Fluvastatin in the Treatment of Dyslipidemia Associated with Chronic Kidney Failure and Renal Transplantation

Abstract

Premature atherosclerotic coronary heart disease driven by multiple risk factors is a major cause of morbidity and mortality among the 6 million patients in the United States with chronic renal failure. Consensus is that kidney failure and renal transplantation patients should be treated aggressively for dyslipidemia. Major medical literature databases were searched for published information about fluvastatin, a HMG-CoA reductase inhibitor, use in patients with impaired renal function. This article characterizes the dyslipidemia observed in these clinical settings and reviews the clinical experience with fluvastatin.

• atherosclerotic coronary heart disease
• chronic renal failure
• renal transplantation
• dyslipidemia
• fluvastatin

INTRODUCTION

Chronic kidney failure ranging from mild renal insufficiency to end-stage disease is a common condition that may affect as many as 6 million individuals in the United States.[1] Premature atherosclerotic coronary heart disease driven by multiple risk factors is a major cause of morbidity and mortality among such patients. Data also indicate that cardiovascular complications contribute to a significant proportion of adverse outcomes in many of the approximately 14,000 patients per year receiving kidney transplants in the United States. Cardiovascular events were responsible for 35% to 45% of deaths among renal transplant recipients dying with a functioning graft.[2-4] In both settings, atherogenic lipid abnormalities contribute to the accelerated atherosclerotic process and, consequently, to the high prevalence of cardiovascular disease observed in uremic patients and those who have undergone renal transplantation.

Given the strong evidence of risk reduction and the benefits of lipid-lowering treatment in the general population, the emerging consensus is that kidney failure and renal transplantation patients should be treated aggressively for dyslipidemia.[5&6] This article characterizes the dyslipidemia observed in these clinical settings and reviews the clinical experience with fluvastatin, a HMG-CoA reductase inhibitor, that may be particularly suitable for use in kidney failure and renal transplantation patients.

LIPID DISORDERS IN KIDNEY FAILURE AND RENAL TRANSPLANT PATIENTS

Dyslipidemia in Kidney Failure Patients

Abnormal lipid profiles vary according to the stage of renal disease. During the asymptomatic stages of renal insufficiency, dyslipidemia develops and becomes more pronounced as renal failure advances. In patients with less advanced renal insufficiency, the alteration is characterized more by its abnormal apolipoproteins rather than its lipid profile.[7&8] With the progression of renal failure, the prominent features of uremic dyslipidemia include an increase in serum triglyceride (TG) levels (reflecting increased production from free fatty acids and decreased clearance of very low density lipoprotein [VLDL] and intermediate-density lipoprotein [IDL]) and lowhigh-density lipoprotein cholesterol (HDL-C). Low-density lipoprotein cholesterol (LDL-C) often is normal, but the cholesterol may originate from the atherogenic small and dense LDL subclass (sdLDL). The apolipoprotein B (apoB100, the primary protein component of LDL, may undergo enzymatic modifications contributing to impaired LDL receptor-mediated clearance from plasma and to prolong its residence time in the circulation.[9] The qualitative characteristics of renal dyslipoproteinemia are not modified substantially by dialysis treatment.

The pathophysiologic links between the renal insufficiency and the abnormalities of lipoprotein transport are still poorly defined, and the clinical significance of renal dyslipidemia has not yet been clearly established. Nevertheless, it is believed that renal dyslipoproteinemia may contribute to the development of atherosclerotic vascular disease and progression of glomerular and tubular lesions with subsequent deterioration of renal function.[10-12]

Dyslipidemia in Renal Transplantation

Patients who undergo renal transplantation often have end stage renal disease (ESRD) for years and many of them already have lipid derangement before transplantation. After successful renal transplant, though the renal function returns to normal, the lipid profile is reported to remain abnormal. The prevalence of posttransplant hyperlipidemia ranges from 16%–78% of recipients,[13] depending on at which time point posttransplantation serum lipid levels were obtained. Hypercholesterolemia occurs within 6 months in most patients (82%), whereas the peak incidence of hypertriglyceridemia is at 12 months after transplantation.[14]

