Dr Alan Jardine, University of Glasgow, Dept of Medicine and Therapeutics, Western Infirmary, Glasgow G12 8QQ, U.K. Tel:+44 (0)141 2112320; fax:+44 (0)141 3392800; e-mail: agj3 email@example.com
Cardiovascular disease remains a significant cause of morbidity and mortality in patients who have undergone renal transplantation, with one of the main risk factors being post-transplantation hyperlipidaemia. To date, however, optimal management of elevated lipid levels in such patients has been hindered by the lack of both effective and safe treatments, coupled with concerns over probable interactions with immunosuppressive therapy, particularly cyclosporin. Numerous studies confirm that the 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, such as fluvastatin, are effective lipid-lowering agents in renal transplant recipients, supporting findings in other patients’ groups. Moreover, based on investigations of metabolic profile and clinical observation, fluvastatin (at dosages of up to 80 mg/day) is well tolerated in renal transplant recipients receiving cyclosporin. In clinical trials to date, no instances of rhabdomyolysis have been observed during co-administration of fluvastatin and cyclosporin. The potential of fluvastatin for improving survival in renal transplant recipients, in terms of both cardiovascular mortality and graft rejection, is currently being investigated in two ongoing studies: ALERT (Assessment of Lescol [fluvastatin] in Renal Transplantation) and SOLAR (Study of Lescol [fluvastatin] in Acute Rejection). The results of these landmark studies should confirm the safe utility of fluvastatin in the renal transplantation setting.
Advances in renal transplantation have revolutionized the management of patients with end-stage renal failure. The introduction of effective immunosuppressive agents such as cyclosporin (cyclosporin A) has improved long-term survival of organ allograft recipients (1). Three-year graft survival rates in excess of 70% have been reported since the clinical introduction of cyclosporin A (2). However, despite advances in transplantation science, long-term patient survival is relatively poor for renal allograft recipients, with a predicted 10 years patient survival rate of approximately 60%. The paradox of the success of transplantation is that patients now die from accelerated premature cardiovascular disease rather than renal failure. Indeed, the cardiovascular death rate is 20–40-fold higher among individuals receiving renal replacement therapy (including dialysis and transplant recipients) compared with the age- and sex-matched background population (3–5). In the U.S.A., the percentage of deaths due to cardiovascular causes among renal transplant recipients is around 50% (6); this figure may be as high as 70% in some countries (5) and may be higher still, as many of the patients for whom a cause of death cannot be attributed die suddenly and unexpectedly of possible cardiac causes.
It is well established that hyperlipidaemia is a risk factor for cardiovascular disease in the general population, as shown by large-scale epidemiological studies (7). Moreover, hyperlipidaemia is a frequent complication in the post-renal transplantation period, the lipoprotein profile of which is characterized by an increase in total cholesterol level with excess low-density lipoprotein (LDL) particles (8–11) (Fig. 1). An increase in total cholesterol of around 27% is typical (9), although higher levels may be seen, with the peak incidence of hypercholesterolaemia occurring 6 months post-transplantation (12). It is estimated that 60% of the renal transplant population has a total cholesterol level > 6·2 mmol/l and LDL-cholesterol level > 3·4 mmol/l (13). The aetiology of post-transplantation hyperlipidaemia is multifactorial, involving both immunosuppressive drugs and other agents, including diuretics, in addition to reduced renal function and proteinuria (14, 15). Although the major drug-related increases are attributable to corticosteroids, post-transplantation hyperlipidaemia has also been related to treatment with cyclosporin (12, 16, 17). For example, total cholesterol levels were 0·77–0·92 mmol/l higher in renal transplant patients treated with cyclosporin in addition to prednisolone and azathioprine compared with those who received prednisolone and azathioprine alone (17). Specifically, trough levels of cyclosporin correlate with increases in LDL-cholesterol but not triglycerides (18).
