Innovent's Mazdutide Demonstrates Superior Glycemic Control and Weight Loss Compared to Semaglutide in Phase 3 DREAMS-3 Trial
Breakthrough Clinical Results
Innovent Biologics announces positive results from its Phase 3 DREAMS-3 clinical trial of mazdutide, a glucagon-like peptide-1 (GLP-1) and glucagon (GCG) dual receptor agonist. The trial demonstrated that mazdutide showed superior efficacy to semaglutide in Chinese patients with type 2 diabetes (T2D) and obesity, achieving a higher proportion of participants with HbA1c < 7.0% and a ≥10% body weight reduction at week 32. Mazdutide also showed greater mean reductions in HbA1c and body weight compared to semaglutide. The safety profile of mazdutide was consistent with previous studies. Mazdutide is already approved in China for weight management and glycemic control in adults with T2D.
Key Highlights
- Mazdutide shows superior efficacy to semaglutide in glycemic control and weight loss in T2D and obese Chinese patients.
- DREAMS-3 trial met its primary endpoint, with a significantly higher proportion of participants achieving HbA1c < 7.0% and ≥10% weight reduction with mazdutide.
- Mazdutide is the world's first approved GCG/GLP-1 dual receptor agonist for both weight management and T2D treatment.
- The safety profile of mazdutide was consistent with previous clinical studies.
Emerging End Points
Key Endpoints Emerging for Diabetes
Biomarkers and Prediction Models
- Islet autoantibodies against insulin/proinsulin, GAD65, IA-2, and ZnT8 serve as enrichment biomarkers for type 1 diabetes prevention studies
- Accelerated failure time models incorporating islet autoantibody permutations predict time-varying probability of T1D diagnosis
- Prediction accuracy improves with variables including baseline age, sex, blood glucose measurements, and hemoglobin A1c
- Metabolomics is emerging for precision diabetes medicine to discover biomarkers for diagnosis, prognosis, and management
- Machine learning models integrating genomic and proteomic data achieve 95% prediction accuracy for GLP-1 therapy response
Cardiovascular Outcomes
- Bempedoic acid shows significant cardiovascular risk reduction in diabetes patients (HR 0.83; 95% CI 0.72-0.95)
- SGLT-2 inhibitors reduce total stroke compared to placebo (RR, 0.81; 95% CI, 0.67 to 0.98)
- GLP-1 agonists demonstrate lower stroke risk compared to placebo
- Semaglutide shows lower stroke risk in real-world data compared to DPP4 inhibitors
- Major adverse cardiovascular events (MACE) serve as common primary endpoints in diabetes trials
Microvascular Function
- Cardiovascular magnetic resonance identifies ischemic heart disease and quantifies coronary microvascular dysfunction
- Diabetes patients with heart failure show higher prevalence of silent IHD (31%)
- Stress myocardial blood flow is lowest in diabetes patients (1.53 ± 0.52)
Metabolic Endpoints
- C-peptide area under the curve at 12-24 months is the primary endpoint for β-cell function preservation trials
- 2-hydroxybutyric acid emerges as a promising biomarker for identifying T2D and insulin resistance
- Inflammatory and redox status biomarkers including AOPPs, AGEs, CRP, and interleukins show significant differences between T2D patients and controls
- Blood DNA methylation associates with diabetes risk through several differentially methylated positions
- Red blood cells serve as both biomarkers and mediators in diabetes
- Vaspin shows correlation with insulin levels and obesity in diabetes
Treatment Response
- Approximately 40% of patients do not respond well to GLP-1 agonist therapy
- 5 genomic variants and 45 proteomic markers help differentiate GLP-1 therapy responders from non-responders
- Sitagliptin-based therapies are commonly prescribed in combination with other medications
- Treatment regimens vary based on comorbidities
Recent Studies
Recent Diabetes Studies: Interventions and Outcomes
FAST Study (2021)
Intervention: Fasting Algorithm for Singaporeans with Type 2 Diabetes (FAST) during Ramadan
Efficacy Outcomes: - HbA improvement was 4 times greater in intervention group (-0.4%) than control group (-0.1%) - Mean fasting blood glucose decreased in intervention group (-3.6 mg/dL) but increased in control group (+20.9 mg/dL) - Mean postprandial glucose showed greater improvement in intervention group (-16.4 mg/dL) vs control group (-2.3 mg/dL)
Safety Outcomes: - Fewer minor hypoglycemic events in intervention group (4) vs control group (6) - No significant difference in glycemic variability between groups - No between-group differences in diabetes distress
mySugr PRO Study (2022/2024)
Intervention: Digital self-management application (mySugr PRO)
Efficacy Outcomes: - Significantly reduced diabetes distress compared to control group (adjusted between-group difference: -2.20)
