Insulin Resistance in Pulmonary Arterial Hypertension
Condition: Hypertension, Pulmonary
MeSH terms: Pulmonary Arterial Hypertension; Hypertension, Pulmonary; Hypertension; Insulin Resistance
Intervention: bosentan; Pioglitazone
Intervention description: Bosentan 62.5 mg BID for 4 weeks, then 125mg BID for duration of study.; Pioglitazone 15 mg a day for 4 weeks then Pioglitazone 30 mg a day for the duration fo the study.
Intervention MeSH terms: Pioglitazone; Bosentan
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 2.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: pulmonary hypertension & insulin resistance

Summary:

      The purpose of this study is to evaluate 1) the incidence of insulin resistance (a
      pre-diabetic state) in patients with pulmonary hypertension, and 2) test the utility of a
      validated PH therapy (Tracleer) versus Pioglitazone in the treatment of those patients found
      to have insulin resistance.
    

Eligibility criteria:

        Inclusion Criteria:

        Patients with Pulmonary Arterial Hypertension (PAH) must be stable on therapy for at least
        3 months prior to enrollment in the trial. We will include patients with idiopathic PAH and
        Familial PAH 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 Endothelin-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.