Significant elevations in total cholesterol (TC) levels are typical, with most of the increase due to elevations in LDL-C, although significant increases in VLDL-C and VLDL-TG are also frequently seen.[15-17] In addition, elevated apo B and lipoprotein (a) plasma levels have been reported, and LDL oxidation may increase following transplantation.[15], [17-24] Changes in HDL-C posttransplantation are more variable, with the literature reporting no change, decreases, or increases.[15], [25&26] Changes in lipids may be seen as early as 3 weeks after transplantation, but typically are observed during the first 3 to 6 months after transplantation, with initial changes persisting over time.[27]

The causes of posttransplant hyperlipidemia (PTHL) are complex and not fully understood, however several classes of immunosuppressants including the corticosteroids,[14], [28-30] calcineurin inhibitors (cyclosporine),[31-34] (tacrolimus),[35-37] and (sirolimus)[38] appear to play a role. Current data suggest that the discrepancies in the relative incidence and severity of PTHL are largely accounted for by this difference in corticosteroid dose.[39]

Posttransplant hyperlipidemia may not only contribute to increased cardiovascular morbidity and mortality in the transplant population,[40-42] but also may be a factor in the development and progression of chronic vascular rejection and chronic graft dysfunction.[43-45]

ROLE OF FLUVASTATIN FOR DYSLIPIDEMIA IN THE KIDNEY FAILURE AND RENAL TRANSPLANTATION

As a drug class, the six statins available in the United States (atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin) all effectively lower LDL-C. Yet, there are differences among them with respect to 1) pharmacokinetic properties; 2) effects on the entire lipid profile; and 3) evidence for pleiotropic effects. Evidence from experimental and clinical outcome trials have shown that substantial benefits are associated with treatment with fluvastatin in patients with chronic kidney failure and following successful renal transplantation.

Pharmacokinetic Properties

The pharmacological features of fluvastatin make it useful in the setting of kidney failure and renal transplantation patients (Table 1). Cytochrome P450 (CYP) 2C9, not CYP3A4, is the major hepatic enzyme responsible for fluvastatin metabolism.[46] Fluvastatin has no detectable active circulating metabolites. After single or multiple doses above 20 mg, fluvastatin exhibits saturable first-pass metabolism resulting in higher-than-expected plasma fluvastatin concentrations. This phenomenon might be due to the saturation of CYP2C9 enzymes:[46&47] an effect totally prevented by the 80 mg fluvastatin slow-release formulation.[48] Furthermore, fluvastatin is not a substrate of p-glycoprotein.[46] Urinary excretion accounts for just 6% of fluvastatin clearance, while the fecal route is responsible for 90%.[47] The pharmacokinetics (PK) of fluvastatin were assessed in subjects with various degrees of renal impairment including patients on hemodialysis and nephrotic syndrome by Appel-Dingemanse et al.[49] renal impairment did not affect the PK of fluvastatin after a single oral dose.

Table 1. Clinical pharmacokinetics of HMG-CoA reductase inhibitors.

Parameter	Atorva	Fluva	Fluva XL	Lova	Prava	Rosuva	Simva
Tmax (h)	2–3	0.5–1	4	2–4	0.9–1.6	3	1.3–2.4
Cmax (ng/mL)	27–66	448	55	10–20	45–55	37	10–34
T1/2 (h)	15–30	0.5–2.3	4.7	2.9	1.3–2.8	20.8	2–3
Bioavailability (%)	12	19–29	6	5	18	20	5
Protein binding (%)	80–90	> 99	> 99	> 95	43–55	88	94–98
Metabolism	CYP3A4	CYP2C9	CYP2C9	CYP3A4	Sulfation	CYP2C9, 2C19 (minor)	CYP3A4
Metabolites	Active	Inactive	Inactive	Active	Inactive	Active (minor)	Active
P-glycoprotein substrate	Yes	No	No	Yes	Yes	No	Yes
Urinary excretion (%)	2	6	6	10	20	10	13
Fecal excretion (%)	70	90	90	83	71	90	58

Atorva = atorvastatin; Fluva = fluvastatin; Lova = lovastatin; Prava = pravastatin; Rosuva = rosuvastatin; Simva = simvastatin. Based in a 40-mg dose, with the exception of fluvastatin XL (80 mg).

