**4. Therapies to address hyperlipidemia**

Hyperlipidemia is associated with significant morbidity and mortality rates in transplant recipients [87]. Many strategies have been investigated to target dyslipidemia in transplant patients. A number of excellent comprehensive reviews have been published on the clinical management of hyperlipidemia and its risks (eg [88,89]). We will therefore restrict our comments to a very brief summary of this area.

#### **4.1. Statins**

Statins inhibit HMG-CoA reductase, the rate limiting enzyme in the cholesterol synthesis pathway and are world-wide the drug of choice to lower plasma LDL-C levels. Various statins have been tested in transplant patients and all show significant lowering of plasma cholesterol, LDL-C and apoB levels with some indicating improved survival rates (for review see [88,89,90]). A randomized trial, investigating the safety and efficacy of statins in renal transplant patients, the Assessment of LEscol in Renal Transplantation (ALERT) study, showed that fluvastatin effectively lowered LDL-C by 32% and reduced cardiac death and non-fatal myocardial infarction incidence significantly [91]. Importantly, statins may provide beneficial effects other then their lipid-lowering properties [92]. Wissing et al [93] reported improved flow mediated brachial artery vasodilatation by atorvastatin in kidney transplant patients and significant reductions in acute rejections have been observed in cardiac transplant patients [94].

Rhabdomyolysis, one of the few serious side effects of statins, is more common with high dose statin treatment. The risk is elevated in patients with renal disease and in patients taking drugs affecting statin metabolism, especaily in those taking CsA [88,89]. All statins have the potential to interact with CsA, as CsA substantially increases plasma levels of all statins. Although this is most notable for those metabolized via the Cyp3A4 pathway, statins not metabolized via the Cyp3A4 pathway [95] such as pravastatin and fluvastatin are also affected [95], suggesting that the interaction of CsA and statins may involve other mechanisms such as inhibition of drug transporters. Simvastatin poses the highest risk of myopathy, and particular care must be taken with higher doses of this agent, with recommendations that doses of 10mg/d are not exceeded in transplant patients [89]. Because statin therapy has been associated with mortality benefit after transplantation, correction of hyperlipidemia using lower doses of statins is mandatory after transplantation. Therefore careful clinical monitoring of patients as well as measurement of creatine kinase levels to detect muscle injury is advised, and the use of statins that are not metabolized via CYP3A4, such as fluvastatin or pravastatin may be preferential [95].

#### **4.2. Fibrates**

346 Lipoproteins – Role in Health and Diseases

contributing to hypercholesteremia *in vivo*.

**4. Therapies to address hyperlipidemia** 

comments to a very brief summary of this area.

**4.1. Statins** 

The effects of CsA on CYP27A1 may relate to effects of CsA on cholesterol metabolism. 27 hydroxycholesterol is a potent negative feedback regulator of HMG-CoA reductase [74] and decreased CYP27A1 activity may therefore explain increased HMG-CoA reductase mRNA and cholesterol levels [57]. Although important in macrophages, it should be noted however that it is not clear whether such a feedback loop exists in liver cells [75]. Increased cholesterol synthesis could subsequently lead to downregulation of LDLr levels as observed in some CsA

Besides effects on bile acid synthesis CsA may affect bile flow. CsA treatment is associated with increased plasma bile acid concentrations and cholestasis in humans as well as in animal models [9,52,76]. Studies in rat indicate that bile flow and the secretion of bile salts, proteins and lipids into the bile are dose-dependently inhibited by CsA [52,76,77]. Interestingly, the changes in serum levels of bile acids are consistent with CsA-mediated inhibition of hepatocellular uptake of individual bile acids [78,79]. The inhibitory effect was greater for phosholipid secretion than that for cholesterol [80] and in some studies no inhibition of cholesterol excretion was observed [81], suggesting differential effects on transport mechanisms. Transport pumps involved in bile synthesis and secretion belong to the family of the ATP-binding cassette transporters which include, multidrug resistance proteins (MDR) and P-glycoprotein, and most of which are effectively inhibited by CsA [79,82]. Interestingly, comparison of the bile salt export pump (BSEP) activity from different species, showed that CsA inhibits bile salt transport with species and bile salt specific variation [83]. Rat BSEP was for example more effectively inhibited than mouse BSEP. Biliary cholesterol secretion is mediated via ABCG5 and ABCG8 [84]. Although both members of the ATPbinding cassette family, it has not been investigated whether CsA inhibits ABCG5/8 activity. As phospholipids are transported via MDR3, it is likely that differences in efficacy of CsA between inhibition of MRD3 and ABCG5/8 exist. It is clear that CsA can affect bile flow and secretion in cultured cells and animal models. It should be noted however, that in humans no inhibitory effect of CsA on secretion of bile acids and lipids or on bile composition after liver transplantation was observed [85]. Others have shown that although cholate synthesis was reduced by CsA, compensatory increased intestinal absorption counteracted this decrease [86]. It remains therefore unclear to what extent inhibition of bile flow and secretion by CsA are

Hyperlipidemia is associated with significant morbidity and mortality rates in transplant recipients [87]. Many strategies have been investigated to target dyslipidemia in transplant patients. A number of excellent comprehensive reviews have been published on the clinical management of hyperlipidemia and its risks (eg [88,89]). We will therefore restrict our

Statins inhibit HMG-CoA reductase, the rate limiting enzyme in the cholesterol synthesis pathway and are world-wide the drug of choice to lower plasma LDL-C levels. Various

studies, also contributing to increased plasma cholesterol levels (see section 3.2.1).

Fibrates lower plasma triglyceride levels via activation of the Peroxisome Proliferator Activated Receptor alpha (PPARα) and may be useful in transplant patients with elevated plasma triglycerides especially in combination with statin treatment to lower plasma cholesterol levels. Gemfibrozil was found to significantly lower plasma triglyceride levels in heart transplant patients and increase long term survival [96,97]. Fenofibrate is less well studied in transplant patients and may be associated with increased nephrotoxicity [88,98]. Care must be taken administering fibrates with CsA, particularly in combination with statins as drug-drug interactions exist via CYP3A4 as well as the hepatic uptake transporter the organic anion transporting polypeptide 1B1 (OAT1B1).

#### **4.3. Ezetimibe**

Inhibition of intestinal cholesterol absorption to lower high plasma cholesterol levels may be used when statins or fibrates are ineffective or are not tolerated. Ezetimibe proved to be an effective drug lowering plasma LDL-C levels significantly by blocking cholesterol absorption in the small intestine [99]. To that point though, various studies showed effective LDL-C lowering in liver, cardiac and renal transplant recipients [99]. Although, drug-drug interaction between CsA and ezetimibe were suggested (See [88]), CsA levels in studied transplant patients were not affected by combined ezetimibe use (reviewed in [99]). Coadministration of ezetimibe with (low-dose) statins has been found to effectively reduce high plasma cholesterol levels in transplant recipients and may be useful in patients that resistant to high-dose statin or where target plasma lipid levels can not be achieved by statin therapy alone [100,101].
