Transplantation Reviews xxx (2014) xxx–xxx

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Transplantation Reviews

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mTOR inhibitors and dyslipidemia in transplant recipients: A causefor concern?

Hallvard Holdaas a,⁎, Luciano Potena b, Faouzi Saliba c

a Section of Nephrology, Department of Transplant Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norwayb Heart Failure and Heart Transplant Program, Academic Hospital S. Orsola-Malpighi, Alma-Mater University of Bologna, Bologna, Italyc AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Villejuif, France

a b s t r a c t

Post-transplant dyslipidemia is exacerbated bymammalian target of rapamycin (mTOR) inhibitors. Early clinicaltrials of mTOR inhibitors used fixed dosing with no concomitant reduction in calcineurin inhibitor (CNI) expo-sure, leading to concerns when consistent and marked dyslipidemia was observed. With use of modernconcentration-controlledmTOR inhibitor regimenswithin 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 ofnormal, or indicate borderline risk, in kidney and liver transplant recipients, and are lower in heart transplant pa-tients under near-universal statin therapy. Of note, it is possible that mTOR inhibitors may offer acardioprotective effect. Experimental evidence for delayed progression of atherosclerosis is consistent with evi-dence from heart transplantation that coronary artery intimal thickening and the incidence of cardiac allograftvasculopathy are reduced with everolimus versus cyclosporine therapy. Preliminary data also indicate thatmTOR inhibitors may improve arterial stiffness, a predictor of cardiovascular events, and may reduce ventricularremodeling and decrease left ventricularmass through an anti-fibrotic effect. Post-transplant dyslipidemia undermTOR inhibitor therapy should be monitored and managed closely, but unless unresponsive to therapy shouldnot be regarded as a barrier to its use.

© 2014 Elsevier Inc. All rights reserved.

1. Introduction

Cardiovascular disease is the leading cause of death following kidneytransplantation [1]. The risk of fatal or non-fatal cardiovascular events inkidney transplant patients is estimated to be 50-fold higher than in thegeneral population [2], with cardiovascular events occurring in up to 5%of kidney transplant recipients each year [2–4]. Following liver trans-plantation, the risk of cardiovascular events is also increased comparedto controls, though to a lesser extent than after kidney transplantation[5,6]. In heart transplant patients, as might be expected, cardiovasculardisease is the most common cause of death, mainly related to cardiacallograft vasculopathy (CAV) [7,8].

The nature of chronic kidney disease means that transplant patientsare generally a high-risk group. In the last 20 years, for example, theproportion of patients wait-listed for kidney transplantation in the USaged 50 years or older has more than doubled [9]. In addition, thesecontributory factors are frequently compounded by an extended periodof chronic kidney disease prior to transplantation [10]. Poor renal func-tion after transplantation, moreover, can lead to progressive anemia, anupward influence on blood pressure and chronic inflammation. Finally,

⁎ Corresponding author at: Section of Nephrology, Department of Transplant Medicine,Oslo University Hospital, Rikshospitalet, Postbox 4950 Nydalen, N-0424 Oslo, Norway.Tel.: +47 23 07 00 00; fax: +47 23073865.

E-mail address: hallvard.holdaas@rikshospitalet.no (H. Holdaas).

http://dx.doi.org/10.1016/j.trre.2014.08.0030955-470X/© 2014 Elsevier Inc. All rights reserved.

Please cite this article as: HoldaasH, et al, mTOR inhibitors and dyslipidemihttp://dx.doi.org/10.1016/j.trre.2014.08.003

all organ transplant patients are exposed to the adverse effects of main-tenance immunosuppression [11]. The influence of immunosuppres-sion on cardiovascular risk is generally indirect, via increased risk ofhypertension, diabetes, nephrotoxicity and dyslipidemia.

In kidney [12], liver [5] and heart [13] transplantation, a significantassociation has been shown between increased total cholesterol andcardiovascular events and represents one of the major modifiable riskfactors. Indeed, an elevated cholesterol level confers a greater increasein risk for ischemic heart disease following kidney transplantation com-pared to non-transplanted controls [12].