In addition to a possible increase in cardiovascular disease, evidence now suggests that hyperlipidaemia is an important risk factor for long-term graft outcome (11). Chronic rejection of renal allografts is characterized by graft vascular disease with intimal and medial vascular proliferation (19). The proliferative vascular changes are morphologically similar to those of atherosclerosis in the general population. Moreover, there is a clear link between graft and patient survival (20). Thus, a strong rationale exists to implement effective lipid-lowering therapy in the post-transplantation period to improve both long-term morbidity and, ideally, mortality. To date, however, this approach has been hindered by the lack of both effective and safe treatments for elevated lipids, coupled with concerns over possible interactions with immunosuppressive therapy, particularly cyclosporin. The aim of this review is to outline the clinical efficacy of fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor, when used for the treatment of elevated lipids in renal transplant recipients. Particular focus is paid to the safety and interaction potential of fluvastatin when co-administered with cyclosporin.
TREATMENT OPTIONS FOR POST-TRANSPLANTATION HYPERLIPIDAEMIA
Dietary therapy alone does not provide adequate control of hyperlipidaemia following renal transplantation (21). Pharmacotherapy is therefore required in addition to dietary modification. Until recently, however, there have been no lipid-lowering agents available that could be used easily, safely and effectively in renal transplant patients with minimal or predictable effects on the patient's immunosuppressive therapy. In the case of bile acid sequestrants (resins), for example, it is well established that cholestyramine may alter the absorption of cyclosporin (22). Similarly, the dose of fibrates has to be reduced to minimize the risk of myositis, while the poor tolerability profile of nicotinic acid precludes its general use (23).
The HMG CoA reductase inhibitors (statins) have proven efficacy and safety for the treatment of hyperlipidaemia in the general population (24–31). With regard to fluvastatin, in a general practice study of over 5000 patients with hypercholesterolaemia, fluvastatin 20–40 mg/day was well tolerated and reduced mean total cholesterol levels by 27%, LDL-cholesterol by 38% and high-density lipoprotein (HDL)-cholesterol levels were raised by a mean of 27% (32). Numerous clinical trials have been performed with this agent in patients with hyperlipidaemia following organ transplantation (Table 1). Typically, these studies have utilized a fluvastatin dosage of 20–40 mg/day, administered for up to one year (33). Some studies have titrated the dosage of fluvastatin to 40 mg/day (34–36), with one study using 80 mg/day in a small subgroup of patients (37). The efficacy findings of the latter study are summarized in Fig. 2. Overall, LDL-cholesterol was decreased by nearly 40% at the highest dosage, with parallel, dose-dependent, changes in total cholesterol and triglycerides; significant increases in HDL-cholesterol were also observed (37). Across all studies included in Table 1, the overall decreases in LDL-cholesterol and total cholesterol at a fluvastatin dosage of 20–40 mg/day are 26% and 19%, respectively, which is comparable to therapeutic efficacy observed for fluvastatin in non-transplant patients (38, 39). One study reported more modest changes in lipid parameters, which the study authors attributed to the inclusion of two patients with very high baseline total cholesterol levels (23). Increasing fluvastatin dosage from 20 to 40 mg/day further reduced LDL-cholesterol levels by 7% in one study (34). With regard to changes in HDL-cholesterol, while some studies reported statistically significant increases during fluvastatin ther- apy of up to 36% (23, 33, 36), others reported minimal changes and in some instances a decrease in HDL-cholesterol was observed (Table 1). Changes in serum triglyceride levels were generally modest at fluvastatin dosages of 20–40 mg/day, although more marked changes were apparent with increasing dosage (37). Interestingly, changes in triglycerides were more marked among corticosteroid-free patients treated with fluvastatin compared with those receiving prednisone as part of their immunosuppressive regimen (40). Overall, however, the response to fluvastatin was qualitatively similar between corticosteroid-free and corticosteroid-treated patients in the latter study.
Table 1. Summary of the efficacy of fluvastin (F) for the treatment of hyperlipidaemia in renal transplant patients
Clinical studies therefore confirm that the efficacy and safety profile of fluvastatin in renal transplant recipients is similar to that in other populations.
