Effects of Post-Transplant Drugs on Lipids and Treatment Options

Epidemiology
The ever- increasing population of patients living after organ transplantation has added an important dimension to the specific management needs of these patients. One major area in this regard pertains to the effects of post-transplant immunosuppressive drugs on lipids and lipoproteins. In addition, a number of agents in this expanding arena cause several metabolic perturbations that lead to development of new-onset diabetes after transplantation (NODAT), with or without high blood pressure (Table 1). It has been estimated that rates of NODAT are approximately 20%-50% after renal transplant, 10%-30% after liver transplant, and up to 30% after heart transplant at one year or later post-transplant, depending on age, BMI, ethnic and genetic background and the nature of the immunosuppressive regimen.^1,2 The consequences of NODAT include additional features of dyslipidemia linked to the pathophysiology of diabetes itself, compounded by the specific effects of post-transplant drugs. Moreover, patients with chronic kidney disease (CKD), the most numerous transplantation category, often present with years of suboptimal treatment of background dyslipidemia and atherosclerosis prior to transplantation. In a large cohort of 1.2 million people, followed for a period of four years, the incidence of myocardial infarction (MI) without prior history of MI was greater in those with CKD Stage 3 or worse (GFR < 60ml/min) than in those with diabetes without CKD, and two-fold higher in those with GFR < 45 ml/min, compared to those with diabetes without CKD.³ However, the incidence of coronary heart disease (CHD)-related events and mortality is highest when diabetes and CKD coexist, as documented in the NHNES III survey.⁴ The prevalence of CKD in patients with prior diabetes has been increasing because of the increasing prevalence of the latter.⁵

Mechanism of dyslipidemia related to post-transplant drugs
Immunosuppressive agents used to preserve a transplanted organ’s function have variable lipid effects. This is particularly relevant in post-renal transplant patients, given their increased underlying atherosclerosis related to CKD for years prior to transplantation and compounded by numerous alterations in lipoprotein pathophysiology related to progressive proteinuria, azotemia, malnutrition and catabolic state.^6,7 These include changes in virtually all apolipoprotein B (apo B) lipoproteins, remnant particles, lipoprotein lipase, apoprotein CII/CIII ratio, cholesteryl ester transfer protein (CETP) and highdensity lipoprotein (HDL) metabolism. While total cholesterol levels are often increased in the presence of nephroticrange proteinuria and hypoalbuminemia, the progression to ESRD is typically characterized by increased triglyceride levels due to impaired apo CII/CIII ratio, impaired LPL activity leading to atherogenic IDL and remnant particle accumulation, as well as low HDL . The latter is propagated by reduced hepatic lipase, and increased CETP activity, and inadequate maturation of HDL 3 to HDL-2.⁶

Glucocorticoids, the mainstay of an immunosuppressive regimen, have pronounced effects on metabolic pathways, including induction of insulin resistance, inhibiting pancreatic b-cell function and augmenting α-cell function.^8,9 By enhancing lipolysis and promoting relocation of adipose tissue, these agents promote visceral adiposity and dyslipidemia of insulin resistance.

Mycophenolic acid (MMF) and calcineurininhibitors (CNIs) (such as cyclosporine and tacrolimus) were introduced as a major advancement in the pursuit of a glucocorticoid-sparing regimen in posttransplant patients, and are often used as the preferred combination therapy after short-term use of glucocorticoids in the induction phase. MMF is largely devoid of metabolic effects. CNIs, however, have significant dose-related metabolic effects, primarily related to their effects on b-cell function and apoptosis.² Tacrolimus has a more pronounced effect on glycemia than cyclosporine, but the latter has a more pronounced effect on blood pressure.^2,10

Mammalian targets of rapamycin (mTOR) inhibitors, such as sirolimus and everolimus, represent an alternative immunosuppressant option when CNIs may be ineffective.^11,12,13 mTOR is a PI_3- kinase like serine/threonine protein kinase that has emerged as a significant regulator of lipogenesis, lipolysis and adipogenesis.¹² It exists as two complexes, mTORC-1 and mTORC-2, both of which are likely inhibited by rapamycin (sirolimus). The precise mechanism of effects of sirolimus on lipid biology is unclear, but it inhibits catabolism of apo-B-100, raises free fatty acid (FFA) levels and decreases lipoprotein lipase activity.¹¹ Everolimus, another mTOR inhibitor currently approved for certain cancer treatments, has been reported to cause severe hypertriglyceridemia and cases of acute pancreatitis.^11,13 In a 12-month comparative trial of 1,645 patients receiving renal transplants(The Symphony trial), comparing a low-dose regimen of cyclosporine, low-dose tacrolimus and low-dose sirolimus with standard-dose cyclosporine, the cyclosporine-based regimen was associated with a greater increase in blood pressure and sirolimus was associated with the worst lipid profile.¹⁰ The mean LDL-C and Triglycerides levels in the sirolimus group were 11% and 25% greater respectively, at 1 year, compared to the patients on Tacrolimus ( p< 0.05), and 39%, compared to 26% respectively needed lipid-lowering medications.¹⁰ It has been postulated that the development of specific mTORC-1 inhibitors might limit the side effects of mTOR inhibitors.¹³

Management Considerations
Based on extensive meta-analyses, statins are the mainstay for the risk-reduction strategy in all patients at high risk of CHD, including those with CKD.^14,15,16 Two large randomized controlled trials in patients on hemodialysis however, provided a lack of evidence of cardiovascular benefits in such patients, despite the high risk of CVD and mortality.^17,18 In another large trial reporting CHD risk reduction with simvastatin plus ezetimibe, a substantial number of patients with advanced CKD initiated dialysis during the trial.¹⁹ In the only clinical trial conducted in > 2000 renal-transplant patients,²⁰ a 1 mmol reduction in low-density lipoprotein cholesterol (LDL-C) after treatment with fluvastatin 40 mg-80 mg compared to placebo resulted in a significant reduction in cardiac death and definite MI (RR 0.65, CI 0.48-0.88; p < 0.005) after five years^20,21 ( Figure 1). The 10- year risk of coronary death or MI in this trial was > 20% and these results were in line with the effects of statins in the general population.¹⁴ In view of the overall evidence of the benefits of statins, the recent update of the Kidney Disease: Improving Global Outcomes (KDIGO) working group recommended treating all post-renal transplant patients with a statin,²² while adjusting the statin dosage according to the higher risk of adverse effects in such patients or the possibility of drug interactions because of pharmacokinetic differences in patients with residual renal insufficiency²³(Table 2).This also is highlighted by the updated National Kidney Foundation guidelines for the selection and dosage for fibrate therapy.¹⁵ There is no definitive evidence that supports the use of fibrates in pre- or post-transplant patients.

The most recent American Heart Association/American College of Cardiology²⁴ and the KDIGO cholesterol guidelines²² do not advocate routine measurements of LDL-C if the optimal dosage of statin therapy is utilized as recommended; however, it may be prudent to monitor lipid levels and renal status periodically in post-transplant patients, because the dosage may need to be adjusted if renal function deteriorates over time or the choice of immunosuppressant drug therapy needs to be revised according to clinical circumstances. The AHA/ACC recommendations do support lipid monitoring to assure that appropriate percentage reductions in LDL-C have been achieved.

In statin-intolerant patients, bile acid sequestrants or niacin are alternatives, although there are no studies in patients with CKD or post-transplant patients.

Disclosure statement: Dr. Ganda has received research funding from Amarin Corp. and has received honorarium from Janssen Pharmaceuticals, Inc. and Boehringer-Ingelheim.