Insulin Resistance in Pulmonary Arterial Hypertension

Inclusion Criteria:

Patients with PAH must be stable on therapy for at least 3 months prior to enrollment in the trial. We will include patients with IPAH and FPAH as well as PAH associated with collagen vascular disease or drug or toxin exposure. With the exception of PAH, subjects must be free of major medical illnesses, including diabetes mellitus (must have fasting plasma glucose < 126 mg/dL and taking no anti-hyperglycemic agent), malignancy or significant hepatic or renal disease. Subjects may be hypertensive and on anti-hypertensive medications as long as blood pressure is < 150/100 mm Hg. Subjects may also be dyslipidemic and/or taking drugs to improve abnormalities of lipid metabolism, but they will be excluded if they are taking medications known to alter insulin sensitivity, including glucocorticoids, niacin, anti-retrovirals, thiazolidinediones, or metformin. Use of oral contraceptives or estrogen and/or progesterone replacement therapy is permitted. Weight must be stable and the subjects agree not to change their eating habits or exercise regimen during the study period. There will be no restrictions with regard to race or socioeconomic status, and the racial/ethnic composition of the study population will be reflective of the communities surrounding the Stanford University Medical Center.

Exclusion Criteria:

* Vulnerable subject status.

• Concurrent ET-1 antagonist therapy
• Concurrent Thiazolidinedione therapy
• New York Heart Class III or IV
• PAH related to other etiologies.
• Diabetes Mellitus with Fasting Glucose Levels > 126 mg/dL
• Allergy or hypersensitivity to pioglitazone or bosentan administration.
• Current treatment with statin therapy.
• Initiation of PAH therapy (prostacyclin analogues, phosphodiesterase-5 inhibitors) within three months of enrollment.
• Inability or unwillingness to avoid systemic steroid containing medications for four months. Inhaled steroid use is acceptable.
• Current or recent use or planned treatment with: glyburide, cyclosporine, nilotinib, nisoldipine, ranolazine, thioridazine
• Hepatic transaminases > 2x the upper limit of normal at the center at screening.
• Current or recent (< 6 months) chronic heavy alcohol consumption.
• Current use of another investigational drug (non-FDA approved) for PAH.
• Lung transplant recipients.
• History of myositis.
• Renal failure (Cr 2.0).
• Hospitalized or acutely ill.
• Chronic liver disease (cirrhosis, chronic hepatitis, etc.).
• Abnormalities of the arm or hand or radical mastectomy (preventing brachial artery ultrasound).
• Pregnant or lactating women.