2. Dyslipidemia after organ transplantation

Dyslipidemia is a routine finding in solid organ transplantation,affecting more than half of all kidney transplant patients during thefirst year post-transplant [11]. Typically, patients show an initial in-crease in total cholesterol and triglyceridemia during the first threemonths after transplantation which then tends to decline to a plateauaround 6–9 months (Fig. 1) [14,15], at least partly in response to useof lipid-lowering therapy [14,15]. In liver transplant patients, a persis-tent increase in serum lipid levels has also been documented [16],while in heart transplant recipients an increase in plasma levels oftotal cholesterol, low-density lipoprotein (LDL cholesterol) and triglyc-erides is typical within the first few months post-transplant [17]. Priorto near-universal use of statin therapy in heart transplant recipients,

a in transplant recipients: A cause for concern?, Transplant Rev (2014),

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Fig. 1.Mean total cholesterol level and use of lipid-lowering therapy during the first yearafter kidney transplantation inpatients randomized to standard-exposure tacrolimuswithsirolimus (target C0 8 ng/mL), tacrolimus with MMF or standard-exposure CsA withsirolimus (target C0 8 ng/mL), all with concomitant steroids [14].

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a clear correlationwas demonstrated between higher lipid levels andincreased risk of CAV [18].

Several factors influence the risk of dyslipidemia, including acuterejection, graft dysfunction, proteinuria and the immunosuppressive reg-imen [19]. Post-transplant dyslipidemia can be caused or exacerbated bycorticosteroids or calcineurin inhibitors (CNIs), but the most notablechanges in lipid status have been observed following the introduction ofmammalian target of rapamycin (mTOR) inhibitors [20]. When consider-ing the lipogenic effect of mTOR inhibitors, two distinct issues need to beassessed: first, any adverse effect on lipid status, and second, a potentialcardioprotective effect which may offset increased lipid levels.

3. Etiology of mTOR inhibitor lipogenic effect

The lipogenic effect of mTOR inhibitors, as for CNI therapy, arisesfrom several mechanisms [21] which are not fully elucidated. ThemTOR signaling pathway plays a role in regulating the uptake of lipidsinto adipose tissue and their breakdown by lipoprotein lipase [22]. Dis-ruption of the mTOR pathway appears to inhibit uptake of lipids intoadipocytes, resulting in 20–30% reduction in lipid storage [21]. mTORinhibitors also promote lipolysis, increasing basal lipolysis by approxi-mately 20%, and enhance the expression of lipogenic genes in adiposetissue [21,23]. The antilipolytic effect of insulin is impaired in thepresence of sirolimus, and mTOR inhibitors may delay the peripheralclearance of fatty acids [24] resulting in reduced incorporation of fattyacids into very low density lipoprotein (VLDL) [25]. Levels of free fattyacids have been shown to rise in mice after administration of sirolimusdue to augmented lipolysis and suppressed adipocyte storage [25].

4. Dyslipidemic effect of mTOR inhibitors: early clinical evidence

The early clinical trials of mTOR inhibitors used fixed dosing, oftenwith a substantial loading dose, and did not reduce concomitant expo-sure to CNIs. Results from these studies raised concerns about thelipogenic effect of such regimens. A pooled analysis [26] assessed datafrom two large controlled studies of 1295 de novo kidney transplantpatients receiving sirolimus 2 mg/day or 5 mg/day with standard-exposure cyclosporine (CsA) and steroids versus azathioprine orplacebo [27,28]. Compared to controls, mean cholesterol and triglyceridelevels were 17 mg/dL and 59 mg/dL higher in the sirolimus 2 g/daycohort, and 30 mg/dL and 103 mg/dL higher, respectively, in thesirolimus 5 mg/day cohort at one year post-transplant. Levels peakedaround months 2–3 and responded to lipid-lowering therapy [26].

Please cite this article as: Holdaas H, et al,mTOR inhibitors and dyslipidemihttp://dx.doi.org/10.1016/j.trre.2014.08.003

Similar observations were made in a pooled analysis of two randomizedtrials in which sirolimus dose was concentration-controlled but withhigh trough concentrations (30 ng/mL tomonth 2 and 15 ng/mL thereaf-ter), although again the effectwasmanageablewith lipid-lowering agents[29]. Ameta-analysis of trials performedup to 2005 confirmed thatmTORinhibitorswere associatedwith an increased risk of hypercholesterolemiacompared to antimetabolite therapy [30]. A wider systematic review ofstudies published up to 2008, which compared sirolimus or everolimusversus various non-mTOR inhibitor regimens, also concluded that therewas an increased prevalence of lipid-lowering treatment and higherlevels of cholesterol and triglycerides among kidney transplant patientsreceiving an mTOR inhibitor [20].