Adapted from data in Refs. [47], [50]

^*Apparent half life.

Patients with varying degrees of renal insufficiency, as well as recipients of kidney transplants, are at high risk for drug–drug interactions due to their need for multiple medications. Drug interaction may cause the levels of concomitant drugs to increase, and, thus, increase the risk of side effects. Variability in pharmacokinetic propertiesamong the statins results in some important differences in their drug interaction potential. Most of the clinically important drug interactions that occur with certain of the statins are attributed to the co-administration of the statins that are metabolized by Cytochrome P450 (CYP)3A4 and other agents that are potent inhibitors or substrates of this enzyme. The CYP3A4 isoenzyme is responsible for the metabolism of atorvastatin, lovastatin, and simvastatin.[46] Three statins demonstrate only minor metabolism by CYP3A4: fluvastatin, pravastatin, and rosuvastatin.[46&47], [50] Of particular concern is the potential for pharmacokinetic interactions with other lipid-lowering agents, such as fibrates and niacin, and with immunosuppressive agents, such as prednisone, tacrolimus, and cyclosporine, which are used posttransplant. Interestingly, the interaction between statins and fibrates appears to involve more that a single mechanism and not CYP3A4 metabolism.[50-54]

Drug disposition can also be altered by mechanisms independent of CYP-induced metabolism and thereby may influence the interaction potential of statins. P-glycoprotein (PGP) is a transmembrane drug-efflux pump that transports many drugs across cells including those of the liver and intestine. As such, PGP can be a locus contributing to drug interactions.[55&56] That is, PGP can often be the mechanism for significant pharmacokinetic drug interactions when two or more drugs are competing for the PGP transport site.

Statin and Cyclosporine Interactions

The interaction of cyclosporine and certain statins via the CYP3A4 system is a major concern. Moreover, PGP is responsible, at least in part, for the low and variable bioavailability of cyclosporine, and the cyclosporine-pravastatin interaction may occur at the PGP level.[57] Cyclosporine increases the plasma levels of atorvastatin, cerivastatin, lovastatin, pravastatin, simvastatin, and to a very minor extent, that of fluvastatin (Table 2). Concomitant therapy with these statins has been reported to greatly increase the risk of myopathy that may eventually progress to rhabdomyolysis, and many cases of rhabdomyolysis have indeed occurred in transplant patients taking cyclosporine together with statins.[57] There have been no reports of rhabdomyolysis when fluvastatin isco-administered with cyclosporine. The reduced potential for pharmacokinetic interaction between fluvastatin and cyclosporine theoretically is due its predominant metabolism by CYP2C9, rather than CYP3A4, and its not being a substrate for PGP. Recently, it has been reported that cyclosporine also increased the plasma levels of rosuvastatin (up to 11-fold, probably due to an interaction between cyclosporine and rosuvastatin at the liver organic anion transporting polypeptide (OATP-C).[58&59]

Table 2. Effect of co-administered cyclosporine on pharmacokinetic parameters of statins.

	AUC		Cmax
Cerivastatin	↑ × 3.7		↑ × 4.8
Fluvastatin	↑ × 1.9		↑ × 1.3
Lovastatin	↑ × 20		−
Pravastatin	↑ × 5–23		↑ × 8
Simvastatin	↑ × 3–8		−
Atorvastatin	↑ × 6		↑ × 6
Rosuvastatin	↑ × 11		↑ × 7

AUC, area under the plasma concentration-time curve; Cmax, maximum plasma concentration.

Adapted from A.Corsini. Cardiovascular Drugs and Therapy 2003;17:257–277.

^*Values shown are the changes relative to the statin alone. Analytical procedures have been utilized for all statins with the exception of atorvastatin where a bioassay (inhibition of HMG-CoA reductase activity) has been employed.

