Efficacy and Safety of Mazdutide in Patients With Type 2 Diabetes Mellitus and Moderate to Severe Nonalcoholic Fatty Liver Disease Previously Treated With Semaglutide: A Multicenter, Prospective, Randomized Controlled Trial (IIT)
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 发起方
- 入组人数
- 72
- 主要终点
- Absolute change in liver fat content measured by MRI-PDFF
研究概览
简要总结
This is a multicenter, prospective, randomized controlled investigator-initiated trial (IIT) aimed at evaluating the efficacy and safety of switching to mazdutide therapy in patients with type 2 diabetes mellitus (T2DM) and moderate-to-severe non-alcoholic fatty liver disease (NAFLD) who have achieved glycemic control.
Chinese patients with type 2 diabetes mellitus (T2DM) are susceptible to visceral fat accumulation, which increases the risk of cardiometabolic diseases and mortality. Metabolic associated fatty liver disease (MAFLD) is highly prevalent among Chinese T2DM patients, and the coexistence of T2DM and moderate-to-severe fatty liver significantly elevates liver-related and all-cause mortality. The vicious cycle of hepatic lipid deposition and insulin resistance aggravates T2DM progression, while weight loss has been proven to alleviate hepatopancreatic fat accumulation and improve the management of T2DM.
GLP-1 receptor agonists (GLP-1RAs) including semaglutide are standard therapies for T2DM with glycemic improvement and weight-loss benefits. However, nearly a quarter of patients show poor response to semaglutide. Long-term semaglutide treatment may cause GLP-1 receptor desensitization, and the agent lacks direct regulatory effects on adipose tissue and hepatic lipid metabolism. Clinically, many patients still have persistent moderate-to-severe fatty liver despite standardized semaglutide therapy, highlighting an unmet clinical need for optimized treatment.
Mazdutide is a novel dual GLP-1R/GCGR agonist. GCGR is highly expressed in the liver and adipose tissues. Via GCGR activation, mazdutide directly inhibits hepatic lipogenesis, promotes hepatic fat decomposition and fatty acid oxidation, and improves adipose tissue browning and thermogenesis. Compared with single GLP-1RAs, mazdutide exerts more direct and comprehensive regulatory effects on hepatic and systemic lipid metabolism, making it a promising option for T2DM patients with residual moderate-to-severe fatty liver after semaglutide treatment.
This study is a multicenter, prospective, stratified randomized controlled design and enrolls T2DM patients with persistent moderate-to-severe NAFLD after receiving subcutaneous semaglutide 1.0 mg once weekly for ≥28 weeks. with 1:1 group allocation and concealed grouping. Eligible subjects are randomized into two groups without drug washout: the intervention group switches to mazdutide therapy, while the control group continues semaglutide treatment. All baseline concomitant medications for metabolic diseases remain stable throughout the study to avoid confounding factors.
Mazdutide is titrated per official instructions, initiating at 2 mg once weekly and escalating to a 4 mg once weekly maintenance dose based on patient tolerability and efficacy. All participants maintain their habitual diet and exercise routines with regular lifestyle supervision to ensure study stability. After the initial intervention phase, patients with <30% reduction in hepatic fat content will receive a mazdutide dose increase to 6 mg once weekly. Meanwhile, the control group will cross over to mazdutide treatment, and all patients will enter the subsequent observational stage.
The primary endpoint is the change in hepatic fat content from baseline to study endpoint, measured by MRI-PDFF and liver elastography, to evaluate the efficacy of mazdutide on hepatic steatosis. Secondary endpoints include inter-group differences in glycemic control, body composition, islet function, liver enzymes and lipid profiles. The efficacy changes during the crossover period are also observed. All adverse events are recorded to assess the safety and tolerability of mazdutide in this patient population.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Aged between 18 and 60 years (inclusive) at the time of informed consent signing.
- •Diagnosed with type 2 diabetes mellitus.
- •Received once-weekly semaglutide 1.0 mg treatment for at least 16 consecutive weeks verified by medication records.
- •Diagnosed with moderate-to-severe fatty liver, defined as hepatic attenuation ≥269 dB/m by transient elastography and hepatic fat fraction >10% measured by MRI-PDFF.
- •HbA1c level <7%.
- •Body mass index (BMI) ≥24 kg/m².
- •Glycemic and weight management regimens without adjustments within 3 months prior to screening.
- •Voluntarily signed written informed consent and agreed to comply with the study protocol.
排除标准
- •History of alcoholic fatty liver, drug-induced fatty liver, viral hepatitis, autoimmune diseases, or acute gallbladder diseases.
- •Use of medications affecting fatty liver metabolism within 3 months prior to screening, including but not limited to SGLT-2 inhibitors, vitamin E, GLP-1R/GIPR agonists, liver-selective thyroid receptor β agonists, PPAR agonists, and aspirin.
- •Use of weight-loss drugs or alternative weight-loss therapies within 3 months prior to screening.
- •Addition to sulfonylureas, glinides, dorzagliatin, or various insulin preparations within 3 months prior to screening.
- •History of bariatric surgery or planned bariatric surgery during the study (excluding acupuncture, liposuction and abdominal liposuction performed more than 1 year before screening).
- •Diagnosed with type 1 diabetes or latent autoimmune diabetes in adults.
- •Personal history of acute or chronic pancreatitis, personal or family history of medullary thyroid carcinoma (MTC), or family history of multiple endocrine neoplasia type 2 (MEN2).
- •Presence of severe cardiovascular, cerebrovascular, hepatic or renal insufficiency, uncontrolled diabetes, malignancy, cirrhosis or advanced liver fibrosis.
- •Pregnant or lactating females, those planning pregnancy within half a year, or with recent major surgery or severe infection.
- •Mental disorders or cognitive disorders that may interfere with study compliance, or any other conditions judged inappropriate for study participation by the investigator.
- •Contraindications to MRI examination, including implantation of pacemakers, metallic heart valves, magnetic surgical clips, implantable electronic infusion pumps, severe claustrophobia, or inability to tolerate MRI scanning.
结局指标
主要结局
Absolute change in liver fat content measured by MRI-PDFF
时间窗: Baseline, Week 16, Week 32
Absolute change in liver fat content measured by liver transient elastography
时间窗: Baseline, Week 16, Week 32
次要结局
- Number of allergic reaction events(Baseline through Week 32)
- Absolute change in body weight(Baseline, Week 16, Week 32)
- Absolute change in total cholesterol (TC)(Baseline, Week 16, Week 32)
- Number of Grade 2 clinically significant hypoglycemic episodes(Baseline through Week 32)
- Absolute change in fibrosis-4 index (FIB-4)(Baseline, Week 16, Week 32)
- Number of adverse events(Baseline through Week 32)
- Absolute change in body mass index (BMI)(Baseline, Week 16, Week 32)
- Absolute change in triglycerides (TG)(Baseline, Week 16, Week 32)
- Absolute change in high-density lipoprotein cholesterol (HDL-C)(Baseline, Week 16, Week 32)
- Number of Grade 3 severe hypoglycemic episodes(Baseline through Week 32)
- Absolute change in fasting plasma glucose (FPG)(Baseline, Week 16, Week 32)
- Absolute change in glycated hemoglobin (HbA1c)(Baseline, Week 16, Week 32)
- Changes in derived indices from oral glucose tolerance test (OGTT) from baseline to study endpoint(Baseline, Week 16, Week 32)
- Absolute change in liver stiffness measurement (LSM)(Baseline, Week 16, Week 32)
研究者
Zhenqiang Song
Principal Investigator, Professor of Endocrinology
Tianjin Medical University