However, as evidence accumulated it became apparent that theeffect of mTOR inhibitors on lipid status is dose-dependent. For bothsirolimus [27,31] and everolimus [32], a lower fixed dosewas associatedwith smaller changes in lipid profile thanhigher doses, even in the pres-ence of standard-exposure CNI therapy. Modern mTOR regimens arenow routinely concentration-controlled, with no loading dose foreverolimus and smaller loading doses (if any) for sirolimus, and targettrough concentrations have declined over the last decade. A maximumtrough concentration target of 8 ng/mL for everolimus, and usually10 ng/mL for sirolimus, is generally considered suitable in kidney,liver and heart transplantation [33,34], most frequently administeredin combination with reduced-dose CNI when used as de novo immuno-suppression, or in a CNI-free regimen when introduced in maintenancepatients. This raises the question of whether the dyslipidemic effect ofmTOR inhibitors is still a cause for concern when using modern, lessintensive regimens with widespread administration of statin therapy.

5. Clinical experience using modern mTOR inhibitor regimens

No trials have been undertaken specifically to compare the lipogeniceffect of mTOR inhibitors versus other immunosuppressants. Interpre-tation of data from comparative clinical trials is complicated by thefact that the use and dose of lipid-lowering drugs are generally notspecified in the study protocol, and changes in their administrationover time are not usually recorded. Also, trials of mTOR inhibitors typi-cally exclude patients with very high lipid levels, and discontinuationdue to lipid abnormalities can potentially skew results in favor of themTOR inhibitor treatment group.With these caveats in mind, however,examination of lipid parameters in studies which have used contempo-rary, concentration-controlled regimens can be informative. TheEVERHEART study, which is currently ongoing, includes a standardizedhypolipidemic protocol to specifically study hypercholesterolemia withor without everolimus in the first fewweeks after heart transplantation(NCT01017029).

5.1. Kidney transplantation

Randomized trials of de novo kidney transplant patients comparingeverolimus or sirolimus versus mycophenolate mofetil (MMF) usingcontemporary mTOR exposure levels, and which reported lipid levels,are summarized in Table 1 [14,35,36]. Where the mTOR inhibitor wasadministered with standard-exposure CNI, use of lipid-loweringtherapy was higher in the mTOR inhibitor arm, with mixed resultsconcerning an effect on total cholesterol, LDL-cholesterol and triglycer-ides [14,36]. Between-group differences were less marked but persistedin a recent large randomized trial in which everolimus with low-doseCsA was compared to MMF with standard-exposure CsA, an approachwhich is now considered more appropriate. More studies have com-pared de novo mTOR inhibitor therapy in a CNI-free regimen versus aCNI-based regimen in [15,37–41]. Here, lipid-modifying agents wereagain used more frequently in patients receiving an mTOR inhibitor,and total cholesterol was typically higher versus CNI-treated patients,although differences for LDL-cholesterol and triglycerides were lessconsistent (Table 1). Of note, in these studies the increase in LDL was

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accompanied by a concomitant increase inHDL, leading to a stable or re-duced ratio of LDL to HDL such that the estimated lipid-related risk ofcardiovascular events was unchanged or lowered [42].

Several randomized trials in kidney transplant patients have com-pared CNI continuation versus switch to everolimus [43–45] orsirolimus [46–48] more than three months post-transplant, by whichtime lipid changes have typically peaked. In most cases, patients werefollowed for a minimum of one year post-conversion. In all but onereport from an interim analysis [44], mean total cholesterol was signif-icantly higher in the mTOR inhibitor group at last follow-up, with LDL-cholesterol and triglyceride levels also higher than in controls wheredata were provided. Holdaas et al included a third treatment group intheir randomized trial of 394 patients more than six months after kid-ney transplantation, in which patients started everolimus therapywith reduced CNI exposure [43]. As with CNI elimination, total choles-terol and triglycerides were higher after the introduction of everolimus.

For studies in which kidney transplant patients were converted tomTOR inhibitor therapy, mean total cholesterol level at last follow-upwas within the borderline high range (200–239 mg/dL) [43,45–48],LDL-cholesterol was either normal or borderline high (130–159 mg/dL)and triglycerides were borderline high (150–199 mg/dL) or high(≥200 mg/dL). Most trials did not report changes in lipid levels overtime. In the CONVERT trial, the increases in total cholesterol, LDL-cholesterol and triglycerides peaked at two months after conversionto sirolimus then declined [46]. However, more sirolimus-treated pa-tients were treated with lipid-lowering therapy (77.7% versus 54.6% inthe standard CNI group at month 24, p b 0.001).

