Diazoxide for Hyperinsulinemia

(DzST Trial)

Overseen By Zachary D Sone

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Columbia University

Must not be taking: Antidiabetics, Antipsychotics, Corticosteroids, others

Disqualifiers: Diabetes, Cardiovascular diseases, Liver disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Compensation: Varies

Number of Visits: 5

Duration: 1 week

10 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this study is to learn about how the hormone insulin controls blood sugar. The main question it aims to answer is about how much insulin the body actually needs to maintain a normal blood sugar level. People with obesity and high insulin levels will receive eight doses of diazoxide, a drug that suppresses the pancreas's production of insulin, and will have their fasting blood sugar and insulin levels checked daily while taking the drug.

Do I need to stop my current medications to join the trial?

The trial requires that you stop using most antidiabetic medications 30 days before screening, except for metformin, which is allowed. If you are taking other medications for conditions listed in the exclusion criteria, you may need to stop those as well. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug Diazoxide for treating hyperinsulinemia?

Diazoxide is the only FDA-approved drug for treating hyperinsulinism and has been used successfully in various cases, including genetic forms and in infants. It has also been effective in managing hypoglycemia in patients with insulinoma, helping to maintain normal blood sugar levels. ^{1 2 3 4 5}

Is diazoxide safe for treating hyperinsulinemia?

Diazoxide is generally effective but can have serious side effects, including fluid retention, heart problems, and high blood sugar. It is important for patients, especially those on other medications like diuretics, to be closely monitored for these risks. ^{4 6 7 8 9}

What makes the drug Diazoxide unique for treating hyperinsulinemia?

Diazoxide is unique because it is the only FDA-approved drug specifically for treating hyperinsulinemia, making it the first-line treatment option. It works by preventing the release of insulin from the pancreas, which helps manage low blood sugar levels. ^{3 4 9 10 11}

Research Team

Joshua R Cook, MD, PhD

Principal Investigator

Columbia University

Eligibility Criteria

This trial is for individuals with obesity and high insulin levels, known as hyperinsulinemia. It's designed to understand how the body uses insulin to control blood sugar. Participants will be given diazoxide, which affects insulin production.

Inclusion Criteria

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.

My BMI is between 30 and 45.

I can understand English or Spanish, both written and spoken.

Exclusion Criteria

Abnormal resting heart rate: < 60 or ≥ 110 bpm

I can provide informed consent in English or Spanish.

Known allergy/hypersensitivity to any component of the medicinal product formulations (including sulfa drugs) or ongoing clinically important allergy/hypersensitivity as judged by the investigator

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive diazoxide oral suspension at 3 mg/kg per dose for 4 days, with fasting glucose and insulin levels checked daily

1 week

5 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Diazoxide

Trial Overview The study tests diazoxide at a dose of 2 mg/kg, administered in eight doses. The focus is on how this drug influences the pancreas and its ability to produce insulin, thereby affecting blood sugar regulation in obese individuals with high insulin levels.

Participant Groups

Group I: Diazoxide Experimental Treatment 1 Intervention

Subjects will take diazoxide oral suspension at 3 mg/kg per dose for 4 days (total of 8 doses)

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+

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

Collaborator

Trials

2,513

Recruited

4,366,000+

University of Pisa

Collaborator

Trials

153

Recruited

84,700+

Findings from Research

In patients with insulinoma, diazoxide treatment significantly reduced serum insulin levels and improved tissue sensitivity to insulin after just three days of administration.

Before treatment, insulinoma patients showed lower metabolic clearance rates of insulin compared to controls, indicating that diazoxide effectively enhances insulin metabolism in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of euglycaemic clamping in evaluation of diazoxide treatment of insulinoma. Skrha, J., Svacina, S., Srámková, J., et al.[2019]

Diazoxide was used to treat two children experiencing hypoglycemia due to hyperinsulinemia, but it resulted in serious side effects including cardiac failure and truncal ataxia.

The adverse effects observed highlight the potential risks associated with diazoxide treatment in pediatric patients, suggesting a need for careful monitoring and consideration of alternative therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complications of diazoxide in the treatment of nesidioblastosis. McGraw, ME., Price, DA.[2019]

Diazoxide, a benzothiadiazine, has been shown to effectively manage hypoglycemia in frail patients, particularly those at surgical risk.

This case report highlights the successful treatment of insulinoma with diazoxide, suggesting its potential utility in similar clinical scenarios.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A case of insulinoma effectively treated with low-dose diazoxide. Yasuda, A., Seki, T., Kitajima, N., et al.[2020]

In a study of 194 patients with hyperinsulinism, 85.1% were treated with diazoxide, which is the only FDA-approved medication for this condition, and the overall rate of serious adverse events (SAEs) was found to be 9.7%.

Patients with perinatal stress hyperinsulinism experienced a significantly higher rate of SAEs (16.7%) compared to those with genetic forms of hyperinsulinism (3.6%), indicating that caution is needed when prescribing diazoxide to this specific group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rate of Serious Adverse Events Associated with Diazoxide Treatment of Patients with Hyperinsulinism. Thornton, P., Truong, L., Reynolds, C., et al.[2019]

A case study reports successful long-term treatment of persistent hyperinsulinemic hypoglycemia in an infant using diazoxide for 4.5 years, maintaining normal blood sugar levels.

