Mechanisms of SGLT2 Inhibition in Pediatric Steatotic Liver Disease

The overall aim of this pilot study is to evaluate the feasibility and obtain a preliminary estimate of efficacy and safety of the SGLT2 inhibitor, empagliflozin, in adolescents with obesity (BMI-percentile ≥95th) who have MRI-confirmed NAFLD (hepatic fat fraction ≥ 5.5%) and have normal fasting glucose.

Participants will take empagliflozin, once daily, in the morning, with or without food, in addition to receiving lifestyle/behavioral counseling throughout the study.

The following data will be collected throughout the course of the study: Physical exam with tanner staging, safety and fasting labs, fasting blood draw (biomarkers), urine sample, 2-stage clamp (overnight Stay),Stable isotope tracers (overnight Stay), MRI scan (MRS-Liver), BMI/anthropometrics, urine pregnancy test for female participants, iDXA scan (body fat and bone density), arterial stiffness and blood pressure.

Inclusion criteria

For clinical referral to screening visit:

• BMI >30 kg/m2 or >95th BMI-Percentile
• Weight Range of 75kg to 150kg
• 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

-washout period 30 days

• 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)

-can re-screen 30 days after getting on birth control

• 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).