Interventions Against Insulin Resistance in Pulmonary Arterial Hypertension

The investigators propose to test the hypothesis that interventions to improve insulin
resistance will improve exercise capacity and World Health Organization (WHO) functional
class in PAH. The investigators propose three specific aims to test this 1) A prospective 2x2
factorial design 12-week clinical trial of metformin or placebo and activity intervention or
usual care to assess effect on six minute walk and WHO functional class, 2) Assessment of the
interventions in Aim 1 in a subset of patients on right ventricle (RV) and peripheral muscle
function and lipid content and markers of pulmonary vascular disease to define how these
interventions may work in PAH and 3) Identify and prospectively test peripheral blood markers
of metformin response in PAH. The broad goals of this work are to demonstrate the efficacy
and mechanisms of interventions against insulin resistance in PAH and to identify which
patients are most likely to benefit from these interventions, moving to precision medicine in
PAH.

The investigators are planning a factorial design trial. Patients will be randomized twice.
The first is metformin or placebo and is quadruple randomized. The second is mobile health
(mHealth) intervention via texts or standard of care and is not blinded to the patients, but
is to the investigator and thus is triple randomized.

Inclusion Criteria:• Adults aged 18 or older.

- Diagnosed with idiopathic, heritable, or drug- or toxin-associated pulmonary arterial
hypertension (PAH) according to World Health Organization consensus recommendations.

- Stable PAH-specific medication regimen for three months prior to enrollment. Subjects
with only a single diuretic adjustment in the prior three months will be included.
Adjustments in IV prostacyclin for side effect management are allowed.

- Subjects must own a Bluetooth capable modern smartphone capable of receiving and
sending text messages and an active data plan.

- WHO Functional Class I-III

- Ambulatory

Exclusion Criteria:

- Prohibited from normal activity due to wheelchair bound status, bed bound status,
reliance on a cane/walker, activity-limiting angina, activity-limiting osteoarthritis,
or other condition that limits activity

- Pregnancy

- Diagnosis of PAH etiology other than idiopathic, heritable, or associated with drugs
or toxins

- Forced vital capacity <70% predicted

- WHO Functional class IV heart failure

- Requirement of > 1 diuretic adjustment in the prior 30 days

- Preferred form of activity is not measured by an activity tracker (swimming, ice
skating, stair master, or activities on wheels such as bicycling or rollerblading)

- Type I diabetes mellitus

- Prior diagnosis of cirrhosis

- Untreated hypo- or hyper-thyroidism

- estimated glomerular filtration rate (eGFR) by modification of diet in renal disease
(MDRD) <60 milliliters per minute (mL/min)