Potential for interaction with cyclosporin
Although HMG CoA reductase inhibitors are effective for the treatment of hyperlipidaemia in renal transplant patients, a major caveat to their widespread use is the potential for interaction with cyclosporin and an increased likelihood for adverse effects. Of specific concern are musculoskeletal side-effects such as myopathy and rhabdomyolysis. Although the pathophysiology of these effects is not clear, they are directly related to plasma levels of the statin. Thus, there are concerns over observations that, for example, plasma exposure of lovastatin increases 20-fold when administered with cyclosporin (41). The incidence of musculoskeletal adverse effects increases by up to 28% (42) and several instances of myositis and rhabdomyolysis have been reported when lovastatin was co-administered with cyclosporin (43–45). Similarly, plasma exposure of simvastatin following a single 20 mg dose is increased by almost three-fold in the presence of cyclosporin (46) and there have been isolated reports of rhabdomyolysis in patients concomitantly treated with these agents (47, 48). Plasma levels of cerivastatin are also increased approximately three-fold in the presence of cyclosporin (49). While pravastatin reportedly has the lowest propensity to cause myopathy in cyclosporin-treated patients (50), co-administration of these agents in an animal model resulted in increased systemic exposure and a parallel increase in the risk of rhabdomyolysis (51). In addition, there are reports of large increases in plasma levels of pravastatin during concomitant treatment with cyclosporin (41, 52).
The interaction between cyclosporin and HMG CoA reductase inhibitors can be attributed to inhibition of cytochrome P450 (CYP) 3A (53), the major enzyme responsible for the metabolism of most agents of this class including lovastatin (54), simvastatin (55), cerivastatin (56) and atorvastatin. Other mechanisms may also contribute to this interaction, including inhibition of P-glycoprotein (57). Lovastatin, for example, is a substrate for P-glycoprotein (58); increased plasma levels of lovastatin during cyclosporin co-administration could therefore be partly explained by decreased biliary clearance following inhibition of this transport protein. Inhibition of P-glycoprotein or other carrier-mediated transport processes may also explain increased (5–23-fold) plasma levels of pravastatin in the presence of cyclosporin (41, 52), since pravastatin is not thought to be metabolized solely by CYP-dependent processes (59). Cyclosporin-induced cholestasis may also contribute to decreased hepatic elimination of these agents and hence increased systemic exposure (51). It is interesting to note that fluvastatin is not a substrate for P-glycoprotein (60). Moreover, the findings of a recent in vitro study indicate that fluvastatin is metabolized by multiple CYP enzymes including CYP2C9 and, to a lesser extent, CYP3A4 and CYP2C8 (61). The involvement of several enzymes in the metabolism of fluvastatin should therefore minimize the potential for interaction when co-administered with compounds that inhibit one of these enzymes, which confirms clinical experience with this agent (38, 39, 62). In the case of cyclosporin, for example, pharmacokinetic studies show that plasma exposure of fluvastatin (area under the plasma concentration–time curve) increased by only 1·9-fold in the presence of this agent, with minimal changes in other pharmacokinetic parameters (63). Such findings may explain the absence of reports of myopathy or rhabdomyolysis during clinical studies of fluvastatin in renal transplant patients receiving cyclosporin (33–, 40, 63, 64) (Table 2). Indeed, Schrama and colleagues (36) failed to demonstrate a significant increase in creatine phosphokinase and myoglobin elevations during provocative exercise testing among transplant patients treated with fluvastatin. Such findings provide indirect evidence that fluvastatin does not cause subclinical muscle toxicity when administered in conjunction with cyclosporin and although three patients (8%) reported temporary myalgia in one study, these symptoms were not accompanied by elevated creatine phosphokinase levels (65).
Table 2. Pharmacokinetic profile (mean (SD) of fluvastin (20 mg/day) in renal transplant patients receiving concomitant cyclosporin
WILL STATINS IMPROVE SURVIVAL OF TRANSPLANT RECIPIENTS?
