The goal of this clinical trial is to learn about the safety and efficacy of Pioglitazone in people with Pulmonary Hypertension (PH) due to Chronic Lung Disease (CLD). The main question it aims to answer is:

• Whether pioglitazone affects mitochondrial oxygen utilization in patients with PH due to CLD.

Participants will be asked to take pioglitazone or placebo once daily for 28 days followed by a washout period of 2 weeks followed by 28 days of the other study drug (participants randomized to placebo followed by pioglitazone or pioglitazone followed by placebo).

Pulmonary hypertension (PH) is a state of chronic elevated pressure in the pulmonary circulation. PH has multiple possible causes, clinically classified into 5 separate groups according to the World Symposium on PH classification scheme. PH is common in adults, with increasing prevalence with age, and is associated with significant symptom burden and mortality. In the U.S., approximately 1.5 million U.S. adults have PH, including 5-10% of people >65.

Metabolic abnormalities have been highlighted recently as contributing to PH pathogenesis, disease severity, and outcome. In pre-clinical studies, reduced mitochondrial metabolism (oxidative phosphorylation) and reliance on alternative metabolic pathways (glycolysis) have been shown to promote pulmonary vascular remodeling and PH. Mechanistic investigation has shown that reduced PPARγ activity in lung vascular cells is necessary and sufficient to cause cellular proliferation and dysfunction followed by PH, all of which can be reversed by available pharmacotherapies designed to activate PPARγ.

Metabolic changes have been demonstrated in 1) lung vessels from multiple PH animal models and 2) humans with PAH 3) right ventricle from humans with PAH, 4) skeletal muscle from humans with PAH, 5) circulating platelets from humans with PAH and PH due to left heart disease. Clinical trials of therapies that activate PPARγ have not been previously conducted in patients with PH but are believed by experts in the field to be a highly promising therapeutic approach.

In this trial, the investigators will study the mitochondrial metabolic effects ("bioenergetics") of pioglitazone, an available medication from the class of thiazolidinedione (TZD) drugs that activate PPARγ. This medication is FDA-approved for the treatment of Type II diabetes mellitus (DM). Pioglitazone has been studied in non-diabetics with diverse other conditions demonstrating safety.

The study team will assess cellular energy metabolism through a sophisticated assay of bioenergetics. The investigators and others have shown that bioenergetics can be measured in isolated platelets obtained from a peripheral blood draw in patients with PH and other diseases. Furthermore, others have shown that in PAH, platelet bioenergetics correlate with known disease-relevant metabolic changes in lung blood vessels. In this study, the team will assess the effect of pioglitazone on bioenergetic parameters in platelets isolated from whole blood samples.

Inclusion Criteria:

• Provision of a signed and dated informed consent form

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

• Confirmed to have pulmonary hypertension (PH) due to chronic lung disease at screening

  • Pulmonary hypertension is defined based on meeting all three of the following measured at rest during the RHC:

    • Mean pulmonary artery pressure >20 mmHg
    • Pulmonary artery wedge pressure ≤15 mmHg
    • Pulmonary vascular resistance > 2 Wood units

  • Pulmonary hypertension is classified in Group 3: PH associated with lung diseases and/or hypoxia

• Medications approved for the treatment of pulmonary hypertension must be at a stable dose for at least 30 days

• Ability to take oral medication and be willing to adhere to the study intervention regimen

• For females of reproductive potential: agreement to use highly effective contraception during study participation and for an additional 4 weeks after the end of study participation.

• For males of reproductive potential: use of condoms or other methods to ensure effective contraception with a partner

• Agreement to adhere to Lifestyle Considerations (below) throughout the study duration o During this study, participants are asked to arrive in the clinic for study visits in the fasting state. Specifically, participants should abstain from any caloric intake for 6 hours before arrival for the study visit.

Exclusion Criteria:

• Diabetes mellitus (type 1 or type 2), present within the preceding 1 year
• Personal history of symptomatic hypoglycemia within 90 days preceding enrollment
• Personal outpatient use of pioglitazone, rosiglitazone, metformin, insulin, or other medications for the indication of diabetes within 90 days preceding enrollment
• History of left ventricular failure (systolic or diastolic)
• Pulmonary hypertension due to Group 2 PH (PH due to left heart disease)
• History of prior or active bladder cancer
• Thrombocytopenia (diagnosis or known platelet count ≤120) within 90 days preceding enrollment
• Platelet count ≤120 during screening or on the day of enrollment hypertension due to chronic lung disease
• Cystic fibrosis
• Pregnancy or lactation
• Current tobacco use
• Known allergic reaction to components of the study medication (pioglitazone)
• Treatment with another investigational drug within 30 days