Efficacy and Safety of Mazdutide in Patients With Type 2 Diabetes Mellitus and Moderate to Severe Nonalcoholic Fatty Liver Disease Previously Treated With Semaglutide

July 15, 2026 updated by: Zhenqiang Song, Tianjin Medical University

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)

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.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

72

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Mazdutide Treatment Group
Subjects in this arm immediately discontinue subcutaneous semaglutide 1.0 mg once weekly, and switch to subcutaneous mazdutide therapy in accordance with the study protocol. After the initial intervention period, subjects with an intrahepatic fat content reduction rate ≥ 30% continue the original mazdutide dose; subjects with an intrahepatic fat content reduction rate < 30% are titrated to mazdutide 6 mg. Administration route, frequency and standard initial dose follow the approved drug label and study protocol.
Drug: Mazdutide(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.
Active Comparator: Semaglutide Maintenance Group
Subjects in this arm continue maintenance treatment with subcutaneous semaglutide 1.0 mg once weekly, consistent with their pre-study treatment regimen. After the initial intervention period, all subjects in this arm cross over to receive mazdutide therapy and enter the extended follow-up phase. No dose adjustment of semaglutide is allowed during the control treatment period.
Drug: Semaglutide (1 Mg Dose)
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Absolute change in liver fat content measured by MRI-PDFF
Time Frame: Baseline, Week 16, Week 32
Baseline, Week 16, Week 32
Absolute change in liver fat content measured by liver transient elastography
Time Frame: Baseline, Week 16, Week 32
Baseline, Week 16, Week 32

Secondary Outcome Measures

Outcome Measure
Time Frame
Absolute change in fasting plasma glucose (FPG)
Time Frame: Baseline, Week 16, Week 32
Baseline, Week 16, Week 32
Absolute change in glycated hemoglobin (HbA1c)
Time Frame: Baseline, Week 16, Week 32
Baseline, Week 16, Week 32
Changes in derived indices from oral glucose tolerance test (OGTT) from baseline to study endpoint
Time Frame: Baseline, Week 16, Week 32
Baseline, Week 16, Week 32
Absolute change in liver stiffness measurement (LSM)
Time Frame: Baseline, Week 16, Week 32
Baseline, Week 16, Week 32
Absolute change in body weight
Time Frame: Baseline, Week 16, Week 32
Baseline, Week 16, Week 32
Absolute change in total cholesterol (TC)
Time Frame: Baseline, Week 16, Week 32
Baseline, Week 16, Week 32
Number of Grade 2 clinically significant hypoglycemic episodes
Time Frame: Baseline through Week 32
Baseline through Week 32
Absolute change in fibrosis-4 index (FIB-4)
Time Frame: Baseline, Week 16, Week 32
Baseline, Week 16, Week 32
Number of adverse events
Time Frame: Baseline through Week 32
Baseline through Week 32
Absolute change in body mass index (BMI)
Time Frame: Baseline, Week 16, Week 32
Baseline, Week 16, Week 32
Absolute change in triglycerides (TG)
Time Frame: Baseline, Week 16, Week 32
Baseline, Week 16, Week 32
Absolute change in high-density lipoprotein cholesterol (HDL-C)
Time Frame: Baseline, Week 16, Week 32
Baseline, Week 16, Week 32
Number of Grade 3 severe hypoglycemic episodes
Time Frame: Baseline through Week 32
Baseline through Week 32
Number of allergic reaction events
Time Frame: Baseline through Week 32
Baseline through Week 32

Other Outcome Measures

Outcome Measure
Time Frame
Change in pancreatic fat fraction from baseline to study endpoint
Time Frame: Baseline, Week 16, Week 32
Baseline, Week 16, Week 32
Proportion of patients achieving type 2 diabetes remission
Time Frame: endpoint, 12-week diabetes remission extension follow-up
endpoint, 12-week diabetes remission extension follow-up
Absolute change in total lean body mass
Time Frame: Baseline, Week 16, Week 32
Baseline, Week 16, Week 32
Absolute change in appendicular skeletal muscle index (ASMI)
Time Frame: Baseline, Week 16, Week 32
Baseline, Week 16, Week 32

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Tianjin Medical University

Collaborators

Tianjin Third Central Hospital
Tianjin First Central Hospital
Tianjin TEDA Hospital
Tianjin Fifth Central Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

September 15, 2026

Primary Completion (Estimated)

December 31, 2027

Study Completion (Estimated)

February 1, 2028

Study Registration Dates

First Submitted

July 9, 2026

First Submitted That Met QC Criteria

July 15, 2026

First Posted (Actual)

July 20, 2026

Study Record Updates

Last Update Posted (Actual)

July 20, 2026

Last Update Submitted That Met QC Criteria

July 15, 2026

Last Verified

July 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ●JXYJNYYkMEC2026-32

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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