Pioglitazone for Heart Failure in Type 2 Diabetes

(PIOHF Trial)

Overseen By Andrea Hansis-Diarte, MPH

Age: 18+

Sex: Any

Trial Phase: Phase 4

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

Must be taking: Metformin, Sulfonylurea, Insulin

Must not be taking: GLP-1 RA, Thiazolidinedione, SGLT2i

Disqualifiers: Osteoporosis, Coronary artery disease, 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: 24 weeks

78 Participants Needed

Trial Summary

What is the purpose of this trial?

Our goal of the study is to learn the effects of the diabetes medication named Pioglitazone, in type-2 diabetic obese participants with Heart failure. The main question it aims to answer are: 1. To demonstrate that impaired mitochondrial function leading to reduced ATP generation plays a key pathophysiologic role in the development of heart failure with preserved ejection fraction (HFpEF) in obese type 2 diabetic (T2D) individuals. 2. To demonstrate that pioglitazone, improves diastolic (as well as systolic) function by improving myocardial insulin sensitivity and by reducing both myocardial and epicardial fat content.

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 does exclude those taking GLP-1 RA, thiazolidinedione, or SGLT2i medications. If you are on these, you may need to stop them to participate.

What data supports the effectiveness of the drug Pioglitazone for heart failure in patients with type 2 diabetes?

Research shows that Pioglitazone, used for type 2 diabetes, can improve heart function by reducing cardiovascular events and improving insulin sensitivity. However, it may cause fluid retention, which can be a concern for heart failure patients. ^{1 2 3 4 5}

How does the drug pioglitazone differ from other treatments for heart failure in type 2 diabetes?

Pioglitazone is unique because it is primarily an anti-diabetic drug that also affects heart function by improving insulin sensitivity, but it can cause fluid retention, which may worsen heart failure in some patients. Unlike other treatments, it requires careful monitoring for side effects like weight gain and edema, especially in those with existing heart conditions. ^{1 2 3 6 7}

Research Team

Ralph A DeFronzo, MD

Principal Investigator

University of Texas

Eligibility Criteria

This trial is for obese individuals aged 30-70 with type-2 diabetes and heart failure (NYHA class II-III) who have an ejection fraction over 50%. Participants should be on certain diabetes medications but not on GLP-1 RA, thiazolidinedione, or SGLT2i. They must have stable heart medication use and no history of severe heart conditions unrelated to their diabetes.

Inclusion Criteria

For females of reproductive potential: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation and for an additional [4 weeks] after the end of study participation.

Stated willingness to comply with all study procedures and availability for the duration of the study

Provision of signed and dated informed consent form

Exclusion Criteria

I have a history of osteoporosis or diabetic eye disease.

I have been treated with a medication for diabetes that belongs to the SGLT2 inhibitors class.

I do not have heart failure or severe heart conditions.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Pioglitazone or a placebo to examine effects on heart function

24 weeks

Regular visits for monitoring and dose adjustments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Pioglitazone
• Placebo

Trial Overview The study tests Pioglitazone's effect on heart function in diabetic patients with heart failure. It aims to see if the drug can improve energy production in the heart by reducing fat around it and increasing insulin sensitivity. Half will receive Pioglitazone; the other half a placebo.

Participant Groups

Group I: Pioglitazone Administration Group Active Control 1 Intervention

Pioglitazone 15mg/day titrated to 30 mg/day at week 2 and to 45 mg/day at week 4

Group II: Placebo/Control Group Placebo Group 1 Intervention

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+

Findings from Research

In a study of patients with type 2 diabetes and heart failure, pioglitazone led to a higher incidence of hospitalizations for heart failure (13%) compared to glyburide (8%), indicating potential risks associated with its use in this population.

Despite the increased hospitalizations, pioglitazone did not result in higher cardiovascular mortality or worsen cardiac function as measured by echocardiographic assessments, suggesting that while it may pose risks, it does not necessarily lead to worse heart health outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pioglitazone and heart failure: results from a controlled study in patients with type 2 diabetes mellitus and systolic dysfunction. Giles, TD., Miller, AB., Elkayam, U., et al.[2022]

Pioglitazone treatment significantly improved left ventricular diastolic function in patients with type 2 diabetes mellitus (T2DM) who are younger than 55 years, indicating its potential cardiovascular benefits in this age group.

