MASLD in Primary Hypothyroidism and Efficacy of Dapaglifozin (SHIELD)

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Non-Alcoholic Fatty Liver Disease; Hepatic Steato-Fibrosis
• Intervention / Treatment: Drug: Dapagliflozin 10mg Tab; Drug: Levothyroxine Replacement daily; Drug: Placebo

Detailed 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.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: ASHU RASTOGI, MD,DM; Phone Number: 91 9781001046; Email: rastogi.ashu@pgi.ac.in

Study Locations

• India
  • Punjab
    • Chandigarh, Punjab, India, 160012
      • PGIMER
      • Contact: ASHU RASTOGI, MD,DM; Phone Number: 91 9781001046; Email: rastogi.ashu@pgi.ac.in

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Age 18-75 years
2. Patients with Primary Overt hypothyroidism (Low FT3/Low FT4 and TSH>ULN)

Exclusion Criteria:

1. Patients with Diabetes Mellitus(T1DM AND T2DM)
2. Patient with Secondary Hypothyroidism
3. Patients with other Endocrinopathies who are at risk of MASLD (T1DM and T2DM, Growth Hormone Insufficiency,Cushing Syndrome)
4. Patients with concomitant other etiologies for hepatic steatosis or elevated transaminases (chronic viral hepatitis infection, autoimmune hepatitis, Wilson's disease, hemochromatosis, congestive hepatopathy, primary biliary cholangitis, primary sclerosing cholangitis, biliary tract obstruction)
5. Patient with Drug Induced Liver Injury(DILI)
6. Patients with Decompensated Cirrhosis or Portal hypertensionPatients with Cirrhosis or Portal hypertension
7. Patients with HCC or any other malignancy
8. Drugs like OCPS
9. Patients <18 years of age
10. Patients already on Vitamin E or pioglitazone
11. Pregnancy/Lactation
12. Patients who are too sick to carry out the protocol
13. Those who do not consent to participate in the study

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dapagliflozin Plus levothyroxine Group; Dapagliflozin 10mg daily will be given to the treatment arm in addition to Levothyroxine replacement therapy. 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 14 and week 28. They will undergo LSM and CAP By Transient Elastography at baseline, week 14 and week 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 (MRIPDFF <5%) at week 28, reduction of liver fibrosis (LSM) and decrease in hepatic steatosis by 1 stage at week 14 and 28 and other secondary outcomes as mentioned above.	Drug: Dapagliflozin 10mg Tab; Dapagliflozin 10mg daily will be given to the treatment arm.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 14 and week 28. They will undergo LSM and CAP By Transient Elastography at baseline, week 14 and week 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.; Other Names: Dartdapa; Drug: Levothyroxine Replacement daily; Levothyroxine Replacement daily for 28 weeka; Other Names: LT4
Placebo Comparator: Levothyroxine daily and Placebo pill identical to Dapaglifozin for 28 weeks; The placebo pill will be manufactured to identical in appearance to the Dapaglifozin will be given to the Placebo arm in addition to Levothyroxine replacement therapy. 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 14 and week 28. They will undergo LSM and CAP By Transient Elastography at baseline, week 14 and week 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 hepatic steatosis by 1 stage at week 14 and 28 and other secondary outcomes as mentioned above.	Drug: Levothyroxine Replacement daily; Levothyroxine Replacement daily for 28 weeka; Other Names: LT4; Drug: Placebo; The placebo pills will be manufactured to be identical in appearance to the study drug(Dapaglifozin 10 mg tablet).; Other Names: Placib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in liver fat content	Difference in the change in liver fat content between the two groups at week 28 from the baseline as measured by MRI-PDFF	28 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of participants achieving 1 Stage decrease in steatosis at 6 months asassessed by Transient Elastography	Proportion of participants achieving 1 Stage decrease in steatosis at 6 months as assessed by Transient Elastography	28 weeks
Changes in Improvement in hepatic fibrosis measured by non invasive parameters like Fib4 score at 3 and 6 months	Changes in Improvement in hepatic fibrosis measured by non invasive parameters like Fib4 score at 3 and 6 months	28 weeks
Changes in Lipid Profile at 3 and 6 months	Changes in Lipid Profile at 3 and 6 months	28 weeks

Collaborators and Investigators

• Sponsor: Post Graduate Institute of Medical Education and Research, Chandigarh
• Investigators: Principal Investigator: Ashu Rastogi, MD,DM, PGIMER, Chandigarh

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2024
• Primary Completion (Estimated): June 30, 2025
• Study Completion (Estimated): July 30, 2025

Study Registration Dates

• First Submitted: December 17, 2023
• First Submitted That Met QC Criteria: April 15, 2024
• First Posted (Actual): April 18, 2024

Study Record Updates

• Last Update Posted (Actual): August 9, 2024
• Last Update Submitted That Met QC Criteria: August 8, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Dapaglifozin; MRI-PDFF; Primary hypothyroidism
• Additional Relevant MeSH Terms: Digestive System Diseases; Endocrine System Diseases; Thyroid Diseases; Liver Diseases; Hypothyroidism; Fatty Liver; Non-alcoholic Fatty Liver Disease; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: SHIELD (Other Identifier: Jacobs Institute)

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