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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of the diabetes medication Pioglitazone for individuals with type 2 diabetes and heart failure. Researchers aim to determine if Pioglitazone can enhance heart function by improving insulin use in the heart muscle and reducing fat around the heart. Participants will be divided into two groups: one will receive Pioglitazone, and the other will receive a placebo (a pill with no active drug). This trial targets individuals with type 2 diabetes who manage their condition with diet, exercise, or specific medications and have experienced heart failure with preserved ejection fraction (a type of heart function). As a Phase 4 trial, this research seeks to understand how this already 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 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 is the safety track record for Pioglitazone?

Research has shown that pioglitazone is generally well-tolerated by people with type 2 diabetes. One study found that it lowered the risk of death, heart attack, or stroke in these patients. However, some risks exist. More people taking pioglitazone experienced serious heart failure compared to those taking a placebo. Additionally, using pioglitazone with insulin may increase the risk of heart problems.

Pioglitazone is already FDA-approved for managing type 2 diabetes, indicating a known safety record. However, like all medications, it can have side effects. Patients should always discuss potential risks with their doctor before joining a trial or starting a new medication. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Most treatments for heart failure in people with type 2 diabetes focus on reducing fluid retention, improving heart function, or controlling blood sugar levels. However, pioglitazone is unique because it targets insulin resistance, a key issue in type 2 diabetes, which may indirectly benefit heart health. Researchers are excited about pioglitazone because it has the potential to improve both blood sugar control and cardiovascular outcomes by enhancing the body's sensitivity to insulin. Unlike standard treatments that often address one problem at a time, pioglitazone offers a dual action approach, which could be a game-changer for managing heart failure in diabetic patients.

What evidence suggests that pioglitazone might be an effective treatment for heart failure in type 2 diabetes?

This trial will compare the effects of Pioglitazone with a placebo in participants with type 2 diabetes and heart failure. Studies have shown that Pioglitazone can reduce the risk of major heart problems, such as heart attacks or strokes, in people with diabetes. It also helps control blood sugar levels when combined with other diabetes medications. Research suggests that Pioglitazone may improve heart function by enhancing the heart's responsiveness to insulin and reducing surrounding fat. These benefits could be particularly useful for individuals with type 2 diabetes and heart failure. Overall, Pioglitazone has shown promise in managing both diabetes and heart health issues. ^{1 6 7 8 9}

Who Is on the Research Team?

Ralph A DeFronzo, MD

Principal Investigator

University of Texas

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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 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]

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]

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]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10639032/

Association of Pioglitazone With Major Adverse ...

Among a wide range of diabetes patients, pioglitazone is associated with a noticeably lower risk of death, myocardial infarction, or stroke.

2.

accessdata.fda.gov

accessdata.fda.gov/drugsatfda_docs/label/2007/021842s005lbl.pdf

NDA 21-842/S-005 ACTOPLUS MET® (pioglitazone ...

The concomitant use of pioglitazone and metformin has been previously approved based on clinical trials in patients with type 2 diabetes inadequately controlled ...

3.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC3920795/

Do We Still Need Pioglitazone for the Treatment of Type 2 ...

A large randomized controlled trial (RCT) showed that both pioglitazone and metformin reduced HbA1c by 1.5% from baseline (2). In contrast to the more commonly ...

4.

sciencedirect.com

sciencedirect.com/science/article/pii/S014929182400198X

Efficacy and Safety of Pioglitazone Add-on in Patients with ...

The purpose of this study was to determine the efficacy and safety profile of pioglitazone compared with placebo (PBO) in patients with type 2 diabetes (T2D)

5.

clinicaltrials.gov

clinicaltrials.gov/study/NCT00521820

Safety Comparison of Pioglitazone and Glyburide in Type 2 ...

Safety Comparison of Pioglitazone and Glyburide in Type 2 Diabetes Subjects With Mild to Moderate Congestive Heart Failure. ClinicalTrials.gov ID NCT00521820.

6.

fda.gov

fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-updated-fda-review-concludes-use-type-2-diabetes-medicine-pioglitazone

Updated FDA review concludes that use of type 2 diabetes ...

FDA Drug Safety Communication: Updated FDA review concludes that use of type 2 diabetes medicine pioglitazone may be linked to an increased risk ...

7.

sciencedirect.com

sciencedirect.com/science/article/abs/pii/S1056872724002241

Pioglitazone increases risk of ischemic heart disease in ...

Administering pioglitazone plus insulin to patients with T2DM uncontrolled on metformin may increase the risk of IHD.

8.

diabetesjournals.org

diabetesjournals.org/care/article/30/11/2773/4795/Pioglitazone-Use-and-Heart-Failure-in-Patients

Pioglitazone Use and Heart Failure in Patients With Type 2 ...

RESULTS— More pioglitazone (5.7%) than placebo patients (4.1%) had a serious heart failure event during the study (P = 0.007). However, ...

9.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC12106948/

Efficacy and Safety of Pioglitazone Add‐On in Patients With ...

Pioglitazone add‐on to metformin and dapagliflozin significantly improved glycaemic control by reducing HbA1c, fasting blood glucose and HOMA‐IR.