Glycemic Effect of Diazoxide in NAFLD

Inclusion Criteria

• •1. Adults aged 18-70 years (using highly effective contraception if of childbearing potential)
• •2. Body mass index of 27-50 kg/m2
• •3. Able to understand written and spoken English and/or Spanish
• •4. Able to have pre-randomization screening labs drawn and study protocol initiated within 30 days of informed consent
• •5. Diagnosed with, or clinically judged to be at high risk for, non-alcoholic fatty liver disease (NAFLD), also known as metabolic-associated fatty liver disease (MAFLD), by hepatologist or other qualified physician
• •6. Evidence of insulin resistance, represented by any or all of the following criteria:
• •i. Meeting either of the American Diabetes Association's definitions for prediabetes or IFG on screening labs:
• •1. Prediabetes: Hemoglobin A1c 5.7-6.4%
• •2. IFG: plasma glucose of 100-125 mg dL-1 after ≥ 8-h fast
• •and/or
• •ii. Homeostasis Model of Insulin Resistance (HOMA-IR) score ≥ 2.73
• •7. Fasting hyperinsulinemia (fasting insulin level ≥ 13 µIU/mL) on screening labs
• •8. Written informed consent (in English or Spanish) and any locally required authorization (e.g., Health Insurance Portability and Accountability Act) obtained from the participant prior to performing any protocol-related procedures, including screening evaluations.
• •iv. Clinical concern for absolute insulin deficiency (e.g., type 1 diabetes, pancreatic disease)
• •6. Concerns related to lipid metabolism
• •i. Known diagnoses of familial hypercholesterolemia, familial combined hyperlipidemia, or familial hyperchylomicronemia
• •ii. Use of certain lipid-lowering drugs within the 90 days prior to screening:
• •* Statins or PCSK9 inhibitors for secondary prevention or for treatment of familial hypercholesterolemia. Statins or PCSK9 inhibitors for primary prevention of ASCVD are acceptable.
• •* Fibrates (e.g., fenofibrate, clofibrate, gemfibrozil)
• •* High-dose niacin (\>100 mg daily)
• •7. Known, documented history (i.e., not to be newly screened/tested for study purposes), at the time of screening, of any of the following medical conditions:
• •i. Pancreatic pathology, including but not limited to:
• •* Pancreatic neoplasia, unless appropriately evaluated and considered benign and not producing hormones
• •* Chronic pancreatitis
• •* Acute pancreatitis within the previous 5 years
• •* Autoimmune pancreatitis
• •* Surgical removal of any portion of the pancreas
• •ii. Cardiovascular disease (N.B. uncomplicated hypertension is not exclusionary)
• •* Atherosclerotic cardiovascular disease
• •* Stable or unstable angina
• •* Myocardial infarction
• •* Ischaemic or hemorrhagic stroke, or transient ischaemic attack
• •* Peripheral arterial disease (claudication)
• •* Use of dual antiplatelet therapy (aspirin + P2Y12 inhibitor)
• •* History of percutaneous coronary intervention
• •* Heart rhythm abnormalities
• •* Congestive heart failure of any New York Heart Association class
• •* Symptomatic valvular heart disease (e.g., aortic stenosis)
• •* Pulmonary hypertension
• •iii. Chronic kidney disease, Stage 3 or higher (estimated glomerular filtration rate \< 60 mL/min/1.73 m2), of any cause
• •iv. Chronic liver disease other than uncomplicated NAFLD, including but not limited to:
• •* Advanced liver fibrosis, as determined by non-invasive testing
• •* Cirrhosis of any etiology
• •* Autoimmune hepatitis or other rheumatologic disorder affecting the liver
• •* Biliopathy (e.g., progressive sclerosing cholangitis, primary biliary cholangitis)
• •* Chronic liver infection (e.g., viral hepatitis, parasitic infestation)
• •* Hepatocellular carcinoma
• •* Infiltrative disorders (e.g., sarcoidosis, hemochromatosis, Wilson disease)
• •v. Gout
• •vi. Chronic viral illness (N.B. diagnosis based only on medical history; the investigators will not test for any of these viruses at any point in this study)
• •* Hepatitis B virus (HBV), unless previously successfully eradicated with antiviral drugs that have been discontinued for at least 90 days prior to screening
• •* Hepatitis C virus (HCV) infection, unless previously successfully eradicated with antiviral drugs that have been discontinued for at least 90 d prior to screening
• •* Human immunodeficiency virus (HIV) infection
