Safety and efficacy of conventional drugs on Non-alcoholic fatty liver disease

Phase 4

Completed

• Conditions: Type 2 diabetes mellitus with other specified complications,

• Registration Number: CTRI/2019/06/019592
• Lead Sponsor: Self

Brief Summary

Dyslipidemia is a common feature of diabetes. A characteristic pattern, termed Diabetic dyslipidemia (DD) characterized by elevated fasting and postprandial glucose along with triglycerides (TG; >1.7mmol/L), low HDL-cholesterol (HDL-C;<1.3mmo/L in F, <1.0mmol/L in M), elevated/normal LDL-cholesterol (LDL-C; >3.0mmol/L) and with the predominance of small dense LDL particles. In diabetic dyslipidemia, insulin resistance facilitates the increase of free fatty acid (FFA) flux. The increased FFA level boosts TG and VLDL production as well as triggers oxidative stress and lipid peroxidation, all of which closely associated with the development of NAFLD.

The criteria for the definition of NAFLD requires that (a) there is evidence of hepatic steatosis, either by imaging or by histology and (b) there are no causes for subsequent hepatic fat accumulation such as significant alcohol consumption, use of steatogenic medication or hereditary disorders. NAFLD can be categorized histologically into the nonalcoholic fatty liver (NAFL: the presence of ≥5% hepatic steatosis without evidence of hepatocellular injury in the form of hepatocyte ballooning) or nonalcoholic steatohepatitis (NASH: the presence of ≥5% hepatic steatosis and inflammation with hepatocyte injury (e.g., ballooning), with or without any fibrosis). Regarding dyslipidemia as the plausible link for NAFLD, aggressive management of dyslipidemia and prevention may represent a promising addition to the treatment of NAFLD. Thus, the ideal therapeutic strategy for NAFLD management should not only reverse the excessive lipid accumulation in hepatocytes but also attenuate the hepatic inflammatory reaction, endothelial dysfunction, and insulin resistance in the liver, eventually preventing the progression of simple steatosis to NASH.

Saroglitazar is a dual peroxisome proliferator-activated receptor (PPAR) agonist indicated for the treatment of hypertriglyceridemia in Type II diabetics by Drug Controller General of India (DCGI) in June 2013, and also various studies showed its efficacy in improving NAFLD. Ranolazine approved as an antianginal agent in January 2006, but post hoc analyses of various angina trials (like MERLIN-TIMI 36 Randomized control trial) suggested the drug ability to lower HbA1c, and in addition to this, the preliminary studies suggest that ranolazine treatment reverses obesity-induced NAFLD. Different class of drugs with the same actions in mitigating NAFLD brought to this comparative study.

To our knowledge, this study works to adds a new indication for ranolazine in the treatment of NAFLD. Our current work aims to compare the associations of the (Nonalcoholic fatty liver disease) NAFLD with Type ΙΙ Diabetes Mellitus and dyslipidemia (DL). The factors associated with Type 2 DM, DL, NAFLD are to be analyzed. Also, the safety of both drugs (Ranolazine and Saroglitazar) are compared on NAFLD in diabetes dyslipidemic patients. The efficacies of both the drugs in lowering the lipid profile and glucose levels will be monitored.

This study investigates biomarkers for glycemic control (hemoglobin A1c and random blood glucose, insulin), lipid metabolism (triglycerides, total cholesterol, high-density lipoprotein [HDL], and low-density lipoprotein [LDL]), albumin, and hepatic cholestasis (gamma-glutamyl transferase [GGT]) in NAFLD. Its mean purpose was to determine whether these biomarkers could detect improvement in progression of NAFLD in Diabetic dyslipidemic patients receiving Ranolazine and Saroglitazar.

Detailed Description

Not available

Study Timeline

• Study Start: 2019-10-06
• Last Update Posted: 2022-04-05

Recruitment & Eligibility

• Status: Completed
• Sex: All
• Target Recruitment: 270

Inclusion Criteria

• Had ALT above upper limits of normal (19 U per L for women, 30 U per L for men).
• Had ALD or NAFLD Index less than 0.
• Had documented hepatic steatosis (Fatty Liver Index greater than equal to 60, NAFLD-FAT SCORE greater than minus 0.640, Hepatic steatosis index greater than equal to 36, NAFLD fibrosis score less than minus 1.455,Liver Accumulation Product greater than equal to 80).
• HbA1C greater than equal to 7% -Willingness to comply with all protocol required evaluations; provision of written informed consent before any study specific tests or procedures are performed.

Exclusion Criteria

• Presence of other chronic liver diseases (hepatitis B or C, autoimmune hepatitis, cholestatic liver disease, Wilsons disease, hemochromatosis, etc.).
• Average alcohol consumption greater than equal to 21 drinks per week formen, greater than equal to 14 drinks per week for women in the 6 months before enrollment.
• The patients who already used medications known to cause hepatic steatosis for more than two weeks in the past year such as mipomersen, lomitapide, amiodarone, methotrexate, tamoxifen, corticosteroid, valproate, antiretroviral medicines.
• Presence of alternative cause of fatty liver, including Total Parenteral Nutrition, Starvation, Lipodystrophy, -Abetalipoproteinemia, Acute fatty liver of pregnancy, HELLP syndrome, Reye’s syndrome.
• Clinical, imaging, or histological evidence of cirrhosis.
• Use of drugs with a potential effect on NASH such as ursodeoxycholic acid, vitamin E, pioglitazone.
• Pregnant or lactating female.

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
-Change from baseline serum AST, ALT, and GGT, HOMA-IR, HBA1c, BMI, Albumin, Total bilirubin, Triglycerides, Total cholesterol, HDL LDL, miRNA-122.	0, 90th day, 180th day, 270th day and 360th day
-Variation in liver fat content as measured byFatty liver index and Liver accumulation product, NAFLD fibrosis score, Hepatic steatosis index, NAFLD Fat score.	0, 90th day, 180th day, 270th day and 360th day
-Changes in liver fibrosis.	0, 90th day, 180th day, 270th day and 360th day

Secondary Outcome Measures

Name	Time	Method
ADR monitoring during study period	0, 90th day, 180th day, 270th day and 360th day

Trial Locations

Locations (1)

SRM Medical College Hospital and Research Centre; 🇮🇳 Kancheepuram, TAMIL NADU, India

SRM Medical College Hospital and Research Centre

🇮🇳Kancheepuram, TAMIL NADU, India

R Sahithya Ravali

Principal investigator

7386852075

sahithyamavaluru@gmail.com