Control strategies and pharmacogenetic study for the personalized treatment of fatty liver associated with metabolic dysfunction in patients with prediabetes.

INTERVENTION: Trade Name: metformin hydrochloride Pharmaceutical Form: Tablet Pharmaceutical form of the placebo: Tablet Route of administration of the placebo: Oral use Trade Name: pioglitazone hydrochloride Pharmaceutical Form: Tablet Pharmaceutical form of the placebo: Tablet Route of administration of the placebo: Oral use CONDITION: Metabolic Associated Fatty Liver Disease with prediabetes. Therapeutic area: Body processes [G] ‐ Metabolic Phenomena [G03] PRIMARY OUTCOME: Main Objective: To determine which of the three models of therapeutic intervention induces a greater sustained regression of fatty liver associated with long‐term metabolic disease (18 months) measured by non‐invasive techniques (MRI) in patients with Metabolic Associated Fatty Liver Disease and prediabetes. Primary end point(s): Significant decrease in the amount of intrahepatic fat (> 20%) in the absence of liver fibrosis progression. Secondary Objective: • Investigate whether the variations of the 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.; • Explore the changes induced by diet and each pharmacological treatment in the concentration of metabolites derived from mitochondrial function, intestinal microbiota.; • To determine whether the 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.; • Establish which of the three models of therapeutic intervention induces an improvement in the pathogenic factors associated with the development of non‐alcoholic fatty liver: peripheral insulin resistance, hepatic insulin resistance, adipose tissue dysfunction, intestinal microbiota. Timepoint(s) of evaluation of this end point: Baseline and at 18 months of treatment SECONDARY OUTCOME: Secondary end point(s): 1‐ Study of insulin resistance and adipose tissue dysfunction:; 2‐ Search for non‐invasive markers of efficacy of the proposed treatments among circulating metabolites (metabolomic and lipidomic methods).; 3‐ Study of the intestinal microbiota.; 4‐ Pharmacogenetic study: influence of genetic variations on the degree of therapeutic response to drugs.; 5‐ Study of bioimpedanciometry.; 6‐ Collection of adverse events potentially related to the medication and its administration. Timepoint(s) of evaluation of this end point: 1. At Baseline, at 12 months and at 18 months of treatment.; 2. Baseline and at 18 months of treatment.; 3. Baseline and at 18 months of treatment.; 4. Baseline.; 5. Baseline, at 8 months and at 18 months.; 6. From Baseline to 30 days after end of treatment, or study withdrawn. INCLUSION CRITERIA: 1. Patients with HGADM according to the clinical criteria of the International Expert Consensus Statement. 2. Age from 18 to 75 years. 3. Men and postmenopausal women. 4. Evidence of significant nonalcoholic fatty liver disease, defined by a proportional attenuation of the intrahepatic signal> 10% observed by magnetic resonance imaging. 5. Overweight or obese with BMI 25‐40 kg / m2 6. Presence of Prediabetes according to the ADA criteria (fasting blood glucose 100‐125 mg / dl or HbA1c 5.7% ‐6.4% or blood glucose 140‐199 mg / dl at 2 hours after SOG). Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 293 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 97