Overview

This study is a randomized, double-blind, placebo-controlled trial specifically designed to evaluate the preliminary feasibility, initial efficacy and safety of SGLT2 inhibitors for treating NAFLD in adolescents with obesity.

Eligibility

Inclusion 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)

To be obtained at screening visit:

• 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

Exclusion Criteria:

• •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).