Growth Hormone Releasing Hormone Analog to Improve Nonalcoholic Fatty Liver Disease and Associated Cardiovascular Risk

Prior treatment

• Chronic systemic corticosteroid use in the ≤6 months prior to the baseline visit
• Use of physiologic testosterone (men) or estrogen or progesterone (women) unless stable use for a year or more prior to study entry
• Weight loss surgery within 1 year before baseline. Weight loss surgery more than 1 year prior to baseline visit is permissible as long as no active weight loss (\<10% decrease in weight over past 6 months)
• Contraindication to receiving beta-blocker or nitroglycerin (which are part of the coronary angiography)
• Significant radiation exposure, including any history of radiation therapy, or any of the following in the 12 months prior to randomization: a) more than 2 percutaneous coronary interventions; b) more than 2 myocardial perfusion studies; 3) more than 2 computed tomography angiograms
• Active consideration for a procedure or treatment that involves significant radiation exposure as defined above in the 12 months following randomization

Other illness

• Known cirrhosis, Child-Pugh score ≥7, stage 4 fibrosis on biopsy, or clinical evidence of cirrhosis or portal hypertension on imaging or exam. If a subject is not known to be cirrhotic at screen but is found to be cirrhotic based on the results of liver biopsy at baseline, this subject will be referred to a hepatologist for clinical care and will be excluded from further participation in the study.
• Known diagnosis of alpha-1 antitrypsin deficiency, Wilson's disease, hemochromatosis, or autoimmune hepatitis
• Active malignancy
• For men, history of prostate cancer or evidence of prostate malignancy by prostate specific antigen (PSA) \> 5 ng/mL
• Severe chronic illness judged by the investigator to present a contraindication to participation
• History of hypopituitarism, head irradiation or any other condition known to affect the GH axis
• Known hypersensitivity to tesamorelin or mannitol

Lab values

• Known diagnosis of diabetes, use of any anti-diabetic medications (including thiazolidinediones or metformin), fasting glucose \>126mg/dL, or hemoglobin A1c (HbA1c) ≥6.5%. Participants with stable use of metformin ≥6 months will be permitted if it is being used for pre-diabetes or another non-diabetes indication (e.g., PCOS).
• Hemoglobin \< 10.0 g/dL or Creatinine \>1.5mg/dL

Other

• Heavy alcohol use defined as consumption of \> 20 grams daily for women or \> 30 grans daily for men for at least 3 consecutive months over the past 5 years assessed using the Lifetime Drinking History Questionnaire
• Use of any specific pharmacological treatments for NAFLD/nonalcoholic steatohepatitis except vitamin E
• Chronic use of Actigall, methotrexate, amiodarone, or tamoxifen
• Use of growth hormone or growth hormone releasing hormone within the past 6 months
• Change in lipid lowering or anti-hypertensive regimen within 2 months of screening
• Routine magnetic resonance imaging (MRI) exclusion criteria such as the presence of a pacemaker or cerebral aneurysm clip
• For women, positive urine pregnancy test (hCG), trying to achieve pregnancy, or breastfeeding
• For women able to become pregnant, unwillingness to use an acceptable form of birth control during the study.
• Not willing or able to adhere to dose schedules and required procedures per protocol
• Judged by the investigator to be inappropriate for the study for other reasons not detailed above.

• Men and women 18-65yo
• Body mass index (BMI) ≥ 30kg/m2, or, for participants with known steatohepatitis, BMI ≥ 25kg/m2
• Hepatic steatosis as demonstrated by either a) Grade 1+ steatosis on a liver biopsy performed within 12 months of the baseline visit, without \>10% reduction in body weight or addition of medications to treat fatty liver, or b) liver fat fraction ≥5% on hydrogen-magnetic resonance spectroscopy (1H-MRS)
• Hepatitis C antibody and Hepatitis B surface antigen negative. Subjects without known history of Hepatitis C or Hepatitis C treatment who have a positive Hepatitis C antibody but a negative hepatitis C viral load will also be eligible.
• For females ≥50yo, negative mammogram within 1 year of baseline
• If use of vitamin E ≥400 international units daily, stable dose for ≥6 mos
• Up to date with colon cancer screening recommended by the participant's primary care physician, using whatever methodology the primary physician recommends. This will be ascertained by self-report. (If a participant does not have a primary care physician, we will discuss that colon cancer screening is recommended, typically starting at age 50y, and refer the participant to primary care through Partners if s/he desires.)