Clinical trial NCT06218342: Henagliflozin in Relieving Type 2 Diabetes With Non-alcoholic Fatty Liver Disease
Official title: The Study of Henagliflozin in Relieving Progression of Type 2 Diabetes With Non-alcoholic Fatty Liver Disease
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE4
Conditions: Type 2 Diabetes
Non-Alcoholic Fatty Liver Disease
Lead sponsor: Sir Run Run Shaw Hospital
Sponsor class: OTHER
First posted: 2024-01-23
Enrollment: 156
Sex: ALL
Minimum age (years): 20
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study is a randomized, non-blinded clinical trial specifically designed to assess the initial feasibility and efficacy of SGLT2 inhibitors in treating NAFLD among adults diagnosed with type 2 diabetes.

Detailed description: Non-alcoholic fatty liver disease (NAFLD) is a metabolic liver disease that encompasses a spectrum of progressive pathological changes, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). Epidemiological data demonstrate a close association between type 2 diabetes and NAFLD. Approximately 49% to 62% of individuals with type 2 diabetes have concurrent NAFLD, and those with NAFLD have a risk of developing diabetes more than twice that of the general population. NAFLD not only increases the risk of developing type 2 diabetes but also accelerates the progression of diabetes-related target organ damage, leading to adverse metabolic and cardiovascular risks. Currently, there is a global lack of comprehensive public health strategies for addressing NAFLD, and clinically, there are still no approved drugs specifically for treating NAFLD.

NAFLD is diagnosed through abnormal liver function test results and imaging examinations. The NAFLD Fibrosis Score (NFS) and Fibrosis-4 (FIB-4) Index can be used for clinical screening of NASH in individuals with type 2 diabetes. Ultrasound attenuation parameters (UAP) and liver stiffness measurements (LSM) based on transient elastography (TE) can accurately differentiate between liver steatosis and the degree of liver fibrosis. This technique, known for its non-invasive, safe, and reproducible nature, has found widespread application in diagnosing the extent of liver fat and fibrosis in patients with chronic liver diseases.

The primary approach to treating NAFLD involves modifying poor lifestyle habits, however, lifestyle changes are often difficult to sustain in the long term. Currently, neither the U.S. FDA nor the European Medicines Agency has approved any medications specifically for NAFLD treatment. Given the central role of insulin resistance in the development of NAFLD, hypoglycemic medications have become a new focus in the prevention and treatment of NAFLD. Sodium-glucose co-transporter-2 (SGLT-2) inhibitors, by inhibiting SGLT-2 activity, reduce the reabsorption of glucose in the proximal renal tubules, causing excess glucose to be excreted in the urine, thereby lowering blood sugar. Reports suggest that SGLT-2 inhibitors also have several other beneficial effects, including reducing the risk of cardiovascular and kidney diseases, improving blood pressure control, aiding weight reduction, and lowering liver fat content. Previous studies have shown that SGLT-2 inhibitors can improve alanine transaminase, aspartate transaminase, gamma-glutamyl transferase, and the FIB-4 Index in patients with type 2 diabetes complicated by NAFLD, potentially exhibiting anti-fibrotic effects on the liver. Henagliflozin, the SGLT-2 inhibitor used in this study, is a compound independently developed with intellectual property by Jiangsu Hengrui Medicine Co., Ltd. Henagliflozin has demonstrated efficacy and safety in monotherapy for inadequately controlled type 2 diabetes patients with poor diet and exercise control or in combination with metformin for inadequately controlled type 2 diabetes patients.

This study aims to observe the clinical efficacy of henagliflozin treatment for type 2 diabetes complicated by NAFLD in individuals, evaluating its potential to improve liver fat changes and fibrosis indicators in NAFLD, promoting NASH regression, and alleviating the progression of liver fibrosis, building upon lifestyle changes and basic treatments. The secondary objectives include investigating the effects of henagliflozin on liver fat content, visceral fat area, liver enzymes, and blood sugar improvement.

