Pioglitazone for Fatty Liver Disease

Recruiting at1 trial location

Overseen by Luke Norton, PhD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 4

Recruiting

Sponsor: The University of Texas Health Science Center at San Antonio

Must be taking: Metformin, Sulfonylurea

Must not be taking: Glucose metabolism drugs

Disqualifiers: Cirrhosis, Type 1 diabetes, others

Prior Safety Data

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

This trial studies the effects of pioglitazone, a medication that helps the body use insulin more effectively, in patients with type 2 diabetes who have liver conditions like NAFL or NASH. Pioglitazone is a safe and effective option to manage patients with type 2 diabetes and nonalcoholic steatohepatitis (NASH). The goal is to see if this treatment can improve liver function and control blood sugar levels. Researchers will measure various aspects of liver metabolism and insulin sensitivity before and after a few months of treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop your current medications, but you must not be taking any medication that affects glucose metabolism other than antidiabetic medications like metformin or sulfonylurea.

What data supports the effectiveness of the drug Pioglitazone for treating fatty liver disease?

Research shows that Pioglitazone, a drug that helps the body use insulin better, can improve liver health in people with fatty liver disease, especially those with type 2 diabetes or prediabetes. It has been found to reduce liver fat and inflammation, leading to better liver function over time. ^{1 2 3 4 5}

Is pioglitazone safe for humans?

Pioglitazone has been studied for its safety in humans, particularly in patients with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). While it shows promise in treating these conditions, there are concerns about potential side effects, including liver toxicity, which require careful monitoring. ^{1 4 6 7 8}

How is the drug pioglitazone unique in treating fatty liver disease?

Pioglitazone is unique because it targets insulin resistance, a key issue in metabolic syndrome and fatty liver disease, making it a preferred option despite no drugs being specifically approved for this condition. It is particularly effective in patients with fatty liver disease who also have prediabetes or type 2 diabetes. ^{1 2 5 9 10}

Research Team

Luke Norton, PhD

Principal Investigator

University of Texas Health Science Center San Antonio

Eligibility Criteria

This trial is for adults aged 18-80 with Type 2 Diabetes and moderate to severe fatty liver disease, but not advanced fibrosis or cirrhosis. Participants should be in good health overall, have a BMI of 25-40 kg/m2, and an HbA1c level between 7-10%. They must be on stable diabetes treatment with diet, metformin, or sulfonylurea and not taking other glucose-affecting drugs.

Inclusion Criteria

I manage my condition with diet, metformin, or sulfonylurea and am generally healthy.

I am not on medication affecting blood sugar, except for diabetes treatment.

Confirmed T2D based on OGTT (2 h glucose ≥200 mg/dl)

Exclusion Criteria

I have been taking metformin for over 3 months or have taken other medications.

I drink less than 14 units of alcohol per week if female, or 21 if male.

I have Type 1 diabetes or tested positive for GAD antibodies.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive treatment with pioglitazone or placebo for 16 weeks to assess hepatic mitochondrial fluxes and other metabolic parameters

16 weeks

Multiple visits for treatment and assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Pioglitazone (Insulin Sensitizer)
• Placebo (Other)

Trial Overview The study tests the effects of pioglitazone (an insulin sensitizer) compared to a placebo on liver mitochondrial function in patients with Type 2 Diabetes who also have non-alcoholic fatty liver disease. The treatment period lasts for 16 weeks.

Participant Groups

Group I: NASH TZD Experimental Treatment 1 Intervention

T2D with non-alcoholic steatohepatitis (NASH), treated with pioglitazone

Group II: NAFL TZD Experimental Treatment 1 Intervention

T2D with non-alcoholic fatty liver (NAFL), treated with pioglitazone

Group III: NASH Placebo Placebo Group 1 Intervention

T2D with non-alcoholic steatohepatitis (NASH), treated with placebo

Group IV: NAFL Placebo Placebo Group 1 Intervention

T2D with non-alcoholic fatty liver (NAFL), treated with placebo

Who Is Running the Clinical Trial?