Although it is well established that a reduction in serum cholesterol with HMG CoA reductase inhibitors reduces the risk of fatal and non-fatal cardiovascular events in non-transplant patients (66–71), the association between hyperlipidaemia and risk of cardiovascular events in renal transplant patients is far from conclusive (10, 12, 72–75). In a series of 500 cyclosporin-treated renal transplant recipients, for example, Vathsala and colleagues (12) reported a significantly higher incidence of cardiovascular events among hypercholesterolaemic patients compared with those with normal cholesterol levels (15·4% vs. 5·2%; P< 0·001). Similar findings were reported by both Kasiske et al. (74) and Aker et al. (75), who found an association between the development of atherosclerotic cardiovascular disease in the post-transplantation period and elevated cholesterol levels. Indeed, Aker et al. (75) found LDL-cholesterol > 180 mg/dl to be a significant independent risk factor for atherosclerotic cardiovascular disease following renal transplantation (relative risk 2·27; P< 0·05), along with diabetes mellitus, age at transplantation, body mass index > 25 kg/m2, smoking and hyperuricaemia. A small retrospective study by Drüeke and colleagues (10) also reported that renal allograft recipients who experienced cardiovascular events (n=25) had significantly higher mean total cholesterol levels than those without such events (n=29,6·5 and 5·6 mmol/l, respectively; P< 0·05). The findings of the latter study were complicated, however, by the fact that the prevalence of smoking and use of antihypertensive medication was higher among those who experienced cardiovascular events. In contrast to the studies demonstrating an association between hyperlipidaemia and cardiovascular events, Pollock and co-workers (73) found no such association in an average 104-month follow-up study of 192 renal transplant recipients (12 of whom died as a result of cardiovascular disease). Similarly, other studies found no correlation between post-transplantation hyperlipidaemia and patient or graft survival (72, 76).
The lack of consensus regarding the relationship between hyperlipidaemia and risk of cardiovascular events in renal transplantation is compounded by the fact that, to date, no interventional studies have been conducted to assess the effect of HMG CoA reductase inhibitors on the frequency of cardiovascular events specifically in these patients. However, a small number of studies have been performed with these agents in cardiac transplant recipients (77, 78). Since cardiac transplant patients also have post-transplantation hyperlipidaemia with accelerated vascular disease (specifically graft vascular disease [GVD]) (79), it is highly likely that the effect of statins in this patient group can be extrapolated to renal transplant recipients. Wenke and colleagues (78) performed a 4-year prospective study in 72 heart transplant patients, 35 of whom were treated with a relatively low dosage of simvastatin (5 mg/day, increasing to 20 mg/day, if necessary, to attain a target LDL-cholesterol level of 110–120 mg/dl) from Day 4 post-operatively; the remaining patients received dietary advice alone. Simvastatin prevented the increase in total and LDL-cholesterol levels that followed transplantation (Fig. 3). Moreover, simvastatin significantly improved patient survival; after 4 years, 88·6% of simvastatin-treated patients were still alive compared with 70·3% in the control group (P=0·05). However, the differences in survival could not be attributed to an effect on cardiovascular deaths. The study by Kobashigawa and colleagues (77) showed a clear effect of pravastatin on survival in 97 heart transplant recipients at one year post-operation (94% vs. 78% of controls; P< 0·05). In this randomised, placebo-controlled study, treatment with pravastatin was commenced at a dosage of 20 mg/day from 1 to 2 weeks after transplantation, increasing to 40 mg/day after one month. Reduced progression of mean intimal thickness was also observed in pravastatin recipients (P< 0·01 vs. control). One potential limitation of this study, however, is that the control group contained a higher number of patients receiving a second transplant, which may have biased the survival results in favour of pravastatin, as these patients tend to have a poorer outcome. Despite this limitation, the survival benefit of pravastatin was maintained when only patients receiving their first transplant were analysed (77).
Immunomodulatory effects of statins
In addition to an improvement in survival post-transplantation, the studies of Kobashigawa et al. (77) and Wenke et al. (78) provide evidence for an immunomodulatory effect of statins. Pravastatin significantly decreased the rate of haemodynamically important rejection episodes (P< 0·01), associated with improved survival (77). This finding was reproduced in a small pilot study in renal transplant recipients, in whom pravastatin therapy also significantly reduced the incidence of acute rejection episodes (80).