Thus, for fluvastatin, the likelihood for serious metabolic drug interactions is expected to be minimal.[46] Co-administration of fluvastatin with other lipid-lowering agents has been shown to be without relevant drug interactions.[60-62] In terms of its suitability for use in patients with end-stage renal disease on maintenance hemodialysis, plasma fluvastatin concentrations are not influenced by the dialysis membrane, and it does not accumulate in hemodialysis patients with hyperlipidemia.[63]

Effects on Lipid Profile

Considering that the lipid abnormalities associated with accelerated atherosclerosis vary with the stage of renal disease, it is desirable for a lipid lowering agent to favorably affect abnormal apolipoproteins as well as lipid levels. In one randomized, placebo-controlled trial in the elderly (mean age, 75.5 years), fluvastatin XL produced a mean LDL-C reduction of 31% after 6 months treatment.[64] Median decreases in triglycerides levels, in another pooled analysis of 1674 patients with primary hypercholesterolemia,[65] were 19%; and HDL-C levels were increased by 8.7% overall. Favorable changes in and apolipoprotein A-I and apolipoprotein B levels also occurred.

The hypolipidemic potential of fluvastatin may be greater than that expected from its effects on LDL-C and TG alone. For example, fluvastatin 80 mg XL, once daily, decreased total cholesterol and total LDL-C, but in patients with atherogenic dLDL, absolute changes of dLDL were most pronounced, emphasizing the value of fluvastatin treatment in type 2 diabetes and other disease conditions (including posttransplant dyslipidemia)[66] characterized by these lipoprotein phenotypes.[67]

Pleiotropic Effects

Statins may have nonlipid-related (pleiotropic) properties that exert direct beneficial effects on the arterial wall, interfering with the formation and progression of atherosclerotic lesions. Evidence indicates that statins can be differentiated in terms of their pleiotropic properties.[68-70] Preclinical studies of fluvastatin demonstrated significantly altered leucocyte-endothelial cell adhesion responses to platelet-activating factor and leukotriene B4;[71] increased apoptosis in cardiac myocytes;[72] reduced interleukin-6 levels;[73] inhibited proliferation of vascular smooth muscle cells;[74] increased tissue plasminogen activator secretion;[75] reduced macrophage accumulation in carotid lesions;[76] and direct antioxidant effects on LDL-C.[77] Collectively, these actions suggest that fluvastatin has the ability to decrease the thrombogenicity and instability of atheromatous plaques.[78&79]

CLINICAL EXPERIENCE WITH FLUVASTATIN

Kidney Failure/Maintenance Hemodialysis

The impact of atherosclerotic cardiovascular disease in patients with renal insufficiency is well-documented;[6] and there is a growing body of evidence documenting the goals, efficacy, and safety of dyslipidemia treatment among chronic renal insufficiency and dialysis patients. A retrospective investigation of 3716 patients with ESRD showed that statin use was independently associated with a 36% reduction in the risk of cardiovascular mortality,[80] and results of a post hoc subgroup analysis from the recent CARE study showed pravastatin treatment reduced the risk of major coronary events in patients with mild chronic renal insufficiency.[81] Similar results have been obtained with simvastatin in the Heart Protection Study (HPS) trial.[82] With regard to fluvastatin, three studies[83-85] investigated the efficacy and safety of fluvastatin in patients with various stages of chronic kidney disease (CKD) and one small study[63] examined the effect of fluvastatin in hyperlipidemic hemodialysis patients. Over the course of these studies, 90 patients were treated with fluvastatin for durations ranging from 8 to 52 weeks (Table 3).

Table 3. Effects of fluvastatin in patients with impaired renal function.

Reference	Number of patients receiving fluvastatin	Underlying renal disorder	Entry criteria	Duration of active treatment (weeks)	Dosage (mg/day)	Effects on lipids(compared with baseline)				Safety findings
						TC	LDL-C	HDL-C	TG
[83]	32	Dyslipidemic,with or without CKD	TC > 239 mg/dL HDL-C < 35 mg/dL	12	40	− 15%ab	− 21%a,b	N/R	− 7%a,b	No adverse effects noted, including renal or hepatic parameters
[85]	9	Nephrotic syndrome	Hypolipoproteinemia(mean values: TC = 358 mg/dLLDL–C = 236 mg/dL)	52	40	− 31%b	− 28%b	+ 7%	− 19%b	No adverse effects noted; rise in serum creatinine attributed to underlying disease
[84]	44	Stage 3 to 5 CKD	LDL-C ≤ 160 mg/dL	8	40	− 20%a,b	− 26%a,b	0%	− 16%a,b	No serious adverse events occurred during the study; most common nonserious adverse events were gastrointestinal complaints
[63]	5	ESRD on maintenance hemodialysis	TC > 220 mg/dL	26	30	≈ − 30%b	≈ − 46%b	≈ − 13%	≈ − 7%	No adverse effects noted, including renal or hepatic parameters

TC = total cholesterol; LDL-C = low density lipoprotein cholesterol; HDL-C = high density lipoprotein cholesterol; TG = triglycerides.

