Henagliflozin on Liver Fibrosis in Patients with MASLD and T2DM

Intervention of Henagliflozin on Liver Fibrosis in Patients with Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) and Type 2 Diabetes Mellitus (T2DM)

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing due to changes in economic conditions and lifestyle, and it is anticipated to become a significant liver disease burden in the future. This is particularly true for patients with MASLD who also have type 2 diabetes mellitus (T2DM), as the rate of comorbidity between these conditions has risen in recent years due to their shared mechanisms, necessitating careful management of both. Liver fibrosis is a critical concern, as poor blood glucose control can worsen liver fibrosis, which in turn complicates blood sugar management. Therefore, addressing liver fibrosis in patients with MASLD and T2DM is urgent, yet there are currently no targeted therapies to reverse its progression. SGLT2 inhibitors, have shown promise in potentially reversing liver fibrosis, but existing research is limited and has not adequately focused on liver fibrosis improvement, highlighting the need for more robust evidence-based studies.

Study Overview

• Status: Not yet recruiting
• Conditions: Type 2 Diabetes Mellitus; Metabolic Dysfunction-associated Steatotic Liver Disease
• Intervention / Treatment: Drug: Metformin 1700 mg daily; Other: Placebo of Henagliflozin; Drug: Henagliflozin 10 mg daily

• Study Type: Interventional
• Enrollment (Estimated): 190
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Tiansu Jiangsu province hospital of traditional chinese medicine; Phone Number: 025-17397952085; Email: 728294997@qq.com
• Study Contact Backup: Name: TIANSU LV, -; Phone Number: 025+17397952085

Study Locations

• China
  • Jiangsu
    • Nanjing, Jiangsu, China, 210029
      • Jiangsu Province Hospital of Traditional Chinese Medicine
      • Contact: Jiangsu province hospital of traditional chinese medicine; Phone Number: 025-17397952085; Email: 7282894997@qq.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Participants must be aged between 18 and 75 years.
2. Participants must meet the diagnostic criteria for MASLD and T2DM.
3. Participants' HbA1c level between 6.5% and 9%.
4. The LSM obtained via the FibroScan device must be equal to or greater than 8 kPa.
5. Participants must not have experienced a significant change in body weight exceeding 15% within the past four weeks.
6. Participants must not have utilized non-biguanide hypoglycemic medications in the three months preceding the study.

Exclusion Criteria:

