Insulin Infusion for Non-alcoholic Fatty Liver Disease

Overseen By Julia J. Wattacheril, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Columbia University

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

Disqualifiers: Diabetes, Cardiovascular, Liver, 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 explores how varying rates of insulin infusion affect blood sugar levels in individuals with non-alcoholic fatty liver disease (NAFLD). Participants will undergo two different treatment plans to observe their bodies' responses to changes in insulin levels. The researchers aim to understand insulin's impact on those with insulin resistance, a common condition in individuals who are overweight and show early signs of diabetes. Individuals who have been overweight or obese, exhibit signs of insulin resistance, and have a diagnosis or high risk of NAFLD may be suitable candidates for this study. As a Phase 1 trial, this research focuses on understanding 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 does not specify if you need to stop taking your current medications, but it excludes those who have used certain medications within 90 days before screening, like antidiabetic drugs other than metformin and some lipid-lowering drugs. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that insulin has been safely used to treat diabetes for a long time. This study examines how insulin affects blood sugar levels in people with non-alcoholic fatty liver disease (NAFLD) and insulin resistance.

Previous participants generally tolerated insulin well. Some side effects, such as low blood sugar, can occur, but careful monitoring usually manages them effectively. As this is an early phase study, the primary focus is on understanding how the body reacts to different insulin levels. Researchers closely monitor the treatment to ensure participants' safety.

For any concerns about joining this study, always consult a healthcare professional. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this trial because it explores innovative insulin infusion protocols for non-alcoholic fatty liver disease (NAFLD), focusing on managing insulin levels in unique ways. The Maintenance Hyperinsulinemia (MH) protocol aims to sustain high insulin levels to counteract insulin resistance, which is a new approach compared to standard treatments that typically don't focus on insulin management. Meanwhile, the Reduction toward Euinsulinemia (RE) protocol seeks to reduce insulin infusion towards more normal levels, potentially addressing insulin resistance more effectively without maintaining high insulin levels. These strategies could offer new insights into managing NAFLD by directly targeting insulin regulation, which is not typically addressed by current standard treatments like lifestyle changes and medications targeting metabolic syndrome components.

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

Research has shown that insulin treatment can improve liver health in people with non-alcoholic fatty liver disease (NAFLD). In this trial, participants will join one of two treatment arms: the Maintenance hyperinsulinemia (MH) protocol or the Reduction toward euinsulinemia (RE) protocol. Studies have found that insulin helps control blood sugar and lower cholesterol, both crucial for a healthy liver. By improving the body's use of sugar, insulin may reduce fat buildup in the liver. This is particularly important for those with insulin resistance, a common issue in NAFLD. Early findings suggest these benefits can lead to better liver health and fewer liver-related problems. ^{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 adults aged 18-65 with a BMI of 25.0-39.9, who speak English or Spanish, have high fasting insulin levels and are at risk for non-alcoholic fatty liver disease (NAFLD). They must not be pregnant, breastfeeding, or have diabetes, severe infections recently, certain heart conditions or allergies to study materials.

Inclusion Criteria

Your blood insulin level is too high when you haven't eaten for a while.

I understand English or Spanish.

I have been diagnosed with or am at high risk for NAFLD/MAFLD by a specialist.

Exclusion Criteria

I can provide informed consent in English or Spanish.

Concerns arising at screening visit including unwillingness to comply with specified procedures, documented weight loss of ≥ 5% of baseline within the previous 6 months, abnormal blood pressure, abnormal resting heart rate, abnormal screening electrocardiogram, laboratory evidence of diabetes mellitus, positive qualitative β-hCG in women of childbearing potential, liver function abnormalities, abnormal fasting lipids at screening, abnormal screening serum electrolytes, abnormal complete blood count, not fully vaccinated against COVID-19, 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 or breastfeeding, history of diabetes mellitus, use of most antidiabetic medications within the 90 days prior to screening, concerns related to lipid metabolism, known, documented history of specified medical conditions, use of certain medications currently or within 90 days prior to screening, history of certain weight-loss (bariatric) surgery, clinical concern for alcohol overuse, positive urine drug screen, history of severe infection or ongoing febrile illness within 30 days of screening, any other disease, 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, 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 within 6 months prior to screening or within 5 half-lives of an investigational agent, whichever is longer

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 infusion rate on blood glucose levels.