The University of Texas Health Science Center at San Antonio

Lead Sponsor

Trials

486

Recruited

92,500+

Dr. Andrew Masica

The University of Texas Health Science Center at San Antonio

Chief Medical Officer

MD from Indiana University School of Medicine

Dr. Taylor Eighmy

The University of Texas Health Science Center at San Antonio

Acting President

PhD in Civil Engineering from the University of New Hampshire

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

Collaborator

Trials

2,513

Recruited

4,366,000+

Dr. Griffin P. Rodgers

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

Chief Executive Officer since 2007

MD, M.A.C.P.

Dr. Griffin P. Rodgers

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

Chief Medical Officer since 2007

MD, M.A.C.P.

Findings from Research

Pioglitazone significantly improves liver histology in patients with prediabetes or type 2 diabetes combined with non-alcoholic fatty liver disease (NAFLD), particularly in reducing steatosis, inflammation, and ballooning grades, based on a systematic review of 4 studies.

The treatment also enhances insulin sensitivity and lowers fasting blood glucose and liver function markers, although it does not significantly improve fibrosis stage compared to placebo, indicating a need for further long-term studies to confirm its safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pioglitazone for NAFLD Patients With Prediabetes or Type 2 Diabetes Mellitus: A Meta-Analysis. Lian, J., Fu, J.[2022]

Pioglitazone and vitamin E are currently the most effective drugs for treating nonalcoholic fatty liver disease (NAFLD), with pioglitazone targeting insulin resistance, a key factor in the disease's development.

Despite no specific drugs being approved for NAFLD, existing medications for metabolic syndrome, like pioglitazone, may be underutilized in treating NAFLD, suggesting a need for clinicians to consider these options in practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

What Are the Current Pharmacological Therapies for Nonalcoholic Fatty Liver Disease? David, D., Eapen, CE.[2022]

Pioglitazone has shown significant histological improvement in patients with non-alcoholic steatohepatitis (NASH) associated with type 2 diabetes, with benefits observed within 6 months and lasting for at least 3 years, suggesting it may become the standard treatment for this condition.

Emerging treatments, such as glucagon-like peptide 1 receptor agonists, along with ongoing development of various agents targeting different pathways, indicate a promising future for combination therapies in managing NASH and improving patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of patients with type 2 diabetes and non-alcoholic fatty liver disease: current approaches and future directions. Cusi, K.[2022]

In a study of 886 men with type 2 diabetes, both pioglitazone and metformin significantly improved liver health as indicated by the liver-to-spleen ratio compared to a control group, while sitagliptin did not show similar benefits.

Pioglitazone was found to be the most effective in improving nonalcoholic fatty liver disease (NAFLD) features, with strong correlations to inflammation and abdominal fat in the treated groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Oral Antidiabetic Drugs on Changes in the Liver-to-Spleen Ratio on Computed Tomography and Inflammatory Biomarkers in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease. Yabiku, K., Mutoh, A., Miyagi, K., et al.[2019]

In a study of patients with nonalcoholic steatohepatitis (NASH) treated with pioglitazone for 18 months, higher concentrations of pioglitazone and its metabolites were significantly associated with better treatment outcomes, including reductions in liver inflammation and fat accumulation.

The study developed a predictive model that combines baseline liver health and pioglitazone exposure, which could help identify patients who are most likely to benefit from pioglitazone therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concentration-dependent response to pioglitazone in nonalcoholic steatohepatitis. Kawaguchi-Suzuki, M., Bril, F., Kalavalapalli, S., et al.[2018]

In a study of 117 patients with non-alcoholic steatohepatitis (NASH), PXL065 demonstrated a significant reduction in liver fat content (21-25%) compared to placebo, indicating its efficacy in treating NASH.