1. Patients diagnosed with non-MASLD, which encompasses conditions such as viral hepatitis, autoimmune liver disease, liver tumors, and drug-induced liver injury, among others;
2. Individuals exhibiting ALT and/or AST levels that exceed the normal range by threefold or more;
3. Patients currently using or having used medications associated with secondary MASLD (including, but not limited to, corticosteroids, estrogen, amiodarone, methotrexate, etc.) within the preceding three months;
4. Individuals utilizing or having utilized medications within the last three months that possess the potential to ameliorate hepatic steatosis or fibrosis in MASLD (including, but not limited to, ursodeoxycholic acid, bicyclol tablets, silymarin capsules, polyene phosphatidylcholine capsules, vitamin E, etc.);
5. Patients with known or suspected elevated alcohol consumption (females exceeding 12 grams per day; males exceeding 24 grams per day) or those on medications that may contribute to increased consumption;
6. Individuals who have experienced severe acute complications such as hypoglycemia, ketoacidosis, hyperglycemia, or hyperosmolar states within the past month or during the course of medication;
7. Patients who have undergone metabolic bariatric surgery or are currently participating in bariatric treatment;
8. Individuals with significant primary systemic pathologies, including but not limited to respiratory, circulatory, digestive, urinary, neurological, hematological, rheumatological, endocrine diseases, tumors, or AIDS;
9. Female participants who are pregnant, breastfeeding, or of childbearing potential and not employing a highly effective contraceptive method;
10. Individuals with known allergies or potential allergies to the medications utilized in this study, rendering them intolerant;
11. Patients with a history of recurrent or severe urinary and genital tract infections;
12. Individuals exhibiting severe cognitive impairment or mental illness that impedes their ability to cooperate;
13. Patients currently engaged in clinical observation of other pharmacological agents.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Control Group; Placebo + Metformin 1.7g/d	Drug: Metformin 1700 mg daily; The metformin utilized in this study is Metformin Hydrochloride Extended-release Tablets, manufactured by Bristol-Myers Squibb Company. This formulation of metformin is available in a dosage of 0.85 grams per tablet, necessitating that patients administer two tablets daily to acquire the dose of 1.7g daily, to be taken within thirty minutes prior to breakfast and dinner respectively. However, adjustments to the metformin dosage were not permitted during follow-up visits.; Other: Placebo of Henagliflozin; The placebo was supplied by the pharmaceutical company responsible for Henagliflozin, ensuring that both the placebo and Henagliflozin were indistinguishable in terms of appearance, taste, and odor, while lacking any significant pharmacological effect. Administration of the placebo was recommended to occur in the early morning.
Experimental: Intervention Group; Henagliflozin 10mg/d + Metformin 1.7g/d	Drug: Metformin 1700 mg daily; The metformin utilized in this study is Metformin Hydrochloride Extended-release Tablets, manufactured by Bristol-Myers Squibb Company. This formulation of metformin is available in a dosage of 0.85 grams per tablet, necessitating that patients administer two tablets daily to acquire the dose of 1.7g daily, to be taken within thirty minutes prior to breakfast and dinner respectively. However, adjustments to the metformin dosage were not permitted during follow-up visits.; Drug: Henagliflozin 10 mg daily; Henagliflozin (SHR3824) is a hypoglycemic agent classified as an SGLT2i, which has been independently developed by Jiangsu Hengrui Pharmaceutical Co., Ltd. (China) and Shanghai Hengrui Pharmaceutical Co., Ltd (China). It received marketing authorization in China on December 31, 2021 (ID: H20210053).The prescribed dosage of Henagliflozin is 10 mg per day, as indicated on the drug label, with administration recommended in the early morning. In instances where a participant forgot to take the medication in the morning, they were permitted to do so until 12:00 PM on the same day.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Liver stiffness measurements (LSM) of subjects	As determined by magnetic resonance elastography (MRE)	From enrollment to the treatment at 24 and 48 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy Evaluation of MASLD in fibrosis	This includes: Difference from baseline in LSM of subjects based on FibroScan;; The proportion of LSM of subjects on MRE reduced by ≥15%;; The proportion of LSM of subjects on FibroScan reduced by ≥15%	From enrollment to the treatment at 24 and 48 weeks
Efficacy Evaluation of MASLD in liver fatty quantification	This includes: Difference from baseline in liver fatty quantification of subjects based on magnetic resonance imaging proton density fat fraction(MRI-PDFF);; Difference from baseline in liver fatty quantification of subjects based on FibroScan;; The proportion of liver fatty quantification of subjects based on MRI-PDFF was reduced by ≥30%;; The proportion of liver fatty quantification of subjects based on FibroScan was reduced by ≥30%;	From enrollment to the treatment at 24 and 48 weeks
Efficacy Evaluation of MASLD in non-invasive biological indicators related to liver fibrosis	This includes:1.NAFLD fibrosis score(NFS) = - 1.675 + [0.037 ×Age] + [0.094 × body mass index(BMI) (kg/m2)] + [1.13 × fasting plasma glucose(FPG)/ Diabetes (Yes=1，No= 0)] + [0.99 × aspartate aminotransferase(AST)/alanine aminotransferase(ALT)] - [0.013 × platelet count(PLT) (×109/L)] - [0.66 × Albumin(ALB) (g/dL)]; NFS <-1.455, -1.455-0.675, and >0.675 mean expressed as low, medium, and high risk, respectively(39); 2.Fibrosis-4(FIB-4) index= [Age× AST (U/L)]/[PLT (×109/L)× ALT (U/L)1/2];	From enrollment to the treatment at 24 and 48 weeks
Renal function	This includes:This includes:Difference from baseline in renal function related parameters of subjects, primarily including uric acid(UA), urea nitrogen(BUN), creatinine(Cr), urine albumin-to-creatinine ratio(UACR).	From enrollment to the treatment at 24 and 48 weeks
Liver function	This includes:Difference from baseline in liver function related parameters of subjects, primarily including AST, ALT, gamma-glutamyl transferase(GGT), alkaline phosphatase(ALP), ALB, total bilirubin(TBiL).	From enrollment to the treatment at 24 and 48 weeks
Lipid metabolism	This includes:Difference from baseline in lipid metabolism related parameters of subjects, primarily including Triglyceride(TG), total cholesterol(TC), low-density lipoprotein cholesterol(LDL-C), high-density lipoprotein cholesterol(HDL-C).	From enrollment to the treatment at 24 and 48 weeks
Efficacy Evaluation of T2DM	FPG	From enrollment to the treatment at 24 and 48 weeks
Efficacy Evaluation of T2DM	fasting insulin concentrations(FINS)	From enrollment to the treatment at 24 and 48 weeks
Efficacy Evaluation of T2DM	fasting C-peptide(FCP)	From enrollment to the treatment at 24 and 48 weeks
Efficacy Evaluation of T2DM	hemoglobin A1c(HbA1c)	From enrollment to the treatment at 24 and 48 weeks
Efficacy Evaluation of T2DM	homeostatic model assessment of insulin resistance(HOMA-IR)	From enrollment to the treatment at 24 and 48 weeks

Collaborators and Investigators

• Sponsor: Xiqiao Zhou
• Collaborators: Jiangsu Hengrui Pharmaceutical Co., Ltd.

Study record dates

Study Major Dates

• Study Start (Estimated): December 31, 2024
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: December 17, 2024
• First Submitted That Met QC Criteria: January 1, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 1, 2025
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: type 2 diabetes mellitus; SGLT2i; Liver fibrosis; Henagliflozin; metabolic dysfunction-associated steatotic liver disease
• Additional Relevant MeSH Terms: Endocrine System Diseases; Pathologic Processes; Metabolic Diseases; Digestive System Diseases; Glucose Metabolism Disorders; Diabetes Mellitus, Type 2; Diabetes Mellitus; Fibrosis; Liver Diseases; Liver Cirrhosis; Physiological Effects of Drugs; Hypoglycemic Agents; Metformin
• Other Study ID Numbers: 2024NL-195-01

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
• product manufactured in and exported from the U.S.: No