent liver safety with significant improvements in liver enzymes (ALT, AST) rather than hepatotoxicity ^[4][5][10]. The substantial reductions in liver fat content (up to 80.2%) suggest hepatoprotective effects, particularly relevant for patients with metabolic dysfunction-associated steatotic liver disease ^[6]. No liver-related safety concerns emerged across clinical trials.

Special Populations

Adolescents: A 2025 case report demonstrated good tolerability of dose-escalated mazdutide in an adolescent with obesity, type 2 diabetes, and hyperuricemia, with robust metabolic efficacy and no serious adverse events . However, data in adolescent populations remain limited, and a Phase 3 trial in adolescents is planned.

Pregnancy and Lactation: Safety data in pregnant or lactating women are not available. As with other GLP-1 receptor agonists, mazdutide should be used during pregnancy only if clearly needed.

Contraindications and Precautions

Patients should be monitored during dose escalation to minimize gastrointestinal adverse events . Gradual dose titration is recommended to improve tolerability. Patients with a history of pancreatitis should use caution, as this is a class effect of GLP-1 receptor agonists, although no cases were reported in mazdutide trials. Healthcare providers should assess for medullary thyroid carcinoma risk factors, as this is a theoretical concern with GLP-1 receptor agonists based on rodent studies.

Long-term Safety

Phase 3 trials extending to 48 weeks have not revealed new safety signals with longer-term use ^[1][10]. The safety profile remained consistent throughout treatment duration, with gastrointestinal events typically diminishing after the initial titration period ^[1]. Ongoing post-marketing surveillance and long-term studies will continue to evaluate safety in broader patient populations.