Canagliflozin Diabetes Subgroups Study (2022)
Intervention: Canagliflozin (SGLT2 inhibitor)
Efficacy Outcomes: - Different HbA decline among four diabetes clusters - In MOD subgroup, canagliflozin showed robust glucose-lowering effect compared to sitagliptin and glimepiride - ML-ACR model showed canagliflozin reduced risk of albumin progression in high-risk individuals
BRAVO Diabetes Simulation (2025)
Interventions: Tirzepatide (5, 10, 15 mg) vs Semaglutide (1 mg) vs Insulin glargine
Efficacy Outcomes: - Tirzepatide 15 mg showed projected 5-year risk reduction in cardiovascular adverse events (RR 0.64) vs insulin glargine - Tirzepatide 15 mg showed projected microvascular composite risk reduction (RR 0.67) vs insulin glargine - Semaglutide 1 mg showed projected risk reductions in cardiovascular events (RR 0.75) and microvascular composite (RR 0.79)
ASCEND Eye Substudy (2024)
Intervention: Aspirin 100 mg daily
Efficacy Outcome: No significant difference in referable disease events between aspirin (14.6%) and placebo (14.2%) groups
Safety Outcome: No significant difference in sight-threatening eye bleed events between groups
SGLT2 Inhibitor Comparison Study (2022)
Interventions: Empagliflozin vs Dapagliflozin
Safety Outcomes: - Both demonstrated excellent safety profiles with no major adverse effects - Urinary infection occurred more often with dapagliflozin (9.3%) than empagliflozin (4.5%) - Higher incidence of genital infections with dapagliflozin (7.3%) than empagliflozin (3.8%)
Semaglutide Study in Colombia (2024)
Intervention: Once-weekly subcutaneous semaglutide
Efficacy Outcomes: - Mean reduction in HbA1C of -1.47% - Weight loss of -4.23 kg - Albumin/creatinine ratio reduction of -18.6 mg/g - Approximately half of patients achieved HbA1c ≤7%
Pioglitazone Add-on Study (2024)
Intervention: Pioglitazone added to metformin plus dapagliflozin
Efficacy Outcomes: - Significant HbA1c reduction (from 7.80% to 7.27%) compared with placebo - Enhanced insulin sensitivity - Increased adiponectin levels - Raised high-density lipoprotein cholesterol levels - Reduced liver enzyme levels
Multi-Receptor Agonist Drugs for Type 2 Diabetes and Obesity
Several multi-receptor agonist drugs are being developed for the treatment of type 2 diabetes and obesity, sharing similar mechanisms of action. While Mazdutide is not specifically mentioned in the available information, other notable drugs in this class include:
Tirzepatide
Tirzepatide is a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist that has been approved for treating adults with type 2 diabetes or obesity. The drug is administered at 5-15 mg per week via a single-use pre-filled pen.
Intervention models for tirzepatide clinical trials include: - Randomized phase 3 clinical trials (SURPASS program) - Multicentre, randomized, double-blind, parallel-arm studies - Randomized, open-label trials (as seen in SURPASS-SWITCH)
In the SURPASS clinical trials, patients were randomly assigned to receive either tirzepatide, a comparator drug (such as semaglutide 1 mg), or placebo, with endpoint measurements taken at baseline and the end of the treatment period.
Retatrutide
Retatrutide is a novel triple receptor agonist peptide that targets the glucagon receptor (GCGR), glucose-dependent insulinotropic polypeptide receptor (GIPR), and glucagon-like peptide-1 receptor (GLP-1R). This drug is administered once-weekly with dosing in clinical trials ranging from 1 mg to 12 mg.
The clinical development of retatrutide includes: - A multiple-ascending dose phase 1b clinical trial in subjects with type 2 diabetes - Phase II clinical trials for obesity, which demonstrated significant weight reduction (average weight loss of 17.5% at 24 weeks and 24.4% at 48 weeks) - Phase III trials for treating type 2 diabetes mellitus, non-alcoholic fatty liver disease, and obesity, which began on August 28, 2023
Cotadutide
Cotadutide is a peptide co-agonist that acts on GLP-1 and glucagon receptors. In the PROXYMO trial, cotadutide was administered at doses of 300 μg and 600 μg.
These multi-agonist drugs show promise for treating metabolic abnormalities associated with obesity as well as diseases resulting from it due to their distinct mechanisms of action. The clinical evidence for newer agents like retatrutide is still developing, with more phase III studies needed to provide sufficient evidence for effectiveness.
The intervention models for these trials generally follow rigorous scientific protocols, including randomized, double-blind, and placebo-controlled designs to ensure reliable and valid results in assessing their efficacy and safety profiles for treating type 2 diabetes and obesity.