5.2. Liver transplantation

In liver transplantation, three randomized trials have evaluated earlyconversion from CNI therapy to either sirolimus [49] or everolimus[50,51] (i.e. starting by one month post-transplant). Use of lipid-lowering therapy was far lower than in the studies of kidney transplantpatients (typically b20%). Each of the studies showed either total orLDL-cholesterol to be higher in the mTOR inhibitor group (Table 2).The largest trial in this setting, in which everolimus with reduced tacro-limus was administered from month 1 after liver transplantation,showed the combination regimen to be associated with significantlyhigher levels of triglycerides, total cholesterol and LDL-cholesterol atone year post-transplant compared to a standard CNI-based regimen,but also with higher HDL-cholesterol (Table 2) [52]. The use of lipid-lowering therapy in the everolimus/tacrolimus group was similar tothat of the tacrolimus-only cohort (23.3% versus 17.8%, p = 0.944).

Few trials have assessed conversion to anmTOR inhibitor regimen inmaintenance liver transplant patients and have only rarely reportedlipid levels. However the available data have consistently indicated ahigher rate of hypercholesterolemia as an adverse event following con-version from CNI therapy [53–56].Watson et al described a significantlygreater increase in total cholesterol at month 3 after conversion fromCNI to sirolimus therapy versus controls among a small group of 30maintenance liver transplant patients [57]. The difference becamenon-significant at month 12 but more sirolimus-treated patientsreceived statin therapy than in the CNI continuation group [57].

5.3. Heart transplantation

The situation in heart transplantation is somewhat different, sincealmost all patients receive statins or other lipid-lowering drugs. Theonly randomized trial to compare a concentration-controlled mTORinhibitor (everolimus) with early CNI discontinuation versus mainte-nance CsA therapy found no pronounced differences in lipid status atone year [58], while two comparative studies of everolimus versusMMF each showed significantly higher total cholesterol and triglyceridelevels [59,60] in the mTOR inhibitor group (Table 3). Use of lipid-

Please cite this article as: HoldaasH, et al, mTOR inhibitors and dyslipidemihttp://dx.doi.org/10.1016/j.trre.2014.08.003

lowering therapy was slightly higher (5–8% more patients) in thepatients receiving mTOR inhibitor in the latter two studies.

In a randomized trial of heart (n = 190) or lung (n = 92) mainte-nance transplant patients, Gullestad et al observed a significantly great-er increase in total cholesterol, LDL-cholesterol and triglycerides afterconversion to everolimus with reduced CNI exposure versus patientswho remained on standard CNI therapy [61], differences that continuedto two years after randomization [62]. From randomization to two yearspost-transplant, themean change in total cholesterolwas 0.5 mmol/L inthe everolimus group versus 0.1 mmol/L in the control arm (p b 0.001).The changes in LDL-cholesterol (0.3 versus 0.0 mmol/L, p= 0.010) andtriglycerides (0.3 versus 0.0 mmol/L, p= 0.002) were also significantlydifferent [62]. Conversely, Potena et al reported that as a consequence ofstatin dosing, heart recipients randomized to everolimus and very lowCNI showed no difference in lipid levels at three years after randomiza-tion compared to patients receiving MMF and low CNI [63].

5.4. General

Across all three organ types, the mean level of total cholesterol atone year post-transplant was in the range 173–225 mg/dL in patientsreceiving an mTOR inhibitor with various concomitant medications.These values straddle the upper range of ‘normal’ and ‘borderline risk’.For LDL-cholesterol, the mean levels were in the range 104–127 mg/dL,just below ‘borderline risk’. Mean triglyceride levels were in the range89–228 mg/dL, again varying between the upper range of normal andlower values of borderline risk. Presumably due to the high rate oflipid-lowering medication, values were consistently lowest in theheart transplant populations.

6. Possible cardioprotective effects of mTOR inhibitors

Coronary stents coatedwith everolimus or sirolimus arewidely usedin revascularization procedures to reduce restenosis and narrowing ofthe lumen [64,65]. The use of such stents was stimulated by data fromanimal models showing that mTOR inhibitors inhibit transplant athero-sclerosis [66,67]. At the experimental level, mTOR inhibitors have beenfound to delay the progression of atherosclerosis by inhibiting the accu-mulation of lipids, resulting in smaller atherosclerotic plaques[25,67–69]. In mice with cholesterol-induced atherosclerosis, plaquesizes showed a dose-dependent reduction in the presence of everolimus[70]. Moreover, animal models also suggest that mTOR inhibition stabi-lizes plaques, reducing the risk of rupture by promoting macrophageclearance and limiting the inflammatory response within smooth mus-cle cells in the artery walls [71,72].

