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

NCT07713992 | Not Yet Recruiting

• 1 other identifier: ●JXYJNYYkMEC2026-32
• Study Type: interventional
• Target: 72
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Type 2 Diabetes Mellitus (T2DM); Nonalcoholic Fatty Liver Disease (NAFLD) With History of Diabetes Melitus

Keywords

Type 2 Diabetes Mellitus; Nonalcoholic Fatty Liver Disease; Mazdutide; Randomized Controlled Trial; Liver Fat Content

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (14)

• 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

Other Outcomes (4)

• Change in pancreatic fat fraction from baseline to study endpoint

  Baseline, Week 16, Week 32

• Proportion of patients achieving type 2 diabetes remission

  endpoint, 12-week diabetes remission extension follow-up

• Absolute change in total lean body mass

  Baseline, Week 16, Week 32

Study Arms (2)

Mazdutide Treatment Group

EXPERIMENTAL

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)

Semaglutide Maintenance Group

ACTIVE COMPARATOR

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)

Interventions

Semaglutide (1 Mg Dose) DRUG

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.

Semaglutide Maintenance Group

Mazdutide(Dual GLP-1R/GCGR Agonist) DRUG

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.

Mazdutide Treatment Group

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Tianjin Medical University: lead
• Tianjin TEDA Hospital: collaborator
• Tianjin First Central Hospital: collaborator
• Tianjin Third Central Hospital: collaborator
• Tianjin Fifth Central Hospital: collaborator

Related Publications (15)

• Sanchez-Garrido MA, Brandt SJ, Clemmensen C, Muller TD, DiMarchi RD, Tschop MH. GLP-1/glucagon receptor co-agonism for treatment of obesity. Diabetologia. 2017 Oct;60(10):1851-1861. doi: 10.1007/s00125-017-4354-8. Epub 2017 Jul 21.

  PMID: 28733905 BACKGROUND

• Del Prato S, Gallwitz B, Holst JJ, Meier JJ. The incretin/glucagon system as a target for pharmacotherapy of obesity. Obes Rev. 2022 Feb;23(2):e13372. doi: 10.1111/obr.13372. Epub 2021 Oct 28.

  PMID: 34713962 BACKGROUND

• Habegger KM, Heppner KM, Geary N, Bartness TJ, DiMarchi R, Tschop MH. The metabolic actions of glucagon revisited. Nat Rev Endocrinol. 2010 Dec;6(12):689-97. doi: 10.1038/nrendo.2010.187. Epub 2010 Oct 19.

  PMID: 20957001 BACKGROUND

• Al-Massadi O, Ferno J, Dieguez C, Nogueiras R, Quinones M. Glucagon Control on Food Intake and Energy Balance. Int J Mol Sci. 2019 Aug 11;20(16):3905. doi: 10.3390/ijms20163905.

  PMID: 31405212 BACKGROUND

• van Can J, Sloth B, Jensen CB, Flint A, Blaak EE, Saris WH. Effects of the once-daily GLP-1 analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non-diabetic adults. Int J Obes (Lond). 2014 Jun;38(6):784-93. doi: 10.1038/ijo.2013.162. Epub 2013 Sep 3.

  PMID: 23999198 BACKGROUND

• Targher G, Valenti L, Byrne CD. Metabolic Dysfunction-Associated Steatotic Liver Disease. N Engl J Med. 2025 Aug 14;393(7):683-698. doi: 10.1056/NEJMra2412865. No abstract available.

  PMID: 40802944 BACKGROUND

• Nauck MA, Quast DR, Wefers J, Pfeiffer AFH. The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: A pathophysiological update. Diabetes Obes Metab. 2021 Sep;23 Suppl 3:5-29. doi: 10.1111/dom.14496.

  PMID: 34310013 BACKGROUND

• Jones B. The therapeutic potential of GLP-1 receptor biased agonism. Br J Pharmacol. 2022 Feb;179(4):492-510. doi: 10.1111/bph.15497. Epub 2021 May 20.

  PMID: 33880754 BACKGROUND

• Gasoyan H, Butsch WS, Schulte R, Casacchia NJ, Le P, Boyer CB, Griebeler ML, Burguera B, Rothberg MB. Changes in weight and glycemic control following obesity treatment with semaglutide or tirzepatide by discontinuation status. Obesity (Silver Spring). 2025 Sep;33(9):1657-1667. doi: 10.1002/oby.24331. Epub 2025 Jun 10.

  PMID: 40491239 BACKGROUND

• Jiao R, Lin C, Cai X, Wang J, Wang Y, Lv F, Yang W, Ji L. Characterizing body composition modifying effects of a glucagon-like peptide 1 receptor-based agonist: A meta-analysis. Diabetes Obes Metab. 2025 Jan;27(1):259-267. doi: 10.1111/dom.16012. Epub 2024 Oct 21.

  PMID: 39431379 BACKGROUND

• Lean ME, Leslie WS, Barnes AC, Brosnahan N, Thom G, McCombie L, Peters C, Zhyzhneuskaya S, Al-Mrabeh A, Hollingsworth KG, Rodrigues AM, Rehackova L, Adamson AJ, Sniehotta FF, Mathers JC, Ross HM, McIlvenna Y, Stefanetti R, Trenell M, Welsh P, Kean S, Ford I, McConnachie A, Sattar N, Taylor R. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. Lancet. 2018 Feb 10;391(10120):541-551. doi: 10.1016/S0140-6736(17)33102-1. Epub 2017 Dec 5.

  PMID: 29221645 BACKGROUND

• Taylor R. Pathogenesis of type 2 diabetes: tracing the reverse route from cure to cause. Diabetologia. 2008 Oct;51(10):1781-9. doi: 10.1007/s00125-008-1116-7. Epub 2008 Aug 26.

  PMID: 18726585 BACKGROUND

• Yi W, Kim K, Im M, Ryang S, Kim EH, Kim M, Jeon YK, Kim SS, Kim BH, Pak K, Kim IJ, Kim SJ. Association between visceral adipose tissue volume, measured using computed tomography, and cardio-metabolic risk factors. Sci Rep. 2022 Jan 10;12(1):387. doi: 10.1038/s41598-021-04402-5.

  PMID: 35013484 BACKGROUND

• Reijrink M, de Boer SA, Spoor DS, Lefrandt JD, Lambers Heerspink HJ, Boellaard R, Greuter MJ, Borra RJH, Hillebrands JL, Slart RHJA, Mulder DJ. Visceral adipose tissue volume is associated with premature atherosclerosis in early type 2 diabetes mellitus independent of traditional risk factors. Atherosclerosis. 2019 Nov;290:87-93. doi: 10.1016/j.atherosclerosis.2019.09.016. Epub 2019 Sep 25.

  PMID: 31604171 BACKGROUND

• Jia W, Chan JC, Wong TY, Fisher EB. Diabetes in China: epidemiology, pathophysiology and multi-omics. Nat Metab. 2025 Jan;7(1):16-34. doi: 10.1038/s42255-024-01190-w. Epub 2025 Jan 14.

  PMID: 39809974 BACKGROUND

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Non-alcoholic Fatty Liver Disease

Interventions

semaglutide

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Fatty Liver; Liver Diseases; Digestive System Diseases

Central Study Contacts

Zsong

CONTACT

86-22-18602276218; Zsong@tmu.edu.cn

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator, Professor of Endocrinology

Study Record Dates

• First Submitted: July 9, 2026
• First Posted: July 20, 2026
• Study Start (Estimated): September 15, 2026
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): February 1, 2028
• Last Updated: July 20, 2026

Record last verified: 2026-07

Data Sharing

• IPD Sharing: Will not share