Pioglitazone on Heart Failure in Type-2 Diabetes Mellitus Participants (PIOHF)

Pioglitazone, Lipotoxicity, and Heart Failure With Preserved Ejection Fraction (HFpEF)

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.

Study Overview

• Status: Recruiting
• Conditions: Type 2 Diabetes Mellitus in Obese; Heart Failure With Preserved Ejection Fraction
• Intervention / Treatment: Drug: Pioglitazone; Drug: Placebo

Detailed Description

Either Pioglitazone or Placebo Pioglitazone will be administered during this study in this Type 2 Diabetic population with Heart Failure to examine if there are any beneficial effects on diastolic and systolic function.

Myocardial blood flow (MBF) is measured using a PET scan, then participants will be randomized to pioglitazone or a placebo to examine the effects of the study drug on the effects on the systolic and diastolic function of the heart. In addition, myocardial insulin sensitivity change will be measured as well as myocardial fat content. The ratio of ATP: PCr will also be measured.

• Study Type: Interventional
• Enrollment (Estimated): 78
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Sivaram Neppala, MD; Phone Number: 210-358-7200; Email: neppalas@uthscsa.edu
• Study Contact Backup: Name: Andrea Hansis-Diarte, MPh; Phone Number: 210-567-3208; Email: hansisdiarte@uthscsa.edu

Study Locations

• United States
  • Texas
    • San Antonio, Texas, United States, 78229-3900
      • Recruiting
      • Texas Diabetes Institute/UH
      • Contact: Sivaram Neppala, MD; Phone Number: 210-358-7200; Email: neppalas@uthscsa.edu
      • Contact: Ralph DeFronzo, MD; Phone Number: 210-358-7200; Email: defronzo@uthscsa.edu
      • Principal Investigator: Ralph DeFronzo, MD
      • Sub-Investigator: Sivaram Neppala, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Provision of signed and dated informed consent form
2. Stated willingness to comply with all study procedures and availability for the duration of the study
3. Male or female, aged 30-70 years
4. Body Mass Index (BMI) of 27.5-40kg/m²
5. HbA1c of 6.5 to 10%
6. Blood pressure of less than or equal to 145/65mmHg
7. eGFR greater than 45 ml/min/1.73m²
8. Subject must have HFpEF (EF > 50% by ECHO screening)
9. NYHA class II-III heart failure
10. Only T2D patients treated with diet/exercise, metformin, sulfonylurea, metformin/SU, DPP4i or insulin will be studied.
11. 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.
12. For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner.

Exclusion Criteria:

1. Subjects with history of osteoporosis or proliferative diabetic retinopathy
2. Subjects with Heart failure due to restrictive or infiltrative cardiomyopathy, active myocarditis, constrictive pericarditis, severe valvular heart disease, etc. will be excluded
3. Patients with symptomatic coronary artery disease.
4. Subjects with significant change in diuretic management during the month prior to screening (defined by doubling of diuretic dose, or addition of another HF medication).
5. Subjects treated with a GLP-1 RA or thiazolidinedione.
6. Subjects treated with a SGLT2i
7. Pregnancy or lactation
8. Known allergic reactions to components of the study interventions.
9. Any metal plates, parts, screws, shrapnel, pins in body, or cardiac (heart) pacemaker

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Pioglitazone Administration Group; Pioglitazone 15mg/day titrated to 30 mg/day at week 2 and to 45 mg/day at week 4	Drug: Pioglitazone; Participants will be taking Pioglitazone tablets 1/day for 24 weeks.; Other Names: Actos
Placebo Comparator: Placebo/Control Group; Placebo	Drug: Placebo; Placebo for Pioglitazone; Other Names: Placebo tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Systolic function	Measurement of change in systolic function of the heart using cardiac MRI	Baseline and 6-months post treatment (approximately 24 weeks)
Change in Diastolic function	Measurement of change in diastolic function of the heart using cardiac MRI	Baseline and 6-months post treatment (approximately 24 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Myocardial insulin sensitivity	Measurement of change in Free Plasma Glucose (FPG) in blood plasma	Baseline and 6-months post treatment (approximately 24 weeks)
Myocardial fat content	Measurement of change in myocardial fat content	Baseline and 6-months post treatment (approximately 24 weeks)
PCr:ATP ratio	Measurement of change in PCr:ATP ratio	Baseline and 6-months post treatment (approximately 24 weeks)

Collaborators and Investigators

• Sponsor: The University of Texas Health Science Center at San Antonio
• Investigators: Principal Investigator: Ralph A DeFronzo, MD, University of Texas

Study record dates

Study Major Dates

• Study Start (Actual): July 10, 2023
• Primary Completion (Estimated): August 1, 2029
• Study Completion (Estimated): January 1, 2030

Study Registration Dates

• First Submitted: April 10, 2023
• First Submitted That Met QC Criteria: April 20, 2023
• First Posted (Actual): May 1, 2023

Study Record Updates

• Last Update Posted (Estimated): August 27, 2025
• Last Update Submitted That Met QC Criteria: August 26, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Heart Failure; Diabetes Mellitus; Diabetes Mellitus, Type 2; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Substandard Drugs; Pharmaceutical Preparations; Thiazoles; Azoles; Thiazolidinediones; Pioglitazone; Counterfeit Drugs
• Other Study ID Numbers: HSC20220916H

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: IPD data will not be available to other researchers.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No