Clinically, the antiatherogenic effect within graft arteries of everoli-mus has been demonstrated in the recent A2310 study of 721 de novoheart transplant patient randomized to everolimus with low-dose CsAor toMMFwith standard-exposure CsA [59]. In a substudy, 189 patientswere evaluated by intravascular ultrasound at baseline and atmonth 12post-transplant [59,73]. By month 12, themean increase in maximal in-timal thickness of coronary arteries was significantly smaller in theeverolimus group versusMMF (Fig. 2). The incidence of cardiac allograftvasculopathy (defined as an increase of 0.5 mm ormore in themaximalintimal thickness) was also significantly lower with everolimus at oneyear post-transplant (Fig. 2). These results, which confirmed earlydata from a large randomized trial of everolimus versus azathioprine[74], showed that the benefit observed with everolimus was indepen-dent of patients' lipid levels [73]. A direct influence on arterial thicken-ing would be consistent with evidence from kidney transplantationsuggesting that mTOR inhibition in a CNI-free regimen is associatedwith inhibition of fibrosis progression in hepatitis C-positive patientsreceiving a kidney transplant [75,76]. While intravascular ultrasound dataare of course only an indirect assessment of risk, a study in heart trans-plant patients has shown that thosewith an increase inmaximal intimalthickness increases of 0.5 mm or more in the first year after transplant

a in transplant recipients: A cause for concern?, Transplant Rev (2014),

Table 1Randomized studies of concentration-controll mTOR inhibitor therapy versus MPA or CNI therapy in de novo kidney transplant recipients.

Study Follow-up(months)

reatmentroup

n Immunosuppressiona Lipid-modifyingtherapy

P value Total-C P value LDL-C P value MeanHDL-C

P value Triglycerides P value

mTOR vs MPAMendez et al 2005 [35] 6 RL 185 SRL 4–12 ng/mL

TACSteroids

42% 0.003 29.3%N240 mg/dL

0.0003 - - - - 55.6%N200 mg/dL

0.004

MF 176 MMFTACSteroids

22% 12.2%N240 mg/dL

- - 38.0%N200 mg/dL

Ciancio et al 2004 [14] 12 RL/TAC 50 SRL 8 ng/mLTACSteroids

54% P b 0.001 vsTAC/MMF

202 mg/dL P = 0.61 - - - 163 mg/dL 0.19

MF/TAC 50 TACMMFSteroids

16% 193 mg/dL 151 mg/dL

RL/CsA 50 SRL 8 ng/mLCsASteroids

80% P b 0.001 vsTAC/MMF

201 mg/dL 187 mg/dL

Tedesco-Silva et al 2010 [36] 12 VR 274 EVR 3–8 g/mLLow-dose CsASteroids

64.6% - 15.7%N350 mg/dL

- - - 7.7%N270 mg/dL

- 4.4%N750 mg/dL

-

VR 278 EVR 6–12 g/mLLow-dose CsASteroids

72.3% 16.5%N350 mg/dL

- 5.0%N270 mg/dL

6.1%N750 mg/dL

MF 273 MMFCsASteroids

57.5% 6.3%N350 mg/dL

- 6.5%N270 mg/dL

2.6%N750 mg/dL

mTOR vs CNIFlechner et al 2013 [37] 12 RL 152 SRLb

MMFSteroids

61.2% - - - - - - -

RL/TAC 152 SRLb

TAC to week 13Steroids

58.6% - - - - - -

MF/TAC 139 MMFTACSteroids

50.4% - P b 0.05 vsSRL groups

- P b 0.05 vsSRL groups

- - - P b 0.05 vsSRL groups

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Table 1 (continued)

Study Follow-up(months)

Treatmentgroup

n Immunosuppressiona Lipid-modifyingtherapy

P value Total-C P value LDL-C P value MeanHDL-C

P value Triglycerides P value

Ekberg et al 2010 [38]Claes et al 2012 [15]