In contrast, the same treatment did not show significant improvements in left ventricular diastolic function for T2DM patients aged 55 years and older, suggesting that age may influence the efficacy of pioglitazone in improving heart function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Change in left ventricular diastolic function after pioglitazone treatment in patients with type 2 diabetes mellitus: A protocol for systematic review and meta-analysis. Song, H., Li, Y., Yu, R., et al.[2023]

In a study of 39,736 older patients with type 2 diabetes, those treated with pioglitazone had a significantly lower risk of death and heart failure compared to those treated with rosiglitazone, with adjusted hazard ratios of 0.86 and 0.77, respectively.

The research suggests that for every 93 patients treated with rosiglitazone instead of pioglitazone, one additional composite outcome (death or hospital admission for heart failure or acute myocardial infarction) would occur annually, indicating that the use of rosiglitazone may not be justified given its lack of clinical advantage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse cardiovascular events during treatment with pioglitazone and rosiglitazone: population based cohort study. Juurlink, DN., Gomes, T., Lipscombe, LL., et al.[2021]

In a study of 54 patients with type 2 diabetes, adding pioglitazone to existing medications significantly improved glycaemic control, with HbA1c levels decreasing from 7.8% to 6.3% over 26 weeks, and 61% of patients achieving target levels below 6.5%.

While pioglitazone improved insulin sensitivity and beta-cell function, its withdrawal led to a significant rebound increase in HbA1c, indicating the need for continued treatment; however, it also caused an increase in Nt-proBNP, suggesting potential fluid retention as a side effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glycaemic and nonglycaemic effects of pioglitazone in triple oral therapy of patients with type 2 diabetes. Dorkhan, M., Magnusson, M., Frid, A., et al.[2022]

Pioglitazone effectively increases insulin sensitivity and improves glycemic control in patients with type 2 diabetes, whether used alone or in combination with other medications, based on clinical trials.

The medication is generally well tolerated, with weight gain and edema being the most common side effects, and it also shows potential benefits in reducing cardiovascular risk and arteriosclerosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spotlight on pioglitazone in type 2 diabetes mellitus. Waugh, J., Keating, GM., Plosker, GL., et al.[2019]

In a study of 300 patients with type 2 diabetes and mild cardiac disease, pioglitazone did not significantly improve walking distance compared to glyburide, indicating similar efficacy in this aspect of treatment.

While pioglitazone did not lead to significant deterioration in cardiac function, it was associated with more cases of heart failure, edema, and weight gain compared to glyburide, highlighting potential safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of pioglitazone vs glyburide in early heart failure: insights from a randomized controlled study of patients with type 2 diabetes and mild cardiac disease. Giles, TD., Elkayam, U., Bhattacharya, M., et al.[2018]

Pioglitazone, commonly used as an insulin sensitizer, can lead to heart failure even in patients with normal left ventricular function, as demonstrated by a case of a patient who developed congestive heart failure and pulmonary edema within a year of starting the medication.

The mechanism behind this heart failure may be related to a dose-dependent effect on pulmonary endothelial permeability rather than changes in heart structure, highlighting the need for careful monitoring of side effects in patients on pioglitazone therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pioglitazone-induced congestive heart failure and pulmonary edema in a patient with preserved ejection fraction. Jearath, V., Vashisht, R., Rustagi, V., et al.[2020]

References

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

Pioglitazone and heart failure: results from a controlled study in patients with type 2 diabetes mellitus and systolic dysfunction. [2022]

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

Change in left ventricular diastolic function after pioglitazone treatment in patients with type 2 diabetes mellitus: A protocol for systematic review and meta-analysis. [2023]

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

Adverse cardiovascular events during treatment with pioglitazone and rosiglitazone: population based cohort study. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Glycaemic and nonglycaemic effects of pioglitazone in triple oral therapy of patients with type 2 diabetes. [2022]

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

Spotlight on pioglitazone in type 2 diabetes mellitus. [2019]

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

Comparison of pioglitazone vs glyburide in early heart failure: insights from a randomized controlled study of patients with type 2 diabetes and mild cardiac disease. [2018]

7. India pubmed.ncbi.nlm.nih.gov

Pioglitazone-induced congestive heart failure and pulmonary edema in a patient with preserved ejection fraction. [2020]