MASLD in Primary Hypothyroidism and Efficacy of Dapaglifozin — SHIELD  

Non-Alcoholic Fatty Liver Disease Clinical Trial

Official title: MASLD in Primary Hypothyroidism and Efficacy of Dapaglifozin

Status Not yet recruiting

Clinical Trial Summary

Non-alcoholic fatty liver disease (NAFLD) is a global epidemic with a prevalence of 25-40%.Primary Hypothyroidism is one of Endocrinopathies who are at risk of developing NAFLD/NASH and estimated prevalence of Primary Hypothyroidism in NAFLD patients is 10-15 %.Though First line Management is Dietary changes and lifestyle modifications(LSM),unfortunately Adherence to Lifestyle has been poor,rise of Lean NAFLD is on rise, faster progression of NAFLD,evolving risk factors for NAFLD like endocrinopathies,these push need for Pharmacotherapy.Currently therapies for NAFLD patients without diabetes mellitus (DM) are limited, and are associated with various adverse side effects. Sodium-glucose cotransporter type-2 (SGLT2) inhibitors can reduce hepatic fat content in patients with DM which is independent of glycemic control. However, the role of SGLT2 inhibitors in NAFLD patients without DM has not been investigated.Magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) is an emerging non-invasive imaging technique, and is more sensitive than liver biopsy/histology in quantifying liver fat change. Liver stiffness measurement (LSM) by Transient Elastography is a non-invasive method to diagnose fibrosis/cirrhosis with high accuracy.The novelty of utilizing the concept of "drug repositioning" by changing the role of SGLT2 inhibitors in treating DM to treating NAFLD in patients without DM deserves exploration.The investigators propose a double-blind, randomized, placebo-controlled trial to compare the effects of Dapagliflozin (a type of SLGT2 inhibitors) versus placebo (in a 1:1 ratio) in reducing hepatic fat content as measured by MRI-PDFF in NAFLD patients with Primary Hypothyroidism.The study results will determine whether SGLT2 inhibitors can reduce hepatic steatosis/hepatic fibrosis in NAFLD patients with Primary Hypothyroidism.

Clinical Trial Description

Non-alcoholic fatty liver disease (NAFLD) is a global epidemic with a prevalence of 25-40%.Cirrhosis can occur without intervening NASH .Time line of progression is variable - modified by risk factors.Over all average progression from one disease Stage to another can take up 7 years for NASH while 14 years for NAFLD.In general ,10-30% of patient NAFLD progress to NASH ; Of which 15-25 % progress to advanced fibrosis.Amongst advanced fibrosis,20 % Progress to Cirrhosis over 2 years and 20 % of cirrhotics will have decompensation over 2 years.Overall in NAFLD MCC of mortality - CVD>Extrahepatic cancer > Liver specific mortality ( HCC and Hepatic decompensation).Primary Hypothyroidism is one of Endocrinopathies who are at risk of developing NAFLD/NASH and estimated prevalence of Primary Hypothyroidism in NAFLD patients is 10-15 %.

Though First line Management is Dietary changes and lifestyle modifications(LSM),unfortunately Adherence to Lifestyle has been poor,rise of Lean NAFLD is on rise, faster progression of NAFLD,evolving risk factors for NAFLD like endocrinopathies,these push need for Pharmacotherapy.Currently therapies for NAFLD patients without diabetes mellitus (DM) are limited, and are associated with various adverse side effects. Sodium-glucose cotransporter type-2 (SGLT2) inhibitors can reduce hepatic fat content in patients with DM which is independent of glycemic control. However, the role of SGLT2 inhibitors in NAFLD patients without DM has not been investigated.

Magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) is an emerging non-invasive imaging technique, and is more sensitive than liver biopsy/histology in quantifying liver fat change.The Dixon proton density fat fraction sequence is frequently used to determine the liver's fat composition.To estimate PDFF across the entire liver, 9 regions of interest (ROIs) of 200 mm2 to 300 mm2 in the area will be placed in the nine liver segments on the PDFF parametric maps.This fat percentage called PDFF is calculated by the following formula; PDFF

= F / (F +W) x 100% The radiological findings will be examined by the radiology investigator who will be blinded to prior liver fat fraction maps.

Liver stiffness measurement (LSM) by Transient Elastography is a non-invasive method to diagnose fibrosis/cirrhosis with high accuracy.

The novelty of utilizing the concept of "drug repositioning" by changing the role of SGLT2 inhibitors in treating DM to treating NAFLD in patients without DM deserves exploration.

The investigators propose a double-blind, randomized, placebo-controlled trial to compare the effects of Dapagliflozin (a type of SLGT2 inhibitors) versus placebo (in a 1:1 ratio) in reducing hepatic fat content as measured by MRI-PDFF in NAFLD patients with Primary Hypothyroidism.

A total of 60 adult patients will be randomly sampled from the Endocrinology/liver/Internal Medicine clinics from our institute. Dapagliflozin 10mg daily will be given to the treatment arm. The placebo pill will be manufactured to be identical in appearance to the study drug. Eligible subjects will be followed up until week 28, and will undergo clinical, anthropometric and laboratory assessments (including Liver function test and Lipid profile) at baseline, week 4, 12 and 28 weeks. They will undergo LSM/CAP at baseline, week 14 and 28, and MRI-PDFF at baseline and week 28. The primary outcome will be a difference in change of liver fat content (measured by MRI-PDFF) at week 28 from baseline between the two groups. The secondary outcomes will be proportion of participants achieving remission of steatosis (MRI-PDFF <5%) at week 28, reduction of liver fibrosis (LSM) and decrease in steatosis by 1 stage at week 14 and 28, improvement of laboratory results (including liver transaminases and ductal enzymes, fasting glucose, HbA1c, lipid profile), improvement of anthropometric measurements, and cardiovascular events.

The study results will determine whether SGLT2 inhibitors can reduce hepatic steatosis and regress fibrosis in NAFLD patients with Primary Hypothyroidism. ;

Related Conditions & MeSH terms

• Fatty Liver
• Hypothyroidism
• Liver Diseases
• Non-Alcoholic Fatty Liver Disease

• NCT number: NCT06373523
• Study type: Interventional
• Source: Post Graduate Institute of Medical Education and Research, Chandigarh
• Contact: Ashu Rastogi, MD,DM
• Phone: 9781001046
• Email: rastogi.ashu@pgi.ac.in
• Status: Not yet recruiting
• Phase: Early Phase 1
• Start date: May 1, 2024
• Completion date: July 30, 2025