Pioglitazone for Fatty Liver Disease

Recruiting at 1 trial location

Overseen By Luke Norton, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 4

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 This treatment has passed at least one previous human trial

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

Compensation: Varies

Number of Visits: Unknown

Duration: 16 weeks

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate how well pioglitazone, a medication that improves insulin use, works for people with Type 2 diabetes and fatty liver disease. The researchers will compare pioglitazone with a placebo (a pill with no active drug) to assess its effects on liver health. Ideal participants include those with Type 2 diabetes who have non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH), particularly if they have moderate to severe liver fat but not severe liver scarring. As a Phase 4 trial, this research seeks to understand how this FDA-approved and effective treatment can benefit more patients.

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 is the safety track record for pioglitazone?

Research has shown that pioglitazone is generally safe for people with type 2 diabetes and liver conditions such as nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). One study found that pioglitazone was well-tolerated over three years and improved liver health without major safety concerns. It effectively reduced liver fat and improved liver function in these patients. Reports also highlight improvements in insulin use and a reduction in belly fat, which are positive outcomes for patients. While pioglitazone is approved for type 2 diabetes, ongoing studies indicate its promise for liver conditions in terms of safety and effectiveness. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Pioglitazone is unique because it targets insulin sensitivity, which is a root issue in fatty liver diseases like NAFL and NASH, especially in patients with type 2 diabetes. Traditional treatments often focus on weight loss and controlling blood sugar, but pioglitazone directly improves how the body uses insulin, potentially reducing liver fat and inflammation more effectively. Researchers are excited about its dual action on both liver health and diabetes management, offering a promising alternative to current options that may not address both conditions simultaneously.

What is the effectiveness track record for pioglitazone in treating fatty liver disease?

Research has shown that pioglitazone effectively treats non-alcoholic fatty liver disease (NAFLD). Studies have found that it reduces liver inflammation and fat buildup. In people with non-alcoholic steatohepatitis (NASH), pioglitazone has improved liver scarring and slowed disease progression. One study found that pioglitazone reduced disease activity in 58% of participants. In this trial, some participants will receive pioglitazone to test its effectiveness for NAFLD and NASH, while others will receive a placebo for comparison. This treatment is already known to help with some liver conditions, prompting its testing in this trial. ^{1 2 6 7 8}

Who Is on the Research Team?

Luke Norton, PhD

Principal Investigator

University of Texas Health Science Center San Antonio

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Pioglitazone
• Placebo

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.

How Is the Trial Designed?

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

Pioglitazone is already approved in United States for the following indications:

Approved in United States as Actos for:

• Type 2 diabetes mellitus

Who Is Running the Clinical Trial?

The University of Texas Health Science Center at San Antonio

Lead Sponsor

Trials

486

Recruited

92,500+

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 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]

A meta-analysis of seven randomized controlled trials involving 614 patients found that pioglitazone is effective in improving liver histology and reducing liver enzymes in both diabetic and non-diabetic patients with non-alcoholic fatty liver disease (NAFLD).

The study indicated that while pioglitazone did not significantly differ in safety profiles between diabetic and non-diabetic patients, there was a higher incidence of edema in the diabetic group, suggesting a need for monitoring this side effect in patients with type 2 diabetes.

NCBI (Pubmed)

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. Wang, Z., Du, H., Zhao, Y., et al.[2023]

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]

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]

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]

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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10091905/

Response to pioglitazone in non-alcoholic fatty liver disease ... We demonstrated the outcomes of pioglitazone in NAFLD patients on improvements in fibrosis, hepatocellular ballooning, lobular inflammation, and ...

2. diabetesresearchclinicalpractice.com diabetesresearchclinicalpractice.com/article/S0168-8227(21)00343-0/abstract

Pioglitazone even at low dosage improves NAFLD in type ... One-year treatment with pioglitazone even at low dosage significantly improved liver steatosis and inflammation, systemic and adipose tissue ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10307745/

Efficacy of 3 months of additional pioglitazone treatment in ... Additional pioglitazone treatment may have significantly lowered the liver enzyme levels and FIB-4 index in T2D patients with AFLD because the pathogenesis of ...

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

Pharmacological Approaches to Nonalcoholic Fatty Liver ... Of note, the improvement in steatohepatitis with pioglitazone has been reported with doses of 30–45 mg/day (29–34). Because lower pioglitazone ...

5. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/10.1155/2018/9568269

Effects of Pioglitazone on Nonalcoholic Fatty Liver Disease ... Our results showed that NAFLD was improved significantly by pioglitazone in a CAR deletion state. These results might be valuable because they ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5485416/

Concentration-Dependent Response to Pioglitazone in ... Pioglitazone is a safe and effective option to manage patients with type 2 diabetes and nonalcoholic steatohepatitis (NASH). However, there is marked ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT00062764

Treating Nonalcoholic Steatohepatitis With Pioglitazone The primary end point will be improvement in liver histology. Secondary end points will be improvements in insulin sensitivity, reduction in visceral fat, liver ...

8. uspharmacist.com uspharmacist.com/article/pioglitazone-appears-effective-against-common-liver-disease

Pioglitazone Appears Effective Against Common Liver ... Results of the 3-year clinical trial finding pioglitazone safe and effective in certain patients with the chronic disease were published ...