Remarkably, the treatment did not result in any side effects, including the commonly associated hypertrichosis, suggesting a favorable safety profile in this instance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term diazoxide treatment in persistent hyperinsulinemic hypoglycemia of infancy: a patient report. Darendeliler, F., Bundak, R., Bas, F., et al.[2019]

In a study of 295 infants and children treated with diazoxide for hyperinsulinism, 2.4% developed pulmonary hypertension, particularly in those with underlying risk factors like respiratory failure and structural heart disease.

The study also found a notable prevalence of other adverse events, including neutropenia (15.6%), thrombocytopenia (4.7%), and hyperuricemia (5.0%), highlighting the importance of proactive screening for these side effects in patients receiving diazoxide.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prevalence of Adverse Events in Children With Congenital Hyperinsulinism Treated With Diazoxide. Herrera, A., Vajravelu, ME., Givler, S., et al.[2019]

A 5-year-old girl developed hyperosmolar hyperglycemic syndrome (HHS) with a serum glucose level of 529 mg/dL while being treated with diazoxide and diuretics, highlighting the potential risk of hyperglycemia associated with diazoxide use.

Even at low blood levels of diazoxide (25 µg/dL), it can still lead to hyperglycemia, indicating that patients on diazoxide and diuretics require careful monitoring to prevent complications like HHS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hyperosmolar hyperglycemic syndrome induced by diazoxide and furosemide in a 5-year-old girl. Nakazawa, H., Naruse, Y., Mori, M., et al.[2021]

Diazoxide is an effective treatment for stress-related hyperinsulinism in premature infants, but in this case, it led to severe side effects including cardiorespiratory failure and worsening liver function after 7 weeks of treatment.

The infant's low albumin levels may have increased the toxicity of diazoxide, suggesting that monitoring liver function and albumin levels is crucial when administering this medication, as it is highly protein-bound.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liver injury may increase the risk of diazoxide toxicity: a case report. Tas, E., Mahmood, B., Garibaldi, L., et al.[2018]

Diazoxide is the primary medical treatment for hyperinsulism in neonates, but it can lead to severe adverse effects, as demonstrated in a case of a 43-day-old infant who experienced life-threatening complications including fluid retention, congestive heart failure, and respiratory failure after treatment.

After stopping diazoxide, the infant's condition improved significantly within five days, highlighting the importance of monitoring and managing potential intoxication from this medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A case of severe diazoxide toxicity. Silvani, P., Camporesi, A., Mandelli, A., et al.[2022]

This study established a population pharmacokinetic model for diazoxide in 22 children with hyperinsulinemic hypoglycemia, showing that the drug's clearance and distribution are proportional to body weight, with females having a 39% higher clearance than males.

A significant finding was that serum diazoxide concentrations exceeding 100 μg/mL were associated with the development of hyperglycemia, highlighting the need for careful monitoring of drug levels to prevent adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population Pharmacokinetics of Diazoxide in Children with Hyperinsulinemic Hypoglycemia. Kizu, R., Nishimura, K., Sato, R., et al.[2018]

A 21-year-old male with hypoglycemia due to hyperinsulinism did not respond to surgery but showed significant improvement after starting oral Diazoxide, indicating its potential efficacy in managing this condition.

Despite an initial viral pneumonitis and temporary discontinuation of Diazoxide due to hyperglycemia, the patient has been successfully treated with Diazoxide for several years and is now asymptomatic and active, suggesting that Diazoxide can be a viable long-term treatment option when surgery fails.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of hyperinsulinism after partial pancreatectomy: medical or surgical? Schnatz, JD., Siegel, JH.[2013]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Use of euglycaemic clamping in evaluation of diazoxide treatment of insulinoma. [2019]

2. England pubmed.ncbi.nlm.nih.gov

Complications of diazoxide in the treatment of nesidioblastosis. [2019]

3. England pubmed.ncbi.nlm.nih.gov

A case of insulinoma effectively treated with low-dose diazoxide. [2020]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Rate of Serious Adverse Events Associated with Diazoxide Treatment of Patients with Hyperinsulinism. [2019]

5. Germany pubmed.ncbi.nlm.nih.gov

Long-term diazoxide treatment in persistent hyperinsulinemic hypoglycemia of infancy: a patient report. [2019]

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

Prevalence of Adverse Events in Children With Congenital Hyperinsulinism Treated With Diazoxide. [2019]

7. Japan pubmed.ncbi.nlm.nih.gov

Hyperosmolar hyperglycemic syndrome induced by diazoxide and furosemide in a 5-year-old girl. [2021]

8. Germany pubmed.ncbi.nlm.nih.gov

Liver injury may increase the risk of diazoxide toxicity: a case report. [2018]

9. France pubmed.ncbi.nlm.nih.gov

A case of severe diazoxide toxicity. [2022]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Population Pharmacokinetics of Diazoxide in Children with Hyperinsulinemic Hypoglycemia. [2018]

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

Treatment of hyperinsulinism after partial pancreatectomy: medical or surgical? [2013]