SGLT2 Inhibitors as a Novel Treatment for Pediatric Non-Alcoholic Fatty 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: Physicial exam with
tanner staging, safety and fasting labs, fasting blood draw (biomarkers), urine sample, stool
sample, OGTT, CGM sensor placement and removal, MRI scan (MRS-Liver), BMI/anthropometrics,
urine pregnancy test for female pcpts, iDXA scan (body fat and bone dennsity), arterial
stiffness and blood pressure.

Inclusion Criteria:

For clinical referral to screening visit:

1. Age: 12-17 years old

2. Diagnosis of Obesity: BMI-percentile ≥95th (using age- and sex- based Center for
Disease Control definitions) or BMI ≥30 kg/m2

3. Elevated alanine aminotransferase (ALT) more than twice the upper limit of normal by
gender (≥44 U/L for girls, ≥50 U/L for boys)61 within 3 months prior to screening
(used for historic ALT value)

4. Diagnosis of NAFLD from ultrasound, MRI, or participants with biopsy-proven NASH
within 12mo of screening.

5. History of lifestyle modification to treat obesity or NAFLD

To be obtained at screening visit:

1. Confirmation of Obesity

2. Tanner stage ≥ 2

3. Normal fasting glucose tolerance (fasting blood glucose <100 mg/dL)

4. Screening ALT (if > 2x historic ALT value, 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

5. A MRI-derived HFF ≥ 5.5%

6. Willingness to adhere to lifestyle considerations throughout the study

Exclusion Criteria:

1. ALT > 250U/L at screening

2. History of significant alcohol intake or current use

3. Impaired fasting glucose (>100 mg/dL)

4. Diabetes (type 1 or 2)

5. Current or recent (<6 months prior to enrollment) use of weight loss medication(s)

6. Vitamin E supplementation

7. Previous bariatric surgery

8. Use of metformin

9. Recent initiation (<3 months prior to enrollment) of anti-hypertensive or lipid
medication(s)

10. Major psychiatric disorder

11. Known hypothalamic or pituitary dysfunction

12. Current pregnancy or plans to become pregnant

13. Females unwilling to be tested for pregnancy

14. Females who are sexually active and not protects by an effective method of birth
control (e.g. UID or medication or patch)

15. Tobacco use

16. Significant liver dysfunction (levels >5 times the upper limit of normal (ULN)):

17. ALT (ULN = 50 U/L)

18. AST (ULN = 48 U/L)

19. GGT (ULN = 48 U/L)

20. ALP (ULN = 115 U/L)

21. Platelets < 150,000 cells/mm3

22. Total bilirubin 1.3 mg/dL

23. INR 1.3

24. Albumin <3.2 g/dL

25. Gilbert's Syndrome

26. Any known causes of liver disease (except NAFLD and NASH)

27. Significant renal dysfunction (estimated glomerular filtration rate [eGFR] < 90
mL/min/1.73 m2),

28. Diagnosed monogenic obesity

29. History of cancer

30. Untreated thyroid disorder

31. History of decompensation events (ascites, variceal bleeding, hepatic encephalopathy,
or hepatocellular carcinoma)

32. Current or recent (<6 months prior to enrollment) use of medication(s) associated with
weight gain (e.g. atypical anti-psychotics)