The mechanism by which statins may interfere with the aggressive immunologically mediated process underlying allograft rejection remains unclear. One possible mechanism involves an indirect effect on the pharmacokinetics of cyclosporin. As this agent is lipophilic it is transported in the blood in LDL and HDL cores. Cyclosporin binding to lipoproteins accounts for approximately 35% of whole blood levels, thus any change in LDL-cholesterol may interfere with the removal of cyclosporin from the circulation (18). For example, a decrease in LDL-cholesterol during lipid-lowering therapy could reduce LDL-bound cyclosporin and hence give rise to an increase in unbound, and pharmacologically active, cyclosporin. This has been investigated in a study of 12 heart transplant recipients treated with simvastatin (5–15 mg/day) plus cyclosporin (81). Reduction of LDL-cholesterol was associated with a 29% increase in the unbound fraction of cyclosporin A (from 1·4% to 1·8%; P< 0·01). Whether this increase is sufficient to explain the lower incidence of rejection episodes observed in cardiac/renal allograft recipients treated with statins post-transplantation requires further investigation. Indeed, the clinical relevance of an indirect pharmacokinetic interaction between statins and cyclosporin is questioned by the study of Kobashigawa and colleagues (77). They found that 5/14 episodes of rejection accompanied by haemodynamic compromise occurred 1–2 months post-transplantation when no significant differences in lipid levels were apparent between the pravastatin and control groups (82).
An alternative mechanism focuses on a direct effect of statins on immune cells. In their study, Kobashigawa and colleagues (77) studied natural killer (NK) cell activity in terms of in vitro killing of K562 cells (a specific target for NK cells). They found that NK cells from patients treated with pravastatin had reduced effects on K562 cells (9·8% vs. 22·2% specific lysis for controls; P< 0·05), and that this effect was sequential over a 12-week period. Similar studies have been performed for fluvastatin, in which NK cells from healthy individuals were incubated with fluvastatin in vitro (unpublished observations). At a fluvastatin concentration of 5 mmol/l, killing of K562 cells was reduced from around 30% to less than 10% after 4 days’ incubation. This effect was not mediated by a decrease in cell number or viability and was reversed by incubation with mevalonate 1 mM for just 2 h. Statins are therefore able to uncouple the killing mechanism of NK cells without altering their viability. Fluvastatin has similar inhibitory effects on proliferation of lymphocytes, which have a clearer role in rejection than NK cells. Although these observations provide evidence for an immunosuppressive action in vitro, there is no evidence to indicate an increased risk of infection or cancer in statin trials among non-transplanted patients (83). To explain the apparent enhanced immunomodulatory effect in cyclosporin-treated transplant patients, in the absence of evidence for clinical immunosuppression in non-transplanted patients treated with HMG CoA reductase inhibitors, some authors have proposed a synergistic interaction between statins and cyclosporin. In their in vitro study, for example, Katznelson et al. (84) reported synergistic inhibition of cytotoxic T-lymphocyte activity when cells were cultured in the presence of both pravastatin and cyclosporin; by contrast, either agent used alone inhibited cytotoxic T-lymphocyte activity, albeit not significantly. This synergistic effect may occur via blockade of the synthesis of interleukin-2 in immune cells, a hypothesis based on findings that the addition of interleukin-2 restores natural killer cell activity, and partly restores antibody-dependent cytotoxicity that was inhibited by incubation with lovastatin (85).
More recently, Rothe et al. (86) have added to the knowledge relating to the effects of statins on immune cells in renal transplant patients. These authors looked at the size and activation of lymphocyte subpopulations in 44 renal transplant patients receiving fluvastatin 40 mg/day for 8 weeks. Interestingly, the baseline population size of activated (HLA-DR+) T-lymphocytes was negatively correlated with HDLC, suggesting increased allogeneic activation of T-lymphocytes in the presence of low HDL-C. After 8 weeks of treatment, a decrease in the population size and extent of activation of T-lymphocytes exerting non-MHC-specific or MHC class I-restricted cytotoxic effector functions was observed. Clearly, there is a need to explore further the clinical relevance of the potential immunomodulatory effects of statins in the transplantation setting and the potential influence of this mechanism on the beneficial effects of statins in atherosclerosis.
