Glycemic Effect of Diazoxide in NAFLD

The goal of this clinical trial is to compare a two-week course of diazoxide (at two different doses) and placebo in people with insulin resistance-associated non-alcoholic fatty liver disease (IR-NAFLD). The main questions it aims to answer are how mitigation of compensatory hyperinsulinemia with diazoxide affects parameters of glucose and lipid metabolism (how people with IR-NAFLD respond to lowering high insulin levels so that the investigators can see what happens to how the liver handles fat and sugar).Participants will:Take 27 doses of diazoxide (at 1 mg per kg of body weight per dose [mpk] or 2 mpk) or of placebo, over 14 daysHave blood drawn after an overnight fast on six mornings over the two-week study periodConsume their total calculated daily caloric needs as divided into three meals per dayWear a continuous glucose monitor for the two-week study periodResearchers will compare fasting blood tests at intervals during the study period in participants randomized (like the flip of a coin) to diazoxide 1 mpk, diazoxide 2 mpk, or placebo, to see how the drug treatment affects plasma glucose, serum insulin, and serum lipid parameters (triglycerides, free fatty acids, and apolipoprotein B).

Inclusion Criteria:Adults aged 18-65 years (using highly effective contraception if of childbearing potential)Body mass index of 27.0-35.0 kg/m2Able to understand written and spoken English and/or SpanishAble to have pre-randomization screening labs drawn and study protocol initiated within 14 days of informed consentDiagnosed with non-alcoholic fatty liver disease (NAFLD), also known as metabolic-associated fatty liver disease (MAFLD), by hepatologist or other qualified specialist physician and the condition is listed as an active problem in the electronic medical recordMeeting either of the American Diabetes Association's definitions for prediabetes or impaired fasting glucose (IFG) on screening labs:i. Prediabetes: Hemoglobin A1c (HbA1c) 5.7-6.4%ii. IFG: plasma glucose of 100-125 mg/dL after ≥ 8-h fastFasting hyperinsulinemia (fasting insulin level ≥ 15 µIU/mL) on screening labsWritten 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.Exclusion Criteria:Unable to provide informed consent in English or SpanishConcerns arising at screening visit (any of the following):i. Weight loss of ≥ 3.0% of baseline within the previous 6 monthsii. Abnormal blood pressure (including on treatment, if prescribed)Systolic blood pressure < 95 mm Hg or > 160 mm Hg, and/orDiastolic blood pressure < 65 mm Hg or > 100 mm Hgiii. Abnormal resting heart rate ≤ 60 bpm or ≥ 100 bpm• Sinus brady- or tachycardia that has been appropriately evaluated and considered benign by the recruit's personal physician may be permitted at PI's discretioniv. Abnormal screening electrocardiogram (or if on file, performed within previous 90 d) • Non-sinus rhythm • Significant corrected QT segment (QTc) prolongation (≥ 480 ms)New or previously unknown ischaemic changes that persist on repeat EKG:•• ST segment elevations•• T-wave inversionsv. Laboratory evidence of diabetes mellitus:Hemoglobin A1c ≥ 6.5%, and/orFasting plasma glucose ≥ 126 mg/dLvi. Positive qualitative serum β-hCG (human chorionic gonadotropin, beta subunit; i.e., pregnancy test) in women of childbearing potentialvii. Liver function abnormalitiesTransaminases (AST or ALT) > 2.0 x the upper limit of normal, and/orTotal bilirubin > 1.25 x the upper limit of normalviii. Abnormal screening lipidsTriglycerides > 400 mg/dL, and/orLDL-cholesterol > 190 mg/dLix. Abnormal screening serum electrolytes (any of the following)• Sodium, potassium, chloride, or bicarbonate outside of the reference rangeCreatinine equating to estimated glomerular filtration rate < 60 mL/min/1.73 m2x. Abnormal screening thyroid-stimulating hormone (TSH) level (≥10 mIU/L or < LLN)Exempt from TSH screening if previously obtained value within 2 months of screening is availablexi. Uric acid level > upper limit of normalxii. Glucose-6-phosphate dehydrogenase < lower limit of normalCOVID-19 precautionsi. Not fully vaccinated against COVID-19 (4 doses if age ≥ 50, 3 doses if ages 18-49)ii. Unwillingness to comply with masking requirements per hospital policyiii. Active, documented COVID-19 at any time after screeningReproductive concernsi. Women of childbearing potential not using highly effective contraception, defined as:Surgical sterilization (e.g., bilateral tubal occlusion, bilateral oophorectomy and/or salpingectomy, hysterectomy)Combined oral contraceptive pills taken daily, including during the studyIntrauterine device (levonorgestrel-eluting or copper) active at the time of the studyMedroxyprogesterone acetate (Depo-Provera®) injection active at the time of the studyEtonogestrel implants (e.g., Implanon®, etc.) active at the time of the studyNorelgestromin/ethinyl estradiol transdermal system (e.g., Ortho-Evra®) active at the time of the studyii. Women currently pregnant (tested by serum and/or urine β-hCG)iii. Women currently breastfeedingConcerns related to glucose metabolismi. History of having met any of the American Diabetes Association's definitions of diabetes mellitus (i.e., overt diabetes):Hemoglobin A1c ≥ 6.5%, or rapid rise in documented HbA1c values causing clinical concern for evolving insulin deficiencyPlasma glucose ≥ 126 mg/dL after 8-h fastPlasma glucose of ≥ 200 mg/dL at 2 h after ingestion of a 75-g glucose loadRandom plasma glucose ≥ 200 mg/dL associated with typical hyperglycemic symptoms, diabetic ketoacidosis, or hyperglycemic-hyperosmolar stateii. History of gestational diabetes