12 SRL 380 SRL 4-8 ng/mLMMFSteroids

39% 0.007 acrossgroups

- - 119 mg/dL P b 0.05 55 mg/dL n.s. 206 mg/dL b0.05 vs TACand MMF/lowCsA

MMF/CsA 384 Standard CsAMMFSteroids

34% - 112 mg/dL n.s. 55 mg/dL 185 mg/dL

MMF/CsA 408 Low-dose CsAMMFSteroids

32% - 117 mg/dL P b 0.05 55 mg/dL 174 mg/dL

MMF/TAC 403 Low-dose TACMMFSteroids

26% - 107 mg/dL Reference 53 mg/dL 165 mg/dL

Buchler et al 2007 [39] 12 SRL 71 SRL 10–15 ng/mLSteroids to month 5MMF

70.5% 0.03 5.7 mmol/L 0.03 3.3 mmol/L 0.12 1.4 mmol/L - 2.3 mmol/L 0.18

CsA 74 CsASteroids to month 5MMF

51.0% 5.1 mmol/L 3.0 mmol/L 1.4 mmol//L 1.7 mmol/L

Larson et al 2006 [40] 12 SRL 81 SRL 8–12 ng/mLMMFSteroids

- - 219 mg/dL 0.02 - - - -

TAC 84 TACMMFSteroids

- 200 mg/dL - - -

Flechner et al 2002 [41] 12 SRL 31 SRL 5–12 ng/mLMMFSteroids

64.5% - 225 mg/dL 0.72 125 mg/dL 0.61 52 mg/dL 0.79 228 mg/dL 0.38

CsA 30 CsAMMFSteroids

53.3% 220 mg/dL 143 mg/dL 52 mg/dL 205 mg/dL

C, cholesterol; CNI, calcineurin inhibitor; CsA, cyclosporine; EVR, everolimus;HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol;MMF,mycophenolatemofetil;MPA,mycophenolic acid;mTOR,mammalian targetof rapamycin; SRL, sirolimus; TAC, tacrolimus.Lipid values are shown as means unless stated otherwise.

a Maintenance immunosuppression.b Original protocol: 10–15 mg loading dose, 10–15 ng/mL toweek 13, 8–12 ng/mL duringweeks 14–26, 5–12 ng/mL duringweeks 27–104. Revised protocol: 15 mg loading dose × 2, 10–15 ng/mL toweek 26, 8–15 ng/mL duringweeks 27–104.

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Table 2Randomized studies of early conve ion to concentration-controlled mTOR inhibitor therapy versus CNI therapy in liver transplant recipients.

Study Fo w-up(m ths)

Treatmentgroup

n Immunosuppressiona Lipid-modifyingtherapy

P value Total-C P value LDL-C P value Mean HDL-C P value Triglycerides P value

Teperman et al 2013 [49] 12 SRL 148 SRL 5–10 ng/mL from week 4–12MMF±Steroids

13.5% - - - 120 mg/dL 0.001 47 mg/dL 0.55 210 mg/dL 0.07

CsA/TAC 145 CsA/TACMMF±Steroids

4.8% - 101 mg/dL 46 mg/dL 169 mg/dL

De Simone et al 2012 [52] 12 EVRLow-doseTAC

245 EVR 3–8 ng/mL from week 4Low-dose TACSteroids

23.3% 0.944 209 mg/dL b0.001 121 mg/dL b0.001 51 mg/dL b0.001 197 mg/dL b0.001

TAC 243 TACSteroids

17.8% 175 mg/dL 101 mg/dL 47 mg/dL 141 mg/dL

Fischer et al 2012 [50] 12 EVR 101 EVR 5–12 ng/mLCsA to week 8±Steroids

- - 22.8%b ≤0.05 - - 5.9%c n.s.

CsA 102 CsA±Steroids

- 10.8%b - - 2.9%c

Masetti et al 2010 [51] 12 EVR 52 EVR 6–10 ng/mL from day 10CsA to day 30Steroids

9.6% - ~200 mg/dL 0.01 ~120 mg/dL 0.11 ~50 mg/dL 0.03 ~170 mg/dL 0.68

CsA 26 CsASteroids

7.7% ~160 mg/dL ~80 mg/dL ~32 mg/dL ~200 mg/dL

C, cholesterol; CsA, cyclosporine; E , everolimus; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MMF, mycophenolate mofetil; mTOR, mammalian target of rapamycin; n.s., not significant; SRL, sirolimus;TAC, tacrolimus.Lipid values are shown as means u ess stated otherwise.

a Maintenance immunosuppres n.b Incidence of hypercholesterole ia reported as an adverse event by the investigator.c Incidence of hypertriglyceride a reported as an adverse event by the investigator.

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Table 3Randomized studies of concentration-controlled mTOR inhibitor therapy versus MPA or CNI therapy in de novo heart transplant recipients.