• •vii. Malabsorptive conditions
• •* Active inflammatory bowel disease (quiescent and off medication is acceptable)
• •* Celiac disease (in remission on gluten-free diet is acceptable)
• •* Surgical removal of a significant length of intestine
• •viii. Active seizure disorder (including controlled with antiepileptic drugs)
• •ix. Psychiatric diseases that:
• •* Are or have been decompensated within 1 year of screening, and/or
• •* Require use of anti-dopaminergic antipsychotic drugs associated with significant weight gain/metabolic dysfunction (e.g., clozapine, olanzapine), monoamine oxidase inhibitors, tricyclic antidepressants, or lithium
• •x. Glucose-6-phosphate dehydrogenase (G6PD) deficiency
• •* Due to presence of quinine in tonic water placebo
• •xi. Other endocrinopathies:
• •* Cushing syndrome (okay if considered in remission after treatment, provided that no exogenous corticosteroids are required)
• •* Adrenal insufficiency
• •* Primary aldosteronism
• •xii. Venous thromboembolic disease (deep vein thrombosis or pulmonary embolism) or any required use of therapeutic anticoagulation
• •xiii. Active malignancy, or hormonally active benign neoplasm, except allowances for:
• •* Non-melanoma skin cancer
• •* Differentiated thyroid cancer (AJCC Stage I only)
• •8. Clinical concern for increased risk of volume overload or hypotension (systolic blood pressure \<95 and/or diastolic blood pressure \<65 mm Hg), including due to medications and/or heart/liver/kidney problems, as listed above
• •9. Use of certain medications currently or within 90 d prior to screening:
• •i. Prescribed medications used for any of the indications in the preceding list of excluded conditions, or their use within 90 d prior to screening, except allowances for:
• •* Statins for primary prevention of cardiovascular disease
• •* Use of drugs prescribed for indications other than the exclusionary diagnoses/purposes listed above (e.g., non-hydantoin antiepileptic drugs used for non-seizure indications, angiotensin converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB) used for uncomplicated hypertension rather than for congestive heart failure, etc.) •• Note, as above, that antidiabetic drugs for any indication (except metformin) within 90 d of screening are excluded
• •ii. Vasodilating drugs for any indication: hydralazine, nitrates, phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil), minoxidil (oral)
• •iii. Phenytoin or fosphenytoin for any indication
• •iv. Oral or parenteral corticosteroids (at greater than prednisone 5 mg daily, or equivalent) for more than 3 days within the previous 90 days; topical and inhaled formulations are permitted
• •v. Fludrocortisone
• •vi. Opioids
• •10. History of certain weight-loss (bariatric) surgeries, including:
• •i. Roux-en-Y gastric bypass
• •ii. Biliopancreatic diversion
• •iii. Restrictive procedures (lap band, sleeve gastrectomy) performed within past 6 months
• •11. Clinical concern for alcohol overuse, including based on chart review and/or by participant's report of consuming more than 14 standard drinks per week for males or more than 7 standard drinks per week for females
• •12. Positive urine drug screen, except for:
• •* Lawfully prescribed medication
• •* Marijuana/THC positivity is okay, provided that the participant agrees not to use it during the same period that they will abstain from alcohol
• •13. History of severe infection or ongoing febrile illness within 30 days of screening
• •14. Any other disease or condition or laboratory value that, in the opinion of the investigator, would place the participant at an unacceptable risk and/or interfere with the analysis of study data.
• •15. Known allergy/hypersensitivity to any component of the medicinal product formulations (including sulfa drugs), other biologics, IV infusion equipment, plastics, adhesive or silicone, history of infusion site reactions with IV administration of other medicines, or ongoing clinically important allergy/hypersensitivity as judged by the investigator.
• •16. Concurrent enrollment in another clinical study of any investigational drug therapy or use of any biologicals within 6 months prior to screening or within 5 half-lives of an investigational agent or biologic, whichever is longer.