mellitusiii. Use of antidiabetic medications within the 90 days prior to screening, including those prescribed for other indications (e.g., weight control, restoration of ovulation in of polycystic ovarian syndrome), including: • Metformin, thiazolidinediones, sulfonylureas, meglitinides, dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, sodium-glucose cotransporter 2 (SGLT2) inhibitors, amylin mimetics, acarbose, insuliniv. Clinical concern for absolute insulin deficiency (e.g., type 1 diabetes, pancreatic disease)Concerns related to lipid metabolismi. Known diagnoses of familial hypercholesterolemia, familial combined hyperlipidemia, or familial hyperchylomicronemiaii. Use of lipid-lowering drugs other than statins for primary prevention within the 90 days prior to screening, including:Statins for secondary prevention or treatment of familial hypercholesterolemiaPCSK9 inhibitors (alirocumab, evolocumab, inclisiran) (for inclisiran, use within the previous year is exclusionary)Fibrates (e.g., fenofibrate, clofibrate, gemfibrozil)High-dose niacin (>100 mg daily)Fish oils or purified supplements of omega-3 fatty acidsVitamin E supplementsKnown, 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 neoplasiaChronic pancreatitisAcute pancreatitis within the previous 5 yearsAutoimmune pancreatitisSurgical removal of any portion of the pancreasii. Cardiovascular disease (N.B. uncomplicated hypertension is not exclusionary)Atherosclerotic cardiovascular diseaseStable or unstable anginaMyocardial infarctionIschaemic or hemorrhagic stroke, or transient ischaemic attackCarotid artery stenosis on imagingPeripheral arterial disease (claudication)Use of dual antiplatelet therapy (aspirin + P2Y12 inhibitor)History of percutaneous coronary interventionHeart rhythm abnormalitiesCongestive heart failure of any New York Heart Association classValvular heart disease (e.g., aortic stenosis)Pulmonary hypertensioniii. Chronic kidney disease, Stage 2 or higher (estimated glomerular filtration rate < 60 mL/min/1.73 m2), of any causeiv. Chronic liver disease other than uncomplicated NAFLD, including but not limited to:Advanced liver fibrosis, as determined by non-invasive testingCirrhosis of any etiologyAutoimmune hepatitis or other rheumatologic disorder affecting the liverBiliopathy (e.g., progressive sclerosing cholangitis, primary biliary cholangitis)Chronic liver infection (e.g., viral hepatitis, parasitic infestation)Hepatocellular carcinomaInfiltrative disorders (e.g., sarcoidosis, hemochromatosis, Wilson disease)v. Goutvi. 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 screeningHepatitis C virus (HCV) infection, unless previously successfully eradicated with antiviral drugs that have been discontinued for at least 90 d prior to screeningHuman immunodeficiency virus (HIV) infectionvii. Malabsorptive conditionsActive 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 intestineviii. Active seizure disorder (including controlled with antiepileptic drugs)ix. Psychiatric diseases that…Are or have been decompensated within 1 year of screening, and/orRequire use of anti-dopaminergic antipsychotic drugs, monoamine oxidase inhibitors, tricyclic antidepressants, or lithiumx. Glucose-6-phosphate dehydrogenase (G6PD) deficiencyDue to presence of quinine in tonic water placeboxi. Other endocrinopathies:Cushing syndrome (okay if considered in remission after treatment, provided that no exogenous corticosteroids are required)Adrenal insufficiencyPrimary aldosteronismThyroid diseaseHypothyroidism if thyroid-stimulating hormone (TSH) ≥ 10 mIU/L, with or without treatmentHyperthyroidism (TSH < lower limit of normal), with or without treatmentxii. Venous thromboembolic disease (deep vein thrombosis or pulmonary embolism) or any required use of therapeutic anticoagulationxiii. Active malignancy, or hormonally active benign neoplasm, except allowances for:Non-melanoma skin cancerDifferentiated thyroid cancer (AJCC Stage I only)Clinical concern for increased risk of volume overload or hypotension (systolic blood pressure <90 and/or diastolic blood pressure <60 mm Hg), including due to medications and/or heart/liver/kidney problems, as listed aboveUse 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:Levothyroxine treatment of hypothyroidism, if TSH < 10 mIU/L at screeningStatins for primary prevention of cardiovascular diseaseUse 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 within 90 d of screening are excludedii. Thiazide diuretics, loop diuretics, or beta blockers for any indication• Note, as above, that other antihypertensive drugs (e.g., ACEi/ARB, calcium channel blockers, pure alpha blockers) are permittediii. Vasodilating drugs for any indication: hydralazine, nitrates, phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil), minoxidil (oral)iv. Phenytoin or fosphenytoin for any indicationv. 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 permittedvi. Fludrocortisonevii. OpioidsHistory of weight-loss (bariatric) surgery, including:i. Adjustable lap bandingii. Vertical sleeve gastrectomyiii. Roux-en-Y gastric bypassiv. Biliopancreatic diversionClinical concern for alcohol overuse, including phosphatidylethanol ≥ 0.05 µmol/L at screening 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 femalesPositive urine drug screenTobacco smoking currently or within the previous 6 monthsHistory of severe infection or ongoing febrile illness within 30 days of screeningAny 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.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.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.