Given that both simvastatin and pravastatin improved outcomes after cardiac transplantation, it is reasonable to assume that this is an effect common to all agents of this class. However, further evidence is required to identify the survival benefits of treating renal transplant recipients with statins. Based on the good efficacy and safety profile of fluvastatin reported to date in renal transplant patients, together with a low potential for drug interactions, the effect of fluvastatin on cardiovascular morbidity and mortality and rejection rates is currently being investigated in two ongoing studies: ALERT (Assessment of Lescol®[fluvastatin] in Renal Transplantation) and SOLAR (Study of Lescol®[fluvastatin] in Acute Rejection). The objective of the landmark ALERT study is to compare the long-term effect of treatment with fluvastatin 40 mg/day vs. placebo on the major adverse cardiac event-free survival time during 5 years of follow-up in 2100 renal transplant recipients with total cholesterol 4·0–9·0 mmol/l (165–351 mg/dl). This international multicentre, randomised, double-blind study should be completed in 2002. The potential for immunomodulatory effects of fluvastatin in combination with immunosuppressive agents, including cyclosporin, is being investigated in SOLAR. This randomised, double-blind study is designed to determine the short-term effect of treatment with fluvastatin 40 mg/day vs. placebo on the incidence of treated rejection episodes during a 3-month treatment period in approximately 350 renal transplant recipients. The findings of SOLAR will be available in 2000, and will provide pivotal evidence as to the potential immunomodulatory of fluvastatin in renal transplantation.
Accelerated cardiovascular disease remains a significant problem in patients who have undergone renal transplantation. Many of these patients suffer concomitant post-transplantation hyperlipidaemia, although a causal relationship to accelerated cardiovascular disease remains controversial. Against this background, however, evidence is emerging in the cardiac transplantation field that treatment with statins in the post-transplantation period both lowers elevated lipid levels and improves long-term morbidity and mortality. Hence, while there are numerous studies available to confirm the lipid-lowering efficacy of statins in renal transplant recipients, more widespread use has been hindered by concerns over possible interactions with immunosuppressive therapy, particularly cyclosporin. This concern principally relates to the precipitation of serious musculoskeletal adverse events such as myopathy and rhabdomyolysis, and has led to the use of lower doses of statins that may not be optimal in the long term. For example, while the 4S study reported that simvastatin reduces the risk of fatal and non-fatal cardiovascular events in non-transplant patients (66), over a third of patients in this study were receiving a dosage of 40 mg/day. This contrasts with studies in renal transplant patients that conclude that a simvastatin dosage of 10 mg/day is suitable for the majority of patients (87). It is interesting to note that changes in lipid parameters in the study of Arnadottir and colleagues (87) were comparable to those reported in the 4S study; however, there is now evidence to suggest that the beneficial effects of statins extend to beyond lipid lowering alone (88). Moreover, while Wenke and colleagues (78) reported a significant improvement in long-term survival among cardiac transplant recipient treated with an average dosage of simvastatin of 10 mg/day, the survival benefits may have been further increased had higher dosages of simvastatin been utilized. At dosages of up to 80 mg/day, fluvastatin is well tolerated in renal transplant recipients receiving cyclosporin and has markedly reduced potential for the drug interaction associated with other HMG CoA reductase inhibitors. The potential of fluvastatin for improving outcomes following renal transplantation, both in terms of cardiovascular mortality and graft rejection, is currently being investigated in a large programme involving over 2000 transplant patients. The results of such studies should confirm the suitability of fluvastatin as the statin of choice for prophylactic use in the post-transplantation setting. In the interim and in the absence of outcomes data, fluvastatin may be used safely in renal transplant patients receiving cyclosporin A.