Mechanisms of SGLT2 Inhibition in Pediatric Steatotic Liver Disease

Eligibility Criteria

• * For clinical referral to screening visit:
• * BMI \>30 kg/m2 or \>95th BMI-Percentile
• * Age 16 to \<21 at baseline
• * Elevated alanine aminotransferase (ALT) more than twice the upper limit of normal by gender (≥ 44 U/L for girls, ≥ 50 U/L for boys)63 within 3 months prior to screening (used for historic ALT value) OR diagnosis of NAFLD from ultrasound, MRI, or participants with biopsy-proven NASH within 12 months of screening.
• * History of lifestyle modification to treat obesity or NAFLD.
• * Tanner stage \>2
• * Normal fasting glucose (fasting blood glucose \<100 mg/dL)
• * Confirmation of obesity;
• * Tanner stage 2,3,4 or 5;
• * Normal fasting glucose tolerance (fasting blood glucose \<100 mg/dL);
• * If Screening ALT is used as inclusion criteria (if \> 2x historic ALT value (historical value obtained clinically within 12 months of screening visit), repeated after 4 weeks \[unable to randomize until completed\]. If the repeat ALT is more than 50% increased or decreased over the screening ALT, a third ALT should be obtained. If a third ALT is not within 50% of the previous value, then the subject is ineligible but may be rescreened at a later date. If
• * ALT is not used:
• * An ultrasound will be done to diagnose NAFLD if the diagnosis has not previously been made by ultrasound, MRI or biopsy.
• * A MRI-derived HFF ≥ 5.5%
• * Willingness to adhere to lifestyle considerations throughout the study
• * •ALT \> 250U/L at screening
• * History of significant alcohol intake or current use
• * Impaired fasting glucose (\>100 mg/dL)
• * Diabetes (type 1 or 2)
• * Current or recent (\<6 months prior to enrollment) use of weight loss medication(s)
• * Vitamin E supplementation or use of metformin
• * Previous bariatric surgery
• * Prior use of empagliflozin
• * Lower limb infection/ulceration within 3 months of screening
• * Metal or magnetic implants, devices or objects inside of or on the body, which are not MRI compatible
• * Structural and functional urogenital abnormalities, that predispose for urogenital infections
• * Recent initiation (\<3 months prior to enrollment) of anti-hypertensive or lipid medication(s)
• * Major psychiatric disorder
• * Known hypothalamic or pituitary dysfunction
• * Current pregnancy or plans to become pregnant
• * Females unwilling to be tested for pregnancy
• * Females who are sexually active and not protects by an effective method of birth control (e.g. UID or medication or patch)
• * Tobacco use
• * Significant liver dysfunction (levels \>5 times the upper limit of normal (ULN)):
• * ALT (ULN = 50 U/L)
• * AST (ULN = 48 U/L)
• * GGT (ULN = 48 U/L)
• * ALP (ULN = 115 U/L)
• * Platelets \< 150,000 cells/mm3
• * Total bilirubin 1.3 mg/dL
• * INR 1.3
• * Albumin \<3.2 g/dL
• * Gilbert's Syndrome
• * Any known causes of liver disease (except NAFLD and NASH)
• * Significant renal dysfunction (estimated glomerular filtration rate \[eGFR\] \< 80 mL/min/1.73 m2),
• * Diagnosed monogenic obesity
• * History of cancer
• * Untreated thyroid disorder
• * History of decompensation events (ascites, variceal bleeding, hepatic encephalopathy, or hepatocellular carcinoma)
• * Current or recent (\<6 months prior to enrollment) use of medication(s) associated with weight gain (e.g. atypical anti-psychotics).