Pathogenesis of Chronic Kidney Disease Associated With Metabolic Dysfunction- Associated Fatty Liver Disease (MAFLD) and Treatment Response of Oral Semaglutide - a Randomized Controlled Trial.

Official Summary

This project aims to investigate how Chronic Kidney Disease (CKD) develops and progresses in patients who also have Non-Alcoholic Fatty Liver Disease (NAFLD) and to evaluate whether oral semaglutide (a GLP-1 receptor agonist) can slow or prevent this progression. NAFLD and CKD frequently coexist due to shared mechanisms such as insulin resistance, inflammation, oxidative stress, dyslipidemia, and metabolic syndrome. Because of these overlapping pathways, a single therapy targeting both organs may offer major benefits. Semaglutide is known to reduce liver fat, improve inflammation and fibrosis, promote weight loss, and provide renal protection. This project will test whether adding oral semaglutide to standard care leads to better kidney and liver outcomes than standard care alone. The study is designed as a randomised controlled trial conducted at ILBS, enrolling adults having NAFLD with CKD (with specific eGFR and albuminuria criteria). Participants will be followed for 2 years, with regular assessment of kidney function (eGFR, ACR), liver health (FibroScan, ALT/AST), metabolic parameters, and cardiovascular outcomes. A parallel animal study in mice with diet-induced fatty liver disease will validate mechanistic findings through liver and kidney histology, gene expression, metabolic tests, and biochemical markers after semaglutide treatment. Expected outcome: To demonstrate that semaglutide slows CKD progression and improves NAFLD, supporting its use as a therapeutic option for patients with coexisting both conditions.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: DOUBLE
• Enrollment: 90 participants

Interventions

• DRUG: Semaglutide Oral Tablet — GLP1-R agonists GLP1-R agonists (GLP1-RAs) are novel potent antidiabetic agents with proven efficacy in reducing major adverse cardiovascular events. Besides their glucose-lowering action, their beneficial hepatic effects may be related to the influence on the AMPK/mTOR pathway. Semaglutide was associated with significant decreases in body weight, alanine aminotransferase, liver steatosis, and stiffness.GLP1-RAs may also improve histologic features on NAFLD, such as liver fat deposition, steatoh
• OTHER: Placebo — Placebo will be given in the same manner.
• OTHER: Standard medical treatment — Standard medical treatment- 1. Lifestyle first - weight loss , caloric restriction, increased aerobic + resistance exercise, treat obesity and metabolic syndrome. 2. Optimize blood-pressure control and use RAAS blockade when indicated (ACE inhibitor or ARB) to reduce albuminuria and slow CKD progression . 3. Treat dysglycaemia and favour drug classes with kidney + liver benefit when appropriate * SGLT2 inhibitors (dapagliflozin, empagliflozin, canagliflozin) - recommended for people with T2

Primary Outcomes

• Time to first occurrence of a composite primary outcome event defined as persistent eGFR decline of greater than or equal to 50 percentage from trial start, reaching ESRD, death from kidney disease or death from cardiovascular disease. (3 months, 6 months, 12 months,18 months and 24 months)

Secondary Outcomes

• Annual rate of change in eGFR (chronic kidney disease - epidemiology collaboration (CKD-EPI)) (3 months, 6 months, 12 months,18 months and 24 months)
• ime to first occurrence of a composite cardiovascular major adverse cardiovascular event (MACE) endpoint consisting of: Non-fatal myocardial infarction, non-fatal stroke, and cardiovascular (CV) death (3 months, 6 months, 12 months,18 months and 24 months)
• Time to occurrence of all-cause death (3 months, 6 months, 12 months,18 months and 24 months)
• Change in eGFR and proteinuria. (3 months, 6 months, 12 months,18 months and 24 months)
• Annual rate of change in eGFR (CKD-EPI) (chronic eGFR slope) (3 months, 6 months, 12 months,18 months and 24 months)

Trial Locations

• Institute of Liver and Biliary Sciences, New Delhi, National Capital Territory of Delhi, India

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