^aSignificantly lower values than those achieved with placebo treatment (P < 0.05).

^bSignificantly lower than baseline values (p < 0.05).

Each study reported significant reductions in TC, LDL-C, and TG compared to baseline values, with two of the studies[83&84] also demonstrating significant reductions in these parameters compared to placebo. Total cholesterol levels dropped 15% to 32% following fluvastatin treatment, a trend mirrored by 21% to 31% reductions in LDL-C and 7% to 19% reductions in TG. In one study that compared the effects of fluvastatin in patients with or without chronic kidney disease, the degree of renal function (creatinine clearance levels 30 to 60 mL/min or 60 to 90 mL/min) did not appear to affect the lipid-lowering effects of fluvastatin,[83] suggesting that patients with any degree of renal impairment may benefit from fluvastatin treatment. Another study noted significantreductions in serum lipids within 2 months of the onset of treatment, with effects persisting through 1 year.[85]

The largest study was conducted in 45 patients with moderate-to-advanced renal insufficiency (i.e., stage 3 to stage 5 CKD). In addition to the reductions in TC, LDL-C, and TG noted in the other studies, this study also reported beneficial changes in apolipoproteins and lipoprotein particle profiles.[84] Following fluvastatin treatment, the levels of TC, LDL-C, ApoB, and Lp(b) returned to those seen in healthy, normolipidemic people, while levels of TG, VLDL-C, apoCIII, and apoCIII-HP were reduced less substantially.[84] Given the association of abnormalities in these lipoproteins with the progression of renal insufficiency,[86] the results of this study suggest that fluvastatin treatment has the potential to attenuate the progression of chronic kidney disease through its lipid-lowering effects.

No serious adverse events were attributed to fluvastatin treatment in any of the studies, with the most common side effects being gastrointestinal complaints, such as nausea or vomiting. While one study noted a significant rise in serum creatinine levels, this was attributed to decreased glomerular filtration a characteristic of the study population;[85] the other studies found no such increase.

Together, these studies provide evidence that fluvastatin can induce favorable changes in blood lipid parameters; however, further studies must be conducted to determine whether these alterations produce beneficial outcomes with regard to the progression of chronic kidney disease and the development of atherosclerotic processes in patients with impaired renal function.

Renal transplantation

Levels of TC, LDL-C, and HDL-C rise following transplantation; a result of immunosuppressive therapy and altered diet.[14], [42], [87] A total of 20 well-documented studies have examined the lipid effects of fluvastatin in patients who underwent successful renal transplantation (Table 4). During the course of these studies, more than 1500 renal transplant recipients received fluvastatin for durations ranging from 3 months to 6 years. Five of these studies were placebo-controlled,[88-92] with the other studies comparing the effects of fluvastatin to pretreatment serum lipid values in patients with at least moderately elevated TC (> 200 mg/dL) or LDL-C (> 130 mg/dL). Every study reported significant reductions in LDL-C levels following fluvastatin treatment. In 11 of the studies, LDL-C concentrations fell to levels 3% to 38% below baseline values. With respect to the placebo-controlled studies, LDL-C values observed in fluvastatin-treated patients were consistently significantly lower than those seen with placebo treatment.

Table 4. Effects of fluvastatin in renal transplant patients.

