Clinical Trial of Pioglitazone for Prevention of Cardiac Allograft Vasculopathy After Heart Transplantation

• mean coronary artery plaque volume [ Time Frame: baseline and 1 year ] [ Designated as safety issue: No ]
• Change in levels of fasting glucose, lipids, ADMA, and hs-CRP [ Time Frame: Baseline and 1 year ] [ Designated as safety issue: No ]
• Change in levels of circulating markers of inflammation [ Time Frame: Baseline and 1 year ] [ Designated as safety issue: No ]

The purpose of this study is to determine the benefit of using the FDA-approved insulin-sensitizing agent, Pioglitazone, on human heart transplant recipients. The objectives of this project are to (1) determine if pioglitazone effectively treats insulin resistance in heart transplant recipients, and (2) to determine whether pioglitazone therapy after heart transplantation impacts the development or progression of cardiac allograft vasculopathy (CAV), a form of chronic rejection after heart transplantation.

CAV, a rapidly progressive obliterative disease involving the graft coronary arteries, is the leading cause of morbidity and mortality beyond the first year after heart transplantation. This common complication occurs in almost half of recipients within 3 years after heart transplantation, and is associated with high rates of graft failure and mortality. Clinical care of heart transplant recipients in the current era is greatly limited by the lack of effective treatment options to prevent or retard the progression of CAV. CAV appears to be strongly associated with the state of insulin resistance, which is present in over half of heart transplant recipients and is characterized by metabolic abnormalities including glucose intolerance, dyslipidemia, endothelial dysfunction, and high levels of circulating inflammatory markers. Insulin resistance can be effectively treated with pioglitazone, a TZD compound which directly affects tissue insulin sensitivity. In this study, we will enroll 32 insulin-resistant heart transplant recipients and will randomize them to pioglitazone or placebo for a one-year period. We will determine the efficacy of pioglitazone for the treatment of insulin resistance and prevention of the development and progression of CAV after heart transplantation. The data generated from this study will provide important preliminary data for future, larger-scale clinical investigations.

• Drug: Pioglitazone
  15mg pioglitazone taken daily for one month, 30mg pioglitazone taken daily for another month, 45mg pioglitazone taken daily for remaining ten months
  Other Name: Actos
• Drug: Placebo
  placebo taken daily for one year

• Active Comparator: Arm 1
  Pioglitazone
  Intervention: Drug: Pioglitazone
• Placebo Comparator: Arm 2
  Placebo
  Intervention: Drug: Placebo

Inclusion Criteria:

1. Heart transplant recipients, years 1-4 post-transplant
2. Age >= 18 years
3. Fasting TG/HDL ratio>=3.0 or Fasting TG>=150 mg/dL

Exclusion Criteria:

1. Diabetes mellitus
2. Severe liver dysfunction (ALT>=2.5 x upper limit of normal)
3. Severe renal dysfunction (GFR<30 or Stage IV CKD)
4. Moderate-severe fluid retention
5. Clinical or echocardiographic signs of left ventricular dysfunction
6. Contraindication to coronary angiography and/or IVUS