Evaluation of Pioglitazone and Metformin Hydrochloride in Metabolic Associated Fatty Liver Disease with Prediabetes: A Pharmacogenetic Approach

The primary objective of this study is to determine which of the three models of therapeutic intervention induces a greater sustained regression of **fatty liver** associated with long-term metabolic disease over 18 months. This is measured by non-invasive techniques such as MRI in patients with Metabolic Associated Fatty Liver Disease and prediabetes. This objective is clinically relevant as it aims to identify the most effective treatment strategy for reducing liver fat accumulation, which is a critical factor in managing metabolic dysfunction and preventing progression to more severe liver conditions.

Secondary objectives include:

• Investigating whether variations in genes involved consistently determine and/or condition the degree of response to dietary treatment with a hypocaloric Mediterranean diet and to drug treatment with metformin and pioglitazone.
• Exploring the changes induced by diet and each pharmacological treatment in the concentration of metabolites derived from mitochondrial function and intestinal microbiota.
• Determining whether changes in the concentration of alpha-ketoglutarate and other metabolites derived from the mitochondria, induced by the therapeutic intervention models, are associated with the progression or regression of fatty liver.
• Establishing which of the three models of therapeutic intervention induces an improvement in the pathogenic factors associated with the development of non-alcoholic fatty liver, including peripheral insulin resistance, hepatic insulin resistance, adipose tissue dysfunction, and intestinal microbiota.

The clinical trial involves participants diagnosed with **Metabolic Associated Fatty Liver Disease** and prediabetes. The study population includes both men and postmenopausal women aged between 18 and 75 years. Participants are required to have evidence of significant nonalcoholic fatty liver disease, as determined by magnetic resonance imaging, and must be overweight or obese with a body mass index (BMI) ranging from 25 to 40 kg/m². The presence of prediabetes is confirmed according to the American Diabetes Association criteria. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria focus on specific health conditions and demographic factors, ensuring a targeted study group for evaluating therapeutic interventions over an 18-month period.

The clinical trial is designed to evaluate the efficacy of different therapeutic interventions in patients with **Metabolic Associated Fatty Liver Disease** and prediabetes. This study is a randomized, double-blind, controlled trial with a duration of 18 months. Participants will be randomly assigned to one of the three intervention groups, each receiving a specific treatment regimen. The primary objective is to determine which intervention induces a greater sustained regression of fatty liver, as measured by non-invasive techniques such as MRI. Secondary endpoints include the study of insulin resistance, adipose tissue dysfunction, and the search for non-invasive markers of treatment efficacy.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, presence of prediabetes, and evidence of significant nonalcoholic fatty liver disease. Follow-up visits will be scheduled at regular intervals to monitor the participants' health, adherence to the treatment regimen, and any adverse events. The end-of-study visit will occur at the conclusion of the 18-month period, where final assessments will be conducted to evaluate the primary and secondary endpoints.

The expected length of participant involvement is 18 months, with conditions for early termination including significant adverse events or non-compliance with the study protocol. Participants will receive oral administration of either **Pioglitazone Holsten 15 mg tablets** or **Metformin Hydrochloride 500mg tablets**, with the maximum daily doses being 15 mg and 1 g, respectively. The trial aims to provide insights into the personalized treatment of fatty liver associated with metabolic dysfunction, contributing to the development of more effective therapeutic strategies.

The clinical trial involves the administration of **Pioglitazone Holsten 15 mg tablets** as an experimental medication. Pioglitazone is a thiazolidinedione class drug, chemically synthesized, and is administered in the form of oral tablets. Each tablet contains 15 mg of the active substance, pioglitazone. The maximum daily dose is 15 mg, and the treatment period extends up to 18 months. The medication is produced by Holsten Pharma GmbH and is authorized for use in Sweden. Participants are required to take the medication orally, and compliance with the dosing schedule is monitored throughout the study.

In addition to pioglitazone, the study also utilizes **Metformin Hydrochloride 500 mg tablets** as a comparator treatment. Metformin is a biguanide class drug, also chemically synthesized, and is administered orally in tablet form. Each tablet contains 500 mg of metformin hydrochloride, with a maximum daily dose of 1 g. The treatment duration is consistent with that of pioglitazone, lasting up to 18 months. This medication is manufactured by HFA Holdings Limited and is authorized for use in the United Kingdom. Participants are instructed to take the medication orally, and adherence to the prescribed dosing regimen is closely monitored to ensure compliance.

Efficacy in this clinical trial will be assessed through both primary and secondary endpoints. The primary endpoint is defined as a significant decrease in the amount of intrahepatic fat, specifically a reduction greater than 20%, without progression of liver fibrosis. This will be measured using non-invasive techniques, specifically magnetic resonance imaging (MRI), to evaluate changes in liver fat content over the course of the 18-month treatment period.

Secondary endpoints include a comprehensive study of insulin resistance and adipose tissue dysfunction, as well as the identification of non-invasive markers of treatment efficacy through metabolomic and lipidomic methods. Additionally, the trial will investigate the intestinal microbiota and conduct a pharmacogenetic study to assess the influence of genetic variations on the therapeutic response to drugs. Bioimpedanciometry will also be utilized to gather further data. Adverse events potentially related to the medication and its administration will be systematically collected and analyzed.