mTOR inhibitors and dyslipidemia in transplant recipients: a cause for concern?

Abstract

Post-transplant dyslipidemia is exacerbated by mammalian target of rapamycin (mTOR) inhibitors. Early clinical trials of mTOR inhibitors used fixed dosing with no concomitant reduction in calcineurin inhibitor (CNI) exposure, leading to concerns when consistent and marked dyslipidemia was observed. With use of modern concentration-controlled mTOR inhibitor regimens within CNI-free or reduced-exposure CNI regimens, however, the dyslipidemic effect persists but is less pronounced. Typically, total cholesterol levels are at the upper end of normal, or indicate borderline risk, in kidney and liver transplant recipients, and are lower in heart transplant patients under near-universal statin therapy. Of note, it is possible that mTOR inhibitors may offer a cardioprotective effect. Experimental evidence for delayed progression of atherosclerosis is consistent with evidence from heart transplantation that coronary artery intimal thickening and the incidence of cardiac allograft vasculopathy are reduced with everolimus versus cyclosporine therapy. Preliminary data also indicate that mTOR inhibitors may improve arterial stiffness, a predictor of cardiovascular events, and may reduce ventricular remodeling and decrease left ventricular mass through an anti-fibrotic effect. Post-transplant dyslipidemia under mTOR inhibitor therapy should be monitored and managed closely, but unless unresponsive to therapy should not be regarded as a barrier to its use.