Study Follow-up(months)

Treatment group n Immunosuppression Lipid-modifyingtherapy

P value Total-C P value LDL-C P value Mean HDL-C P value Triglycerides P value

mTOR vs MPAEisen et al 2013a [59] 24 EVR 282 EVR 3–8 ng/mL

Low-dose CsA from month 2Steroids

94.6% - 5.0 mmol/L b0.001 2.7 mmol/L 0.054 1.4 mmol/L b0.001 2.3 mmol/L 0.065

MMF 271 MMFStandard CsASteroids

94.0% 4.6 mmol/L 2.6 mmol/L 1.3 mmol/L 2.0 mmol/L

Lehmkuhl et al 2009 [60] 12 EVR 92 EVR 3-8 ng/mLLow-dose CsASteroids

93.4% 5.5 mmol/L 0.002 - - - - 2.3 mmol/L 0.001

MMF 84 MMFStandard CsASteroids

85.5% 5.0 mmol/L - - 1.7 mmol/L

mTOR vs CNIAndreassen et al 2013 [58] 12 EVR 56 EVR

Low-dose CsA to week 7MMFSteroids

91% - 5.3 mmol/L n.s. 2.9 mmol/L n.s. 1.6 mmol/L n.s. - -

CsA 59 CsAMMFSteroids

86% 5.1 mmol/L 2.8 mmol/L 1.6 mmol/L -

C, cholesterol; CsA, cyclosporine; EVR, everolimus; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MMF, mycophenolate mofetil; MPA, mycophenolic acid; mTOR, mammalian target of rapamycin; n.s., notsignificant; TAC, tacrolimus.Lipid values are shown as means unless stated otherwise.

a Randomization to a third treatment group (everolimus 6–12 ng/mL) was terminated early due to higher mortality.

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Fig. 2. (A) Mean (SD) change in maximum intimal thickness of coronary arteries frombaseline to month 12. (B) Proportion of patients with cardiac allograft vasculopathy atmonth 12, defined as ≥0.5 mm increase in maximum intimal thickness from baseline tomonth 12. Data from de novo heart transplant patients randomized to everolimus withreduced-exposure CsA or MMF with standard-exposure CsA, both with steroids, from asubstudy of the A2310 study inwhich intravascular ultrasoundwas performed at baselineand month 12 post-transplant [59].

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experienced a higher rate of death or graft loss, with more majoradverse cardiac events by five years post-transplant [77]. It seems feasi-ble that reduced intimal thickening under mTOR inhibitor therapy mayhelp to counteract the lipogenic effect.

A cardioprotective effect of mTOR inhibitors is also suggested bydata concerning pulsewave velocity, awell-establishedmarker for arte-rial stiffness. Arterial stiffness increases with age, but is exacerbated byatherosclerosis and is known to increase the risk of cardiovascularevents following kidney transplantation [78,79]. A prospective trial of27 maintenance kidney transplant patients found that after conversionfrom CsA to everolimus, pulse wave velocity stabilized over thefollowing ninemonths, but increased in the CsA group, reflecting ongo-ing atherosclerotic processes [80]. Similarly, a subpopulation analysisfrom the randomized CONCEPT trial reported that a CNI-freesirolimus-based regimen reduced aortic stiffness as measured by pulsewave velocity [81].

Lastly, preliminary data from analyses of kidney transplant patientsat one center [82] and heart transplant patients at another center[83,84] have indicated that conversion from CNI therapy to everolimusor sirolimus is associated with reduced ventricular remodeling anddecreased left ventricular mass, with improved diastolic function [84]. Thismay arise from a direct effect on the myocardium [84]. Progressivefibrosis, a key characteristic of endomyocardial remodeling after hearttransplantation, was shown to be significantly attenuated by everoli-mus therapy versus MMF therapy in a prospective study of 132 denovo heart transplant patients [85]. There was a significant differencein the extent of fibrosis on cardiac biopsy as early as one month post-

Please cite this article as: Holdaas H, et al,mTOR inhibitors and dyslipidemihttp://dx.doi.org/10.1016/j.trre.2014.08.003

transplant, with less scarring in the everolimus-treated patients up tothe end of the three-year study.

Overall, the evidence for cardioprotective properties of mTORinhibitors following transplantation is growing and merits fur-ther investigation.