Reference	Number of patients receiving fluvastatin	Entry criteria(lipid parameters)	Duration of active treatment	Dosage	Effects on lipids(compared with baseline)				Safety findings
					TC	LDL-C	HDL-C	TG
RANDOMIZED, PLACEBO-CONTROLLED TRIALS
[88]	1050	TC 154–348 mg/dL	5–6 years	40–80 mg/day	− 16%a	− 32a,b	N/Rd	− 14% (versus placebo)	Similar numbers of treatment discontinuations in fluvastatin and placebo groups; no changes in the observed rates of malignant diseases between treatment groups
[89]	13	TC 200–350 mg/dL	3 years	40 mg/day	− 7%a,b	− 15%a,b	+ 8%	+ 2%	No difference in serum creatinine, CPK, or bilirubin noted between fluvastatin and placebo
[90]	18	TC 200–350 mg/dL	6 months	40 mg/day	− 17%a,b	− 24%a,b	+ 7%	− 10%	No difference in blood pressure, creatinine, CPK, bilirubin, or glucose between fluvastatin and placebo; 1 fluvastatin-treated patient developed myalgia.
[91]	182	No lipid criteria	12 weeks	40 mg/day	+ 15% − 18%a (versus placebo)	+ 2% − 41%a (versus placebo)	+ 37% + 5% (versus placebo)	+ 21% − 25%a (versus placebo)	No differences in adverse events between fluvastatin and placebo; no episodes of rhabdomyolysis; and similar numbers of treatment discontinuations between fluvastatin and placebo
[92]	37	TC 154–348 mg/dL	12 weeks	40 mg/day	+ 2% − 18%a (versus placebo)	− 15% − 34%a (versus placebo)	+ 59% + 11% (versus placebo)	− 1% − 12% (versus placebo)	No difference in blood pressure or GFR between fluvastatin and placebo
TRIALS COMPARING POST-TREATMENT EFFECTS TO BASELINE VALUES
[94]	38	TC > 250 mg/dLLDL-C > 150 mg/d	2 years	40–80 mg/day	− 18%b	− 23%b	+ 2%	− 21%b	Mild and transient adverse effects observed, with no significant variation in hepatic enzymes, uric acid or CPK.
[98]	21 (diabetic)	TC 255–380 mg/dLTG 115–352 mg/dL	1 year	20 mg/day	− 17%b	− 7%b	+ 36%b	− 28%b	No adverse events or alterations in hepatic enzymes; slight and significant rise in CPK that remained in normal reference range
[114]	20	TC > 251 mg/dL	1 year	20–40 mg/day	− 18%b to − 21%b	− 27b% to − 29%b	− 1% to0%	− 16% to − 41%	Fluvastatin discontinued in 1 patient due to nausea and vomiting; no alterations in hepatic enzymes or CPK observed
[115]	20	TC > 243 mg/dL	1 year	20–40 mg/day	− 20%b	− 28%b	− 1%	− 27%	2 patients reported nausea (1 discontinued treatment) and 1 patient reported transient insomnia
[116]	30	“Non-responsive to diet” hyperlipidemia	6 months	20–40 mg/day	− 27% to − 29%b	− 31%b	N/Rd	N/Rd	No significant effect of fluvastatin on CPK, and no adverse events related to myotoxicity
[117]	16	TC > 240 mg/dLLDL-C > 130 mg/dL	6 months	20–40 mg/day	− 16%a,b	− 29%a,b	+ 6%	− 11%	No significant effect of fluvastatin on renal and liver function tests or CPK levels; no myalgiareported.
[95]	14	TC > 240 mg/dLTG < 440 mg/dL	20 weeks	20–40 mg/day	− 27%b	− 38%b	0%	− 23%b	No adverse events or effect on CPK observed.
[102]	20	LDL-C > 160 mg/dLTG < 400 mg/dL	14 weeks	20 mg/day	− 16%b	− 25%b	+ 7%	− 9%	Adverse events generally mild and transient; no evidence of myopathy, rhabdomyolysis, or ophthalmologic abnormalities
[118]	38	TC > 251 mg/dL	12 weeks	20 mg/day	− 23%b	− 30%b	N/Rd	N/Rd	Adverse effects (gastric complaints, myalgia) mild and transient and did not require treatment discontinuation; no significant elevations in hepatic enzymes or CPK
[119]	17	TC > 240 mg/dLLDL-C > 160 mg/dL	12 weeks	20 mg/day	− 18%b	− 25%b	− 6%	− 15%	No statin-related adverse effects reported, and no changes in liver enzymes or CPK
[96]	12	TC > 220 mg/dLLDL-C > 160 mg/dL	12 weeks	20 mg/day	− 25%b	− 31%b	+ 5%	− 20%b	No adverse events or effect on CPK observed
[97]	21 (diabetic)	TC > 255 mg/dLTG < 354 mg/dL	12 weeks	20 mg/day	− 17%b	− 3%b	+ 36%c	− 7%b	No adverse effects reported.
[120]	10	No lipid criteria	12 weeks	20 mg/day	− 17%b	− 28%b	+ 4%	− 11%b	No significant changes in hepatic enzymes or CPK levels observed
[121]	19	TC > 240 mg/dLLDL-C > 130 mg/dL	8 weeks	40 mg/day	− 15%b	− 22%b	+ 7%	− 9%	No effect on hemostatic parameters.
[122]	20 (12 with prednisone and 8 without)	LDL-C > 160 mg/dL or TC/HDL-C ratio > 5.0.	≥ 26 weeks	20 mg/day	− 12%b and − 13%	− 12.%b and − 16.%b	No change	No change	Low dosages of fluvastatin appear to be safe in cyclosporine-treated renal transplant recipients