PXL065 showed a favorable safety profile, lacking the PPARγ-driven side effects associated with pioglitazone, and improved metabolic markers such as HbA1c and insulin sensitivity, suggesting it could be a safer alternative for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of PXL065 - deuterium-stabilized (R)-pioglitazone in patients with NASH: A phase II randomized placebo-controlled trial (DESTINY-1). Harrison, SA., Thang, C., Bolze, S., et al.[2023]

SGLT2 inhibitors and pioglitazone are promising treatment options for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), showing improvements in liver fat content and metabolic parameters based on a review of 18 studies, nine of which were of medium or high quality.

Both treatments have potential benefits in reducing insulin resistance and improving glucose control, but individualized patient considerations are crucial, and further research is needed to establish their long-term efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of SGLT2 Inhibitors Versus Pioglitazone in the Treatment of Non-alcoholic Fatty Liver Disease or Non-alcoholic Steatohepatitis: A Systematic Review. Kaur, S., Sojitra, V., Zahra, A., et al.[2023]

In a long-term study involving 2097 patients with type 2 diabetes, pioglitazone showed no cases of hepatocellular injury, while glibenclamide had a low incidence of 0.38%, suggesting a favorable hepatic safety profile for pioglitazone.

Overall, pioglitazone demonstrated significantly fewer instances of elevated liver enzymes compared to glibenclamide, indicating that it may be a safer option for managing diabetes-related liver issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liver safety in patients with type 2 diabetes treated with pioglitazone: results from a 3-year, randomized, comparator-controlled study in the US. Tolman, KG., Freston, JW., Kupfer, S., et al.[2021]

In a study of 101 adults with biopsy-proven nonalcoholic steatohepatitis (NASH), pioglitazone was found to be effective in reducing liver disease activity in both patients with type 2 diabetes and those with prediabetes, with 48% of diabetic patients meeting the primary outcome compared to 46% of non-diabetic patients.

Patients with type 2 diabetes experienced a significant reduction in liver fibrosis and greater improvements in insulin sensitivity in adipose tissue compared to those with prediabetes, suggesting that pioglitazone may have enhanced benefits for individuals with type 2 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Response to Pioglitazone in Patients With Nonalcoholic Steatohepatitis With vs Without Type 2 Diabetes. Bril, F., Kalavalapalli, S., Clark, VC., et al.[2019]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Pioglitazone for NAFLD Patients With Prediabetes or Type 2 Diabetes Mellitus: A Meta-Analysis. [2022]

2. India pubmed.ncbi.nlm.nih.gov

What Are the Current Pharmacological Therapies for Nonalcoholic Fatty Liver Disease? [2022]

3. Germany pubmed.ncbi.nlm.nih.gov

Treatment of patients with type 2 diabetes and non-alcoholic fatty liver disease: current approaches and future directions. [2022]

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

Effects of Oral Antidiabetic Drugs on Changes in the Liver-to-Spleen Ratio on Computed Tomography and Inflammatory Biomarkers in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease. [2019]

5. England pubmed.ncbi.nlm.nih.gov

Concentration-dependent response to pioglitazone in nonalcoholic steatohepatitis. [2018]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Evaluation of PXL065 - deuterium-stabilized (R)-pioglitazone in patients with NASH: A phase II randomized placebo-controlled trial (DESTINY-1). [2023]

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

Efficacy of SGLT2 Inhibitors Versus Pioglitazone in the Treatment of Non-alcoholic Fatty Liver Disease or Non-alcoholic Steatohepatitis: A Systematic Review. [2023]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Liver safety in patients with type 2 diabetes treated with pioglitazone: results from a 3-year, randomized, comparator-controlled study in the US. [2021]

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

Response to Pioglitazone in Patients With Nonalcoholic Steatohepatitis With vs Without Type 2 Diabetes. [2019]

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

Response to pioglitazone in non-alcoholic fatty liver disease patients with vs. without type 2 diabetes: A meta-analysis of randomized controlled trials. [2023]