Diazoxide for Non-alcoholic Fatty Liver Disease

Overseen By Zachary Sone

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Columbia University

Must not be taking: Antidiabetics, Lipid-lowering, Vasodilators, others

Disqualifiers: Diabetes, Cardiovascular disease, Liver disease, others

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: 2 weeks

72 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop taking most antidiabetic medications (except metformin) and certain lipid-lowering drugs within 90 days before screening. If you're on these medications, you may need to stop them to participate.

How is the drug Diazoxide unique for treating non-alcoholic fatty liver disease?

Diazoxide is unique for treating non-alcoholic fatty liver disease because it is primarily known for its use in managing conditions like high blood pressure and low blood sugar, rather than liver diseases. This makes its application in liver disease novel, as there are no approved drugs specifically for non-alcoholic fatty liver disease. ^{1 2 3 4 5}

What is the purpose of this trial?

The goal of this clinical trial is to compare a two-week course of diazoxide (at two different doses) and placebo in people with overweight/obesity and insulin resistance (IR) with, or at high risk for, non-alcoholic fatty liver disease (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 and 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 days * Take 32 doses of heavy (deuterated) water (50 mL each) over 14 days * Have blood drawn and saliva collected after an overnight fast on four mornings over the two-week study period * Consume their total calculated daily caloric needs as divided into three meals per day * Wear a continuous glucose monitor for the two-week study period Researchers 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). They will also consume heavy (deuterated) water to assess de novo lipogenesis (building of new fatty acids by the liver).

Research Team

Joshua R Cook, MD, PhD

Principal Investigator

Columbia University

Eligibility Criteria

Adults aged 18-70 with overweight/obesity and insulin resistance, at high risk for or diagnosed with NAFLD. Must have prediabetes indicators like fasting plasma glucose of 100-125 mg/dL or HbA1c of 5.7-6.4%. Excludes those with diabetes, abnormal heart rates, recent significant weight loss, certain medical conditions including active COVID-19 within screening period, psychiatric diseases decompensated within a year, known allergies to trial drugs, and women not using effective contraception.

Inclusion Criteria

Able to have pre-randomization screening labs drawn and study protocol initiated within 30 days of informed consent

I have signs of insulin resistance, such as prediabetes or high fasting insulin.

Body mass index of 25.0-39.9 kg/m2

Exclusion Criteria

I can provide informed consent in English or Spanish.

Concerns arising at screening visit including documented weight loss of ≥ 5.0% of baseline within the previous 6 months, abnormal blood pressure, abnormal resting heart rate, abnormal screening electrocardiogram, laboratory evidence of diabetes mellitus, positive qualitative serum β-hCG in women of childbearing potential, liver function abnormalities, abnormal screening triglycerides, abnormal screening serum electrolytes, uric acid level above the upper limit of normal, glucose-6-phosphate dehydrogenase below the lower limit of normal, unwillingness to comply with masking requirements per hospital policy, active, documented COVID-19 at any time after screening, women of childbearing potential not using highly effective contraception, women currently pregnant, women currently breastfeeding, history of having met any of the American Diabetes Association's definitions of diabetes mellitus, history of gestational diabetes mellitus within the previous 5 years, use of most antidiabetic medications within the 90 days prior to screening, clinical concern for absolute insulin deficiency, known diagnoses of familial hypercholesterolemia, familial combined hyperlipidemia, or familial hyperchylomicronemia, use of certain lipid-lowering drugs within the 90 days prior to screening, known, documented history of certain medical conditions at the time of screening, concerns related to glucose metabolism, concerns related to lipid metabolism, known allergy/hypersensitivity to any component of the medicinal product formulations, 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

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive diazoxide or placebo for 14 days to assess the impact on glucose and lipid metabolism

2 weeks

4 visits (in-person) for blood draws and saliva collection

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 weeks

Treatment Details

Interventions

• Diazoxide

Trial Overview The trial tests diazoxide's effect on glucose and lipid metabolism in people with insulin resistance and NAFLD over two weeks. Participants will take diazoxide (1 or 2 mg per kg) or placebo daily while monitoring blood sugar continuously and having regular blood draws to measure the impact on plasma glucose and serum lipids.

Participant Groups

Group I: Diazoxide oral suspension, 2 mg per kg per dose Experimental Treatment 3 Interventions

Participants will ingest diazoxide oral suspension at 2 mg per kg body weight per dose (27 doses over 14 days). Blinding will occur by completely covering single-dose oral syringes with labels.