TC = total cholesterol; LDL-C = low density lipoprotein cholesterol; HDL-C = high density lipoprotein cholesterol; TG = triglycerides.

^aSignificantly lower values than those achieved with placebo treatment (P < 0.05).

^bSignificantly lower than baseline values (P < 0.05).

^dTC = total cholesterol; LDL-C = low density lipoprotein cholesterol; HDL-C = high density lipoprotein cholesterol; TG = triglycerides

^cSignificantly higher than baseline values.

Changes from baseline in the concentrations of TC followed a similar pattern to that of LDL-C. With two exceptions[91&92] the studies demonstrated declines in serum levels of TC that ranged from 7% to 29% lower than baseline values. With respect to these two studies, the comparisons with placebo, however, did show significant differences favoring fluvastatin (− 10% and − 18%, respectively). Indeed, relative to placebo controls, the fluvastatin-mediated changes in TC concentrations were uniformly significant. Specifically, placebo-treated patients completed the studies with TC values that were more than 10% higher than were their fluvastatin-treated counterparts. The reductions in TC and LDL-C occurred within 1 month of initiating fluvastatin therapy.[93&94])and persisted for the duration of the treatment period, even in those studies that exceeded 6 months[89], [94] and persisted for over 5 years in one study [88] Most of the studies reported numerical reductions in TG levels and increases in HDL-C levels; however, these changes were found to be statistically significant when compared to pretreatment values only in certain studies.[94-98] Collectively these studies demonstrate that fluvastatin exerts the same types of lipid-lowering effects in renal transplant patients as it produces in other study populations.[99&100]

Alert Trial

Whether the beneficial lipid effects described above confer better outcomes for renal transplant patients has been addressed in the ALERT (Assessment of Lescol® in Renal Transplantation) trial.[88] This multicenter trial enrolled 2102 patients with functioning renal transplants and mild-to-moderate elevations in serum cholesterol. All patients received concomitant cyclosporine A and 81% received steroid therapy. Nearly all patients also received cardioprotective medications, including beta-blockers, calcium channel antagonists, and aspirin.[88] Patients were randomly assigned to receive fluvastatin at an initial dose of 40 mg/day or placebo for a period of 5 to 6 years. Two years into the study, the dosage of fluvastatin was increased to 80 mg/day based on the more robust blood lipid reductions noted at higher doses in other studies.[99] The primary endpoint of the study was the first occurrence of a major adverse cardiac event (MACE), defined as cardiac death, nonfatal myocardial infarction (MI), or coronary revascularization. In addition, the ALERT trial investigated other combined and individual cardiac and noncardiac endpoints as well as assessing treatment effects on lipid concentrations and safety of the study medication.

After 6 weeks of treatment, fluvastatin therapy had significantly lowered LDL-C concentrations by a mean of 25% compared with placebo, with these effects persisting throughout the study. After a mean follow-up period of 5.1 years, fluvastatin had significantly lowered mean LDL-C by 32% compared with placebo. Furthermore, mean TC and mean TG levels decreased significantly in the fluvastatin group compared with placebo.

