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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether the drug diazoxide (also known as Proglycem or Hyperstat) can aid individuals with non-alcoholic fatty liver disease (NAFLD) by lowering high insulin levels. Participants will receive either a low or high dose of diazoxide or a placebo over two weeks. The study will assess how these treatments affect the liver's processing of fat and sugar. Individuals with NAFLD and insulin resistance who are at high risk of the disease are suitable candidates. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants an opportunity to contribute to early-stage medical research.

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.

Is there any evidence suggesting that diazoxide is likely to be safe for humans?

Research has shown that diazoxide is usually well-tolerated in humans. It has been studied for its ability to lower insulin levels, which might help reduce liver fat in people with insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD). Other studies found that diazoxide does not significantly increase blood sugar levels, indicating that its effect on glucose is manageable.

As this is an early-phase trial, the main goal is to assess the safety and tolerability of diazoxide at different doses. Although complete safety data from this study is not yet available, diazoxide's use in other conditions provides some reassurance about its safety. Participants might experience some side effects, but these are usually mild. The trial will examine these safety aspects more closely. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for non-alcoholic fatty liver disease?

Unlike other treatments for non-alcoholic fatty liver disease, which often focus on diet and exercise or medications like vitamin E and pioglitazone, diazoxide acts on a different pathway. This drug is unique because it targets mitochondrial function and insulin sensitivity, which are crucial in reducing liver fat. Researchers are excited about diazoxide because it could offer a more direct way to tackle the underlying metabolic issues associated with this condition, potentially leading to faster and more effective results. Additionally, the study explores two different dosages, which might help in fine-tuning the treatment's efficacy and safety.

What evidence suggests that diazoxide might be an effective treatment for non-alcoholic fatty liver disease?

This trial will evaluate the effects of diazoxide on non-alcoholic fatty liver disease (NAFLD). Research suggests that diazoxide might help with NAFLD by reducing liver damage and improving energy processing in the body. Studies have shown that diazoxide can lower signs of liver injury, potentially protecting the liver. Additionally, diazoxide reduces insulin release, which might help manage insulin resistance—a major issue in NAFLD. While early results are promising, more research is needed to confirm these effects in people with NAFLD. Participants in this trial will receive either a placebo or varying doses of diazoxide to assess its effectiveness. ^{2 3 4 5 6}

Who Is on the Research Team?

Joshua R Cook, MD, PhD

Principal Investigator

Columbia University

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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 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]

Citations

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withpower.com

withpower.com/trial/phase-1-liver-diseases-2-2023-e2692

Diazoxide for Non-alcoholic Fatty Liver Disease

Dapagliflozin significantly reduces liver enzymes (ALT and AST) and improves metabolic outcomes, such as insulin resistance and body weight, in patients with ...

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centerwatch.com

centerwatch.com/clinical-trials/listings/NCT05729282/glycemic-effect-of-diazoxide-in-nafld

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 ...

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clinicaltrials.gov

clinicaltrials.gov/study/NCT06606327?term=diazoxide&rank=4

Diazoxide Suppression Test P&F Study (DzST)

The investigators expect that suppression of insulin secretion with diazoxide will, in accordance with the GIST, lead to no significant rise in blood glucose ...

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allclinicaltrials.com

allclinicaltrials.com/study/NCT05729282

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 ...

5.

sciencedirect.com

sciencedirect.com/science/article/abs/pii/S0022480410003574

Diazoxide Suppresses Hepatic Ischemia/Reperfusion ...

Results. Liver injury, as judged by transaminase level and histologic examination, was significantly lower in the diazoxide group compared with vehicle controls ...

6.

clinicaltrial.be

clinicaltrial.be/en/details/192116?active_not_recruiting=1&completed=0&enrolling_by_invitation=1&only_active=0&only_eligible=0&only_recruiting=1&per_page=100

Glycemic Effect of Diazoxide in NAFLD

As such, despite its potential impact on glucose tolerance, lowering insulin levels might attenuate the pro-steatotic drive in patients with IR.