Insulin Management for Non-alcoholic Fatty Liver Disease

Overseen By Joshua R Cook, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Columbia University

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

Disqualifiers: Diabetes, Cardiovascular diseases, Liver disease, others

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

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to explore how lowering insulin levels affects liver function in people with insulin resistance, focusing on glucose production and fat creation in the liver. Participants will undergo two different procedures to observe how their liver responds to varied insulin levels. Ideal candidates struggle with being overweight and have insulin resistance, indicated by high fasting insulin levels and prediabetes. As a Phase 1 trial, this research seeks to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial requires that you stop taking most antidiabetic medications, except for metformin, within 30 days before screening. Certain lipid-lowering drugs and other specific medications must also be stopped 30 days prior to screening.

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

Research shows that human insulin is generally safe and well-tolerated. Studies have demonstrated its effectiveness in controlling blood sugar levels, particularly in diabetes. Although limited information exists on using insulin for non-alcoholic fatty liver disease (NAFLD), its widespread use and approval for diabetes suggest it is relatively safe.

This trial is a Phase 1 study, marking the first time this treatment is tested in humans for this specific purpose. The main goal is to ensure safety, so researchers will closely monitor any side effects to protect participants. Since the FDA has already approved insulin for other uses, this offers some reassurance about its safety. However, researchers will carefully monitor participants throughout the study to manage any potential risks. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this trial because it explores new insulin management protocols for non-alcoholic fatty liver disease (NAFLD), a condition often treated with lifestyle changes and medications like metformin. Unlike standard treatments that focus on reducing liver fat through weight loss or controlling blood sugar, this trial investigates the impact of maintaining or reducing insulin levels during precise glucose control using a pancreatic clamp. By adjusting insulin infusion rates to either replicate or reduce fasting insulin levels, researchers aim to understand how these changes affect liver health and metabolism, potentially offering a novel approach to managing NAFLD beyond conventional methods.

What evidence suggests that this trial's treatments could be effective for non-alcoholic fatty liver disease?

This trial will explore different insulin management protocols for non-alcoholic fatty liver disease (NAFLD). Studies have shown that managing insulin is important in treating NAFLD. Insulin controls blood sugar and can lower liver fat, which is crucial for people with this condition. Research suggests that maintaining proper insulin levels might improve liver health in NAFLD patients by reducing liver fat and inflammation. Insulin treatments have effectively reduced liver fat, especially in those with insulin resistance, a common issue in NAFLD. This approach aims to balance insulin to support better liver function. Participants in this trial will follow different protocols to assess the impact of varying insulin levels on liver health. ^{6 7 8 9 10}

Who Is on the Research Team?

Joshua R Cook, MD, PhD

Principal Investigator

Columbia University

Are You a Good Fit for This Trial?

This trial is for people who are overweight or obese, have insulin resistance (evidenced by high fasting insulin levels, prediabetes/impaired fasting glucose, or a HOMA-IR score of at least 2.73), and either have non-alcoholic fatty liver disease (NAFLD) or are at high risk for it.

Inclusion Criteria

Body mass index of 25.0-45.0 kg/m2

Evidence of insulin resistance, as indicated by meeting specific criteria including Hemoglobin A1c levels and fasting glucose levels

Homeostasis Model of Insulin Resistance (HOMA-IR) score ≥ 2.73

Exclusion Criteria

I am unwilling to use only a bedpan or urinal during certain procedures.

Abnormal screening electrocardiogram

High fasting serum triglycerides

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pancreatic Clamp Procedure

Participants undergo two pancreatic clamp procedures to assess the impact of insulin levels on hepatic glucose production and de novo lipogenesis.

Up to 6.5 hours per procedure

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after the pancreatic clamp procedures

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Insulin human

Trial Overview The study tests how lowering insulin affects liver glucose production versus fat creation in the liver. Participants will undergo two procedures with different insulin levels while their liver metabolism is monitored using special tracers.

How Is the Trial Designed?

Group I: Reduction toward euinsulinemia (RE) protocol Experimental Treatment 11 Interventions

On Pancreatic Clamp Visit 1 (RE Protocol), the insulin infusion rate (IIR) will be set to produce serum insulin levels of approximately 50% that of the screening fasting serum insulin level for the full duration of the pancreatic clamp. On Pancreatic Clamp Visit 2 (MH Protocol), the IIR will be set to approximately replicate the full fasting serum insulin for the duration of the pancreatic clamp. In both cases, plasma glucose will be clamped to approximately 140 mg/dL +/- 10%.

Group II: Maintenance hyperinsulinemia (MH) Protocol then Reduction toward Euinsulinemia (RE) Protocol Experimental Treatment 11 Interventions

On Pancreatic Clamp Visit 1 (MH Protocol), the insulin infusion rate (IIR) will be set to approximately replicate participants' endogenous fasting serum insulin levels based on screening visit data for the duration of the pancreatic clamp. On Pancreatic Clamp Visit 2 (RE Protocol), the IIR will be set to reduce serum insulin levels to roughly 50% of the screening fasting serum insulin for the duration of the pancreatic clamp. In both cases, plasma glucose will be clamped to approximately 140 mg/dL +/- 10%.

