Nonalcoholic Fatty Liver Disease (NAFLD) With History of Diabetes Melitus, Type 2 Diabetes Mellitus (T2DM)
Conditions
Keywords
Type 2 Diabetes Mellitus, Nonalcoholic Fatty Liver Disease, Mazdutide, Randomized Controlled Trial, Liver Fat Content
Brief summary
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.
Interventions
DRUGMazdutide(Dual GLP-1R/GCGR Agonist)
Subcutaneous injection, once weekly for 16 weeks (first phase). Subjects switch from previous semaglutide 1.0 mg weekly to mazdutide 4 mg immediately, with no washout period.After 16-week initial treatment phase, subjects with \<30% reduction in liver fat content from baseline will have mazdutide dose titrated up to 6 mg weekly as per study protocol.
Participants in the control group maintain the original treatment regimen of once-weekly subcutaneous semaglutide 1.0 mg throughout the trial without dose adjustment or drug switching. No washout period is implemented prior to randomization. Concomitant hypoglycemic, antihypertensive and lipid-lowering medications remain unchanged as baseline. Subjects will only cross over to mazdutide after completion of the initial intervention phase.
Sponsors
Tianjin Medical University
Tianjin TEDA Hospital
Tianjin First Central Hospital
Tianjin Third Central Hospital
Tianjin Fifth Central Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* 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.
Exclusion criteria
* 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Absolute change in liver fat content measured by MRI-PDFF | Baseline, Week 16, Week 32 |
| Absolute change in liver fat content measured by liver transient elastography | Baseline, Week 16, Week 32 |
Secondary
| Measure | Time frame |
|---|---|
| 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 |
| 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 |
| Number of allergic reaction events | Baseline through Week 32 |
Contacts
CONTACTZsong
Outcome results
None listed