Up to 425 minutes 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

• 20% D-glucose (aq)
• [6,6-2H2] D-glucose
• Glucagon
• Growth Hormone, Human
• Insulin human
• Octreotide Acetate

Trial Overview The study tests how different rates of insulin infusion affect blood glucose during a pancreatic clamp procedure in overweight individuals with NAFLD and insulin resistance. Participants will undergo two procedures comparing maintenance versus reduction of insulin infusion.

How Is the Trial Designed?

Group I: Reduction toward euinsulinemia (RE) protocol Experimental Treatment 10 Interventions

The basal insulin infusion rate (IIR) necessary to maintain participants' mean basal fasting plasma glucose (mbFPG) will be determined during the basal titration period. Then, during the intervention period, the basal IIR will be reduced by up to 50%. Thus, the basal hyperinsulinemia expected due to underlying insulin resistance will be reduced toward euinsulinemia.

Group II: Maintenance hyperinsulinemia (MH) protocol Active Control 10 Interventions

The basal insulin infusion rate (IIR) necessary to maintain participants' mean basal fasting plasma glucose (mbFPG) will be determined during the basal titration period. Then, during the intervention period, the IIR will remain at 100% of basal for the full duration (225 min). The IIR and resulting insulin levels are expected to be relatively high (cf. hyperinsulinemia) because of underlying insulin resistance.

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+

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

Collaborator

Trials

2,513

Recruited

4,366,000+

Albert Einstein College of Medicine

Collaborator

Trials

302

Recruited

11,690,000+

Published Research Related to This Trial

A comparison of insulin lispro and regular human insulin (Humulin R) in 3634 patients with type 1 and type 2 diabetes showed no significant differences in treatment-emergent adverse events, indicating similar safety profiles for both insulins.

Both insulin therapies did not differ in their effects on the progression of chronic diabetes complications, such as retinopathy, neuropathy, cardiovascular disease, or kidney disease, suggesting that insulin lispro is as safe as Humulin R.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of insulin lispro: pooled data from clinical trials. Glazer, NB., Zalani, S., Anderson, JH., et al.[2019]

In a study of 108 individuals with type 2 diabetes and compensated liver disease, lispro insulin resulted in lower glycemic excursions compared to recombinant regular human insulin (RHI), particularly during the night and late post-absorption phases.

Lispro also led to lower early postprandial glucose levels and reduced rates of late postprandial hypoglycemia, suggesting it may be the preferred treatment option for patients with type 2 diabetes and compensated liver disease due to its faster action and reduced liver glucose output.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lispro insulin in people with non-alcoholic liver cirrhosis and type 2 diabetes mellitus. Gentile, S., Guarino, G., Strollo, F., et al.[2018]

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]

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]

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]

Insulin sensitizers, particularly metformin and thiazolidinediones, have been shown to improve insulin resistance and liver function tests in patients with nonalcoholic fatty liver disease (NAFLD), based on a systematic review of nine studies.

However, the evidence is limited, with only two placebo-controlled trials conducted, and while some beneficial histological changes were reported, these need further validation through randomized controlled trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Insulin sensitizers in treatment of nonalcoholic fatty liver disease: Systematic review. Chavez-Tapia, NC., Barrientos-Gutierrez, T., Tellez-Avila, FI., et al.[2019]

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]

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]

In a clinical trial involving 211 diabetic patients over 12 weeks, both Yousilin R and Novolin R significantly reduced glycosylated hemoglobin A1c (HbA1c) levels, indicating effective blood sugar control, with no significant difference between the two treatments.

The safety profiles of Yousilin R and Novolin R were comparable, with similar rates of hypoglycemic events and other adverse effects, suggesting that Yousilin R is a safe alternative to Novolin R for diabetes management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The efficacy and safety of recombinant human insulin injection in the treatment of diabetic patients:a multicenter, randomized, controlled and open-labeled clinical trial]. Che, TT., Wang, X., Liu, YY., et al.[2014]

In a study involving 1008 patients, short-acting insulin lispro and regular insulin Humulin R showed similar effectiveness in controlling blood sugar levels and had comparable safety profiles, with no significant differences in hypoglycemia incidents.