7. Cardiac outcomes

The scale and duration of controlled trials make it difficult to com-pare the rate of cardiac events reliably between different immunosup-pressive regimens. To date, no trial of mTOR inhibitor therapy has hada cardiovascular primary endpoint. During three-year follow-up ofpatients in the SYMPHONY study, the largest trial of immunosuppressionin kidney transplantation to date, data on fatal and non-fatal cardiovas-cular events were recorded [86]. At three years, the incidence of any car-diovascular event was low in all groups with no significant differencebetween the low-dose sirolimus arm and the CNI-based treatmentgroups. Less detailed three-year [87] and five-year [88] follow-up datafrom studies of sirolimus with or without low-dose CNI versus standardCNI regimens have also not indicated any difference in cardiovasculardeaths within kidney transplant populations. In heart transplantation, apivotal trial randomized 634 patients to de novo treatment with everoli-mus at a fixed dose of 1.5 mg/day or 3.0 mg/day (switched toconcentration-controlled therapy after one year) or to azathioprine, allwith standard CsA and steroids [74]. At four years post-transplant, non-fatal major adverse cardiac events (excluding events during month 1)had occurred in 7.9% of everolimus-treated patients versus 13.6% ofazathioprine-treated patients (p = 0.0331) [89], but this difference hasnot been confirmed by other studies. More recently, two-year mortalitywas similar in a study in de novo heart transplant patients randomizedto everolimus (target C0 3–8 ng/mL) with reduced-CsA or MMF withstandard CsA [59]. Recruitment to a third group (everolimus targetingC0 6–12 ng/mL) was terminated early due to a higher rate of infectiousdeaths, but there were no apparent differences in the rate ofcardiovascular-related deaths between any of the three arms.

8. Conclusions

Dyslipidemia is a recognized class effect of mTOR inhibitors whichappears to be more pronounced than that seen with mycophenolicacid (MPA) or CNIs following solid organ transplantation. Interpretationof available studies is complicated by relatively small numbers and fre-quent differences in the use of lipid-lowering therapy between studytreatment groups. Also, longer-term data to two or even five yearspost-transplant would be desirable but have not been widely reported.Nevertheless, the absolute differences in lipid profile between mTORinhibitor-based and other regimens are less marked than during earlystudies and a dyslipidemic effect may be at least partly offset by theantiatherogenic action of mTOR inhibitor therapy. More generally, itshould be borne in mind that use of an mTOR inhibitor permits reduc-tion or elimination of CNI therapy, which could potentially offer advan-tages in terms of reducing CNI-related hypertension and nephrotoxicity[90]. A strong association has been demonstrated between renal func-tion and cardiovascular death in kidney and heart transplant recipients,independent of conventional risk factors for cardiovascular disease[10,91]. Improved renal function has been convincingly demonstratedin a series of trials using mTOR inhibitors with CNI therapy reductionor withdrawal either de novo or in maintenance organ transplantpatients versus standard CNI-based regimens [92–95] although protein-uria, which has an associated lipogenic effect, is a potential concernin maintenance patients with poor renal function [63,96].

Lipid status in kidney transplant patients should be managed as fornon-transplant patientswith chronic kidney disease [11]. Statin therapyis effective in lowering cholesterol levels and appears to reduce the riskof cardiovascular events following kidney transplantation [12,97–99].There does not appear to be a clinically relevant pharmacokinetic

a in transplant recipients: A cause for concern?, Transplant Rev (2014),

9H. Holdaas et al. / Transplantation Reviews xxx (2014) xxx–xxx

interaction between everolimus and statin agents during coadministra-tion [100]. No formal guidelines exist for management of hypercho-lesterolemia in liver transplant patients, but it would seem reasonable tomonitor andmanage as for other high-risk individuals [101]. Use of statintherapy is almost universal following heart transplantation and maylargely negate the effect of elevated total cholesterol on cardiovascularrisk [13].

In conclusion, dyslipidemia in organ transplant patients receivingmTOR inhibitor therapy should be monitored and managed closely,but unless unresponsive to therapy should not be regarded as a barrierto use of this class of immunosuppressant. It would seem reasonable toavoid mTOR inhibitors in patients with significant dyslipidemia beforeor after transplantation [11]. Cardiovascular risk is not higher in thepresence of mTOR inhibitor therapy and increased lipid levels may beat least partly balanced by a direct cardioprotective effect and, potential-ly, reduction in other CNI-related risk factors.

Acknowledgments

A draft of this manuscript was prepared by a freelance writer withfunding from Novartis Pharma AG. The authors were fully responsiblefor all content and editorial decisions and received no financial supportor other form of compensation related to the development of this man-uscript. The opinions expressed in the manuscript are those of theauthors andNovartis Pharmaceuticals had no influence on the contents.

H Holdaas has served as a consultant to Bristol-Myers Squibb,Novartis, AstraZeneca, Astellas and Schering-Plough, and has receivedlecture fees from Novartis and AstraZeneca. L Potena has received lec-ture fees from Novartis and has served as a consultant for Diaxhonitand Biotest. F Saliba has received speaker honorarium and/or grantresearch from Novartis, Astellas, Gilead, Roche, Merck Sharip &Dohme, Pfizer, Gambro and vital therapies.

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