Despite a 17% reduction in the incidence of MACE in fluvastatin-treated patients, the decrease was not significantly different than was that observed for placebo (p = 0.139). Treatment with fluvastatin reduced the risk coronary heart disease, defined as cardiac death or nonfatal MI by 35%, consistent with the beneficial effects of statins in other populations. When these events were assessed individually, fluvastatin treatment reduced the risk of cardiac death and nonfatal MI by 38% and 32%, respectively. These reductions were statistically significant, and support the beneficial effects of fluvastatin in this patient population.[88], [101]

Safety of Fluvastatin in the Studies Overall

In all of the studies, among fluvastatin-treated patients compared with baseline or to placebo, no clinically important alterations in laboratory tests of renal or hepatic function were observed; likewise, in the placebo-controlled studies, no differences in the frequency or severity of adverse events were noted between those receiving fluvastatin and those randomized to placebo. No cases of fluvastatin-induced rhabdomyolysis were reported. Two patients experienced myalgia but did not demonstrate elevated levels of creatine kinase.[90], [102] There was a single patient with an isolated elevation in creatine kinase, resolving even with continuing fluvastatin treatment.[102]

IMPACT OF FLUVASTATIN ON RENAL FUNCTION

Lipid abnormalities in renal disease are also associated with a progressive decline in renal function. Experimental studies demonstrated that potentially atherogenic lipoproteins, such LDL, are associated with renal pathophysiological changes that result in progressive glomerular and interstitial damage and an ultimate reduction in renal function. Furthermore, clinical studies show that renal function declines more rapidly among patients with primary renal disease or diabetic nephropathy who have hyperlipidemia.[103] The underlying pathophysiological mechanisms of the relationship between dyslipidemia and progression of renal insufficiency are not fully understood. However, fluvastatin and other lipid-lowering agents can reduce renal lesions and preserve renal function by virtue of their effect on lipid abnormalities and also by influencing important intracellular pathways that are involved in the inflammatory and fibrogenic responses, which are common components of many forms of progressive renal injury.[104] The later effects are independent of plasma cholesterol lowering.

There is evidence that fluvastatin's beneficial effects on renal function, beyond reducing hyperlipidemia in patients with kidney disease, involve a complex action on several intracellular pathways mediating nitric oxide formation,[105] inflammation[106] and oxidative processes,[107] mesangial cell proliferation,[108] macrophage adhesion,[109] and fibrogensis.[110] Therefore, fluvastatin appears to exhibit an antiproteinuric effect and preserve creatinine clearance[111&112] due to both its lipid-lowering activities and its direct pleiotropic actions on a number of biologically important processes.

CONCLUSIONS

Although the National Cholesterol Education Program Adult Treatment Panel III recommendations that patients achieve a LDL-C less than 100 mg/dL, the optimal extent of LDL-C lowering is even greater, based on a recent statement.[113] Aggressive treatment that lowers LDL-C below the currently recommended goal may further reduce patients' risk of cardiac death. Recently reported trials in patients with proven coronary heart disease suggest that intensive lipid-lowering treatment was beneficial. (Cannon, 2003 #142; Nissen, 2004 #143; de Lemos, 2004 #457.) The rationale for such treatment appears biologically and clinically plausible and may be a relevant approach to the accelerated atherosclerosis seen in renal insufficiency and kidney transplant patients. Chronic kidney failure and renal transplantation are characterized by abnormalities in lipoprotein metabolism, markedly increasing the risk of cardiovascular disease and contributing to the progression of renal disease. Therefore, preventive treatment is necessary in these types of patients. There are no definitive guidelines as to the best statin to use when renal function is impaired. In this context, based on its pharmacokinetic properties and its pleiotropic effects, fluvastatin is a good alternative among the currently available statins for treatment of the dyslipidemia in these high-risk populations. Fluvastatin safely and effectively lowers cholesterol levels in patients with renal disease, and management of dyslipidemia is associated with beneficial effects on proteinuria and creatinine clearance.