Insulin human is already approved in European Union, United States, Canada, Japan, China for the following indications:

Approved in European Union as Humulin for:

• Diabetes mellitus type 1
• Diabetes mellitus type 2

Approved in United States as Humulin for:

• Diabetes mellitus type 1
• Diabetes mellitus type 2

Approved in Canada as Novolin for:

• Diabetes mellitus type 1
• Diabetes mellitus type 2

Approved in Japan as Recombinant Human Insulin for:

• Diabetes mellitus type 1
• Diabetes mellitus type 2

Approved in China as Recombinant Human Insulin for:

• Diabetes mellitus type 1
• Diabetes mellitus type 2

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

Empagliflozin significantly reduces body mass index (BMI), liver stiffness measurement (LSM), aspartate aminotransferase (AST), and insulin resistance in patients with nonalcoholic fatty liver disease (NAFLD), based on a review of four randomized controlled trials involving 244 patients.

The findings suggest that empagliflozin improves liver health and metabolic parameters in NAFLD patients, indicating its potential as a new treatment option, although further research is needed to confirm its long-term efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Empagliflozin on Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. Zhang, Y., Liu, X., Zhang, H., et al.[2022]

In a 52-week weight management trial, semaglutide significantly reduced alanine aminotransferase (ALT) levels by 6%-21% in subjects with elevated ALT, indicating its potential effectiveness in treating non-alcoholic fatty liver disease (NAFLD).

Semaglutide also led to significant reductions in high-sensitivity C-reactive protein (hsCRP) levels by 25%-43% compared to placebo, suggesting an anti-inflammatory effect that may benefit individuals at risk for NAFLD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of semaglutide on liver enzymes and markers of inflammation in subjects with type 2 diabetes and/or obesity. Newsome, P., Francque, S., Harrison, S., et al.[2021]

In a study of 64 NAFLD patients over 12 months, treatment with rosiglitazone (4 mg/day) led to significant improvements in liver enzyme levels and NAFLD activity scores, indicating better metabolic control and histological improvement compared to metformin alone.

The combination of metformin and rosiglitazone also showed benefits, particularly in reducing liver enzyme levels, but metformin alone did not result in significant changes, highlighting the superior efficacy of rosiglitazone in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of insulin-sensitizing agents in nonalcoholic fatty liver disease. Omer, Z., Cetinkalp, S., Akyildiz, M., et al.[2022]

Recombinant leptin treatment shows promising preliminary results in improving non-alcoholic fatty liver disease (NAFLD), a condition with no FDA-approved therapies.

This research highlights the potential of leptin as a therapeutic option for NAFLD, addressing a significant public health issue related to liver disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Finding a sweet spot for leptin. Brown, RJ., Reitman, ML.[2022]

Incretin-based therapies, such as DPP-4 inhibitors and GLP-1 agonists, provide effective glycemic control for type 2 diabetes patients without the weight gain often seen with traditional treatments, making them a favorable option for many.

Clinical trial data suggest that these therapies are safe, showing no negative effects on cardiovascular health, and their integration into treatment plans can enhance options for managing type 2 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New therapeutic options: management strategies to optimize glycemic control. Freeman, JS.[2022]

In a study of 219 morbidly obese patients, type 2 diabetes mellitus was found to be an independent risk factor for severe liver conditions, including severe steatosis and severe fibrosis, indicating its significant role in worsening non-alcoholic fatty liver disease.

Insulin therapy was associated with non-alcoholic steatohepatitis and fibrosis in the overall patient group, but did not show this association when only patients with diabetes were analyzed, suggesting that insulin's impact may vary based on the patient's overall health status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Diabetes Mellitus and Insulin on Nonalcoholic Fatty Liver Disease in the Morbidly Obese. Strey, CBM., de Carli, LA., Fantinelli, M., et al.[2021]

In a study of 659 type 1 diabetes patients, those using continuous subcutaneous insulin infusion (CSII) had significantly lower Fatty Liver Index (FLI) and Hepatic Steatosis Index (HSI) compared to those using multiple daily injections (MDI), indicating a potential benefit of CSII in reducing non-alcoholic fatty liver disease (NAFLD) risk.

The lower NAFLD indices were particularly notable in women using CSII, who also had lower daily insulin doses and plasma triglyceride levels, suggesting that CSII may provide metabolic advantages in this group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Insulin pump therapy in type 1 diabetes is associated with lower indices of Non-Alcoholic Fatty Liver in non-obese women but not men. Pepa, GD., Lupoli, R., Masulli, M., et al.[2023]

Pioglitazone was found to improve liver histology in patients with non-alcoholic fatty liver disease (NAFLD), while metformin showed mixed results and did not improve non-alcoholic steatohepatitis (NASH) stages, indicating that pioglitazone may be more effective for liver health.

Metformin led to weight loss and significant reductions in insulin resistance, but it was less effective than pioglitazone in improving liver parameters, highlighting the need for further research on insulin sensitisers in advanced NAFLD stages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Insulin sensitisers in the treatment of non-alcoholic fatty liver disease: a systematic review. Shyangdan, D., Clar, C., Ghouri, N., et al.[2021]

Citations

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Beneficial effect of anti-diabetic drugs for nonalcoholic fatty ... Nonalcoholic fatty liver disease (NAFLD) is associated with liver-related morbidity, including progression to nonalcoholic steatohepatitis (NASH), advanced ...

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Safety, Tolerability, and Biologic Activity of AXA1125 and... Nonalcoholic fatty liver disease (NAFLD) is associated with a spectrum of hepatic histologic manifestations, including steatosis, nonalcoholic steatohepatitis ( ...

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Understanding the Burden of Nonalcoholic Fatty Liver Disease The prevalence of nonalcoholic fatty liver disease (NAFLD) in the United States is 38%, having increased by 50% within the past 3 decades.

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Unraveling the link between insulin resistance and Non ... However, NAFLD or MAFLD is a spectrum disorder that ranges from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH), which can ...