After a year of continued lispro therapy, glycosylated hemoglobin (HbA1C) levels returned to baseline, indicating that while lispro was well tolerated in the short term, long-term efficacy may need further evaluation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lispro insulin as premeal therapy in type 1 diabetes: comparison with Humulin R. Daniels, AR., Bruce, R., McGregor, L.[2022]

In a study involving 37 individuals with type 2 diabetes, both Gansulin and Humulin N® effectively reduced HbA1c levels, indicating similar efficacy in glycemic control.

There were no significant differences in fasting plasma glucose, bedtime plasma glucose, or hypoglycemic events between the two insulin formulations, suggesting that Gansulin is as safe as Humulin N® for managing diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative study between two recombinant human NPH insulin formulations for the treatment of type 2 diabetes mellitus. Rassi, N., Moraes, SM., Alves, AG., et al.[2023]

Weight loss and lifestyle modifications are the primary interventions for non-alcoholic fatty liver disease (NAFLD), especially in overweight or obese individuals, but require a multidisciplinary approach that is often lacking.

Insulin-sensitizing agents show promise as a treatment for NAFLD by reducing insulin resistance, which contributes to fat accumulation in the liver, with studies indicating improvements in liver function, although long-term outcomes are still uncertain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review article: the treatment of fatty liver disease associated with the metabolic syndrome. Marchesini, G., Natale, S., Manini, R., et al.[2017]

Citations

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Insulin sensitizers for the treatment of non-alcoholic fatty liver ... TZDs improve insulin sensitivity, serum ALT/AST levels and histology in some cases, but there are some concerns about the safety of long-term therapy. Selection ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8472495/

Effectiveness of drug interventions in nonalcoholic fatty ... In this study, glucagon-like peptide-1 receptor agonists and thiazolidinediones were revealed to be the best interventions for nonalcoholic fatty liver disease.

3. translational-medicine.biomedcentral.com translational-medicine.biomedcentral.com/articles/10.1186/s12967-021-02729-1

Insulin treatment improves liver histopathology and decreases ... As expected, insulin treatment in this model had beneficial effects on glucose control and dyslipidemia and increased body weight and fat mass, ...

4. withpower.com withpower.com/trial/phase-1-liver-diseases-1-2023-c905a

Insulin Infusion for Non-alcoholic Fatty Liver Disease The primary outcome will be the absolute and relative changes in steady-state plasma glucose levels at each stepped decline in IIR. Show more. Will I have to ...

5. journals.lww.com journals.lww.com/hep/fulltext/2019/08000/modulation_of_insulin_resistance_in_nonalcoholic.24.aspx

Modulation of Insulin Resistance in Nonalcoholic Fatty... Increased Serum Free Fatty Acids Worsen IR​​ Patients with NAFLD have increased levels of serum free fatty acids (FFAs) compared to those without NAFLD,7 ...

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Insulin Sensitisers in the Treatment of Non-Alcoholic Fatty ... Statin therapy in NAFLD certainly appears safe and should not be avoided because of mildly abnormal LFTs.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10335801/

New anti-diabetic agents for the treatment of non-alcoholic ... This network meta-analysis aims to compare the efficacy and safety of new anti-diabetic medications for the treatment of non-alcoholic fatty liver disease ( ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT01289639

Insulin Resistance in Non-alcoholic Fatty Liver Disease The study is designed to investigate the relationship between insulin resistance and non-alcoholic fatty liver disease (NAFLD)

9. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1262363620300021

Efficacy and safety of anti-hyperglycaemic drugs in patients ... RCT evidence supports the efficacy of some anti-hyperglycaemic agents (especially pioglitazone) in patients with NAFLD or NASH.

10. diabetesjournals.org diabetesjournals.org/spectrum/article/37/1/48/154182/Pharmacological-Approaches-to-Nonalcoholic-Fatty

Pharmacological Approaches to Nonalcoholic Fatty Liver ... This article reviews pharmacological approaches to type 2 diabetes and obesity for people who have NAFLD or NASH and provides a brief description of agents ...