Group II: Diazoxide oral suspension, 1 mg per kg per dose Experimental Treatment 3 Interventions

Participants will ingest diazoxide oral suspension at 1 mg per kg body weight per dose (27 doses over 14 days). Blinding will occur by completely covering single-dose oral syringes with labels.

Group III: Placebo Placebo Group 3 Interventions

Participants will ingest a placebo solution (27 doses over 14 days) formulated to approximate the taste of diazoxide oral suspension. Blinding will occur by completely covering single-dose oral syringes with labels.

Diazoxide is already approved in United States for the following indications:

Approved in United States as Proglycem for:

• Hypoglycemia

Who Is Running the Clinical Trial?

Columbia University

Lead Sponsor

Trials

1,529

Recruited

2,832,000+

University of California, Berkeley

Collaborator

Trials

193

Recruited

716,000+

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Collaborator

Trials

2,513

Recruited

4,366,000+

Findings from Research

Dapagliflozin significantly reduces liver enzymes (ALT and AST) and improves metabolic outcomes, such as insulin resistance and body weight, in patients with nonalcoholic fatty liver disease (NAFLD), based on a meta-analysis of seven trials involving 390 participants.

While dapagliflozin shows efficacy in improving liver function and metabolic health, it may also lead to an increase in total cholesterol levels, with no significant difference in adverse events compared to control groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of dapagliflozin in patients with nonalcoholic fatty liver disease: A systematic review and meta-analysis of randomized controlled trials. Sun, L., Deng, C., Gu, Y., et al.[2022]

In a study of 16 patients with NASH and type 2 diabetes, dapagliflozin treatment for 24 weeks led to significant reductions in body mass index, waist circumference, and body fat, indicating improved body composition.

Dapagliflozin also resulted in significant improvements in liver function tests and metabolic markers, including decreased insulin and fasting plasma glucose levels, suggesting it may be an effective treatment for managing NASH in patients with type 2 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Dapagliflozin on Body Composition and Liver Tests in Patients with Nonalcoholic Steatohepatitis Associated with Type 2 Diabetes Mellitus: A Prospective, Open-label, Uncontrolled Study. Tobita, H., Sato, S., Miyake, T., et al.[2022]

A systematic review of 29 randomized controlled trials involving 2,617 individuals found that certain anti-hyperglycaemic agents, particularly pioglitazone and liraglutide, can improve liver histology in patients with non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

While most anti-hyperglycaemic drugs improved liver enzyme levels, pioglitazone was noted for its potential benefits on liver fibrosis, although caution is advised due to associated weight gain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of anti-hyperglycaemic drugs in patients with non-alcoholic fatty liver disease with or without diabetes: An updated systematic review of randomized controlled trials. Mantovani, A., Byrne, CD., Scorletti, E., et al.[2021]

In a study of 43 patients with type 2 diabetes and non-alcoholic fatty liver disease, treatment with ipragliflozin for 24 weeks led to significant reductions in body weight, hemoglobin A1c, and liver enzymes, indicating improved liver health.

Ipragliflozin was effective in reducing liver steatosis and body fat without affecting muscle mass, suggesting it may be a safe treatment option for managing NAFLD in diabetic patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipragliflozin Ameliorates Liver Damage in Non-alcoholic Fatty Liver Disease. Miyake, T., Yoshida, S., Furukawa, S., et al.[2022]

Metformin, when combined with weight loss, provides modest improvements in liver fat (steatosis) but does not improve liver scarring (fibrosis) in patients with nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM).

Thiazolidinediones (TZDs) show positive effects on liver fibrosis and resolution of nonalcoholic steatohepatitis (NASH), although many patients may not respond, indicating the need for long-term treatment to maintain benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treating nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus: a review of efficacy and safety. Mills, EP., Brown, KPD., Smith, JD., et al.[2022]

References

1. France pubmed.ncbi.nlm.nih.gov

Effects of dapagliflozin in patients with nonalcoholic fatty liver disease: A systematic review and meta-analysis of randomized controlled trials. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Effects of Dapagliflozin on Body Composition and Liver Tests in Patients with Nonalcoholic Steatohepatitis Associated with Type 2 Diabetes Mellitus: A Prospective, Open-label, Uncontrolled Study. [2022]

3. France pubmed.ncbi.nlm.nih.gov

Efficacy and safety of anti-hyperglycaemic drugs in patients with non-alcoholic fatty liver disease with or without diabetes: An updated systematic review of randomized controlled trials. [2021]

4. Poland pubmed.ncbi.nlm.nih.gov

Ipragliflozin Ameliorates Liver Damage in Non-alcoholic Fatty Liver Disease. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Treating nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus: a review of efficacy and safety. [2022]