Pioglitazone for Heart Failure in Type 2 Diabetes

(PIOHF Trial)

Recruiting in Palo Alto (17 mi)

Overseen by Ralph A DeFronzo, MD

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, Insulin

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

Disqualifiers: Osteoporosis, Coronary artery disease, others

Prior Safety Data

Approved in 1 Jurisdiction

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}

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.

Trial 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 (Thiazolidinedione)
• Placebo (Other)

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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Texas Diabetes Institute/UH San Antonio, TX

Who Is Running the Clinical Trial?

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

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] Thiazolidinediones are associated with fluid retention, often interpreted as worsening cardiac function, limiting their use in patients with heart failure (HF). We compared the effects of pioglitazone and glyburide on cardiac function in patients with type 2 diabetes, systolic dysfunction, and New York Heart Association (NYHA) functional Class II/III HF.

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] Pioglitazone is currently used as an anti-diabetic agent and can reduce cardiovascular events in in patients with type 2 diabetes mellitus (T2DM). Left ventricular diastolic dysfunction has been recognized as an early manifestation of myocardial dysfunction in T2DM patients. This systematic review and meta-analysis aimed to investigate changes in the left ventricular diastolic function after the treatment of pioglitazone.

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

Adverse cardiovascular events during treatment with pioglitazone and rosiglitazone: population based cohort study. [2021] To compare the risk of acute myocardial infarction, heart failure, and death in patients with type 2 diabetes treated with rosiglitazone and pioglitazone.

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

Glycaemic and nonglycaemic effects of pioglitazone in triple oral therapy of patients with type 2 diabetes. [2022] To examine pioglitazone as add-on to metformin and insulin secretagogues in patients with type 2 diabetes and inadequate glycaemic control and its effect on glycaemic control, surrogate measures of insulin sensitivity (adiponectin) and beta-cell function (proinsulin/insulin) and fluid retention.

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

Spotlight on pioglitazone in type 2 diabetes mellitus. [2019] Pioglitazone (Actos(trade mark)) is an antihyperglycemic agent that, in the presence of insulin resistance, increases hepatic and peripheral insulin sensitivity, thereby inhibiting hepatic gluconeogenesis and increasing peripheral and splanchnic glucose uptake. Pioglitazone is generally well tolerated, weight gain and edema are the most common emergent adverse events, and there are no known drug interactions between pioglitazone and other drugs. In clinical trials in patients with type 2 diabetes mellitus, pioglitazone as monotherapy, or in combination with metformin, repaglinide, insulin, or a sulfonylurea, induced both long- and short-term improvements in glycemic control and serum lipid profiles. Pioglitazone was also effective in reducing some measures of cardiovascular risk and arteriosclerosis. Pioglitazone thus offers an effective treatment option for the management of patients with type 2 diabetes.

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] Pioglitazone may cause fluid retention, a well-known side effect of thiazolidinediones, and may exacerbate heart failure. Patients with type 2 diabetes and mild cardiac disease (New York Heart Association functional class I) received pioglitazone (n=151) or glyburide (n=149) for 1 year. The primary endpoint was change in distance covered in the 6-minute walk test. Main secondary endpoints included comparison of cardiovascular mortality and morbidity, analysis of changes from baseline in cardiac structure and function by echocardiogram, and lipid panel. There was no significant treatment difference in the mean change from baseline in the 6-minute walk test (-11.7 m [95% confidence interval, -29.79 to 6.42]). Cardiovascular mortality and morbidity were not significantly different between the treatment groups. Echocardiographic data suggested no significant deterioration in cardiac function with pioglitazone, although more heart failure (10 vs 7 patients), edema (21.2% vs 12.8%), and weight gain (2.56+/-4.62 kg vs 0.86+/-3.85 kg) were observed than with glyburide.

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

Pioglitazone-induced congestive heart failure and pulmonary edema in a patient with preserved ejection fraction. [2020] Pioglitazone-induced heart failure is known in patients with underlying heart disease, but is not well documented in patients with normal left ventricular function. Pioglitazone has been very popular as it is an insulin sensitizer and insulin resistance is prevalent among Indians. Fluid retention exacerbates pre-existing heart failure or precipitates heart failure in a patient with underlying left ventricular dysfunction. However, pathogenesis of heart failure in a patient with normal left ventricular function is not known. Probably it is due to dose-related effect on pulmonary endothelial permeability, rather than alterations in left ventricular mass or ejection fraction. We report a patient who developed congestive heart failure and pulmonary edema with normal left ventricular function within 1 year of starting pioglitazone therapy. We have to be careful in monitoring all possible side effects during followup when patients are on pioglitazone therapy.