Eligibility criteria: Inclusion Criteria:

* Age between 20 and 70 years old.
* Diagnosed with type 2 diabetes according to World Health Organization (WHO) diagnostic criteria, with evidence of fatty liver on ultrasound, and FIB-4 index \>1.3.
* Willing to participate in this study and sign an informed consent form. In case the subject lacks the ability to read the informed consent form (e.g., illiterate subjects), the informed process must be witnessed by a designated person who will sign the informed consent form.
* Have not used oral antidiabetic medications or have used one to three oral antidiabetic medications (limited to metformin, Dipeptidyl peptidase-4 (DPP-4) inhibitors, alpha-glucosidase inhibitors, or sulfonylureas) with an HbA1c between 7% and 10%, and fasting venous blood glucose ≤13.3 mmol/L.
* Have not used thiazolidinediones (TZDs), sodium-glucose co-transporter-2 inhibitors (SGLT-2i), glucagon-like peptide-1 receptor agonists (GLP-1RA), or other antidiabetic drugs that may affect liver fat content in the last 90 days.
* Weight change of less than 5% in the last 3 months.
* If of childbearing age, must use reliable contraceptive measures.

Exclusion Criteria:

* Daily alcohol intake of \>30 g in the past 10 years or daily alcohol intake of \>10 g in the last year.
* History of liver diseases such as hepatitis B, chronic hepatitis C, primary biliary cholangitis (PBC), biliary obstruction disorders, drug-induced liver damage, hemochromatosis, liver cirrhosis, autoimmune hepatitis.
* Patients with decompensated liver cirrhosis, concurrent liver cancer, HIV-positive status, or substance abuse.
* Type 1 diabetes.
* Participation in other clinical trials of diabetes treatment drugs in the 3 months prior to the start of this study.
* Occurrence of diabetic ketoacidosis, diabetic lactic acidosis, or hyperosmolar non-ketotic coma in the past 6 months.
* Occurrence of unexplained severe hypoglycemic events in the past 6 months (requiring assistance for recovery) or recurrent hypoglycemia: such as experiencing two or more low blood sugar events (blood glucose ≤3.9 mmol/L) in the month before screening.
* Severe heart disease patients, such as New York Heart Association (NYHA) class IV, unstable angina, or history of myocardial infarction.
* Abnormal liver function, with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels greater than 3 times the upper normal limit, or total bilirubin (TBIL) greater than 2 times the upper normal limit.
* Chronic kidney damage, with a creatinine level (Cr) \>200 µmol/L or an estimated glomerular filtration rate (eGFR) \<30 mL·min-1.
* Use of corticosteroid medications (excluding short-term topical or inhaled use).
* Patients with malignant tumors, active tuberculosis, or acute/chronic infections.
* Vulnerable populations, including pregnant women, individuals with mental illness, critically ill patients, individuals with cognitive impairments, etc.
* History of recurrent urinary tract infections or genital infections, or allergies to the investigational drug or its components.
* Patients assessed by the clinical doctor as having low blood volume.
* Patients deemed unsuitable for participation in this clinical study by the investigator, for reasons not covered above.

Primary outcomes:
measure: Ultrasound attenuation parameter (UAP)
timeFrame: 24 weeks
measure: Liver stiffness measurement (LSM)
timeFrame: 24 weeks
Secondary outcomes:
measure: Non-Alcoholic Fatty Liver Disease Fibrosis Score (NFS)
timeFrame: 24 weeks
measure: Fibrosis Index Based on 4 Factors (FIB-4 Index)
timeFrame: 24 weeks
measure: Liver fat content
timeFrame: 24 weeks
measure: Liver enzymes
timeFrame: 24 weeks
measure: Cholestatic proteins (Chitinase 3-like protein 1, CHI3L1)
timeFrame: 24 weeks
measure: Intrabdominal fat
timeFrame: 24 weeks
measure: Glucose level
timeFrame: 24 weeks
measure: Body weight
timeFrame: 24 weeks
Other outcomes:
Locations:
Study officials:
affiliation: Sir Run Run Shaw Hospital
name: Jiaqiang Zhou
role: PRINCIPAL_INVESTIGATOR
References: