A Retrospective Analysis of Ezetimibe Treatment in Renal Transplant Recipients

Authors


Abstract

A retrospective review was conducted to determine the safety and efficacy of ezetimibe as a treatment option for renal transplant recipients. We evaluated the medical records of 34 adult renal transplant recipients receiving ezetimibe as monotherapy or combination therapy. Fasting lipid profiles were obtained at baseline and at 1–6 months post-ezetimibe initiation. Twenty patients received cyclosporine, 12 patients received tacrolimus, 1 patient received either sirolimus or no calcineurin therapy at the time of ezetimibe initiation. Monotherapy was started in 8 patients, who had all previously failed statins, and combination therapy was utilized in 26 patients. Monotherapy or combination therapy resulted in a mean reduction in total cholesterol of 23.3%, triglycerides 40.2%, low-density lipoproteins 16.8% and high-density lipoproteins 4.8% after 3.1 months of therapy. Ezetimibe as combination or monotherapy is a safe and effective treatment option for dyslipidemia in renal transplant recipients without changes in calcineurin inhibitor levels or renal function.

Introduction

Cardiovascular disease (CVD) is the primary cause of death in renal transplant recipients (1). It has been reported that 55% of deaths in renal transplant recipients with functioning allografts were cardiovascular related (2–5). In addition to the traditional risk factors for CVD, renal transplant recipients have other risks associated with impaired kidney function and also those associated with many immunosuppressive agents (6,7). After transplantation, the most significant rise in total cholesterol (TC) occurs in the first 3–6 months post-transplantation resulting in approximately 70% of renal transplant recipients developing dyslipidemia (1,6–12).

Although there are many agents currently available to reduce lipids, only a few are considered to be safe and effective in transplant recipients. Statin agents are considered first-line therapy because of their efficacy, but they tend to interact with cyclosporine (CyA) and possibly tacrolimus (TAC) (13). Although statins have been shown to be effective in lowering low-density lipoprotein (LDL) cholesterol, many patients do not achieve standard treatment goals as defined by the National Cholesterol Education Program III (NCEP III) (14). While higher doses of statins are more effective, the risk of serious adverse effects seems to be dose dependent (12). Thus, the need for additional lipid-lowering compounds has focused attention on other mechanisms of action.

Recently, a new lipid-lowering agent was approved for the treatment of hyperlipidemia either as monotherapy or concomitantly with a statin. Ezetimibe is a selective inhibitor of the intestinal absorption of cholesterol at the brush border. Thus, ezetimibe leads to a decrease in the delivery of cholesterol to the liver. This process causes a reduction in cholesterol stores and an increase in clearance from the blood. Therefore, this mechanism is complementary to the mechanism of action of the statins (13). Another benefit of ezetimibe is that it has also been shown to not interfere with the absorption of concurrently administered medications (13,19). On the other hand, there have been reports that CyA can increase the mean area under the curve (AUC) and maximum drug concentration (Cmax) values of ezetimibe, as well as, increase CyA mean AUC (13).

To date, the use of ezetimibe has not been evaluated specifically in the transplant population. As a result, this retrospective study was undertaken to evaluate the safety and efficacy of ezetimibe as monotherapy or combination therapy with a statin agent in adult renal transplant patients.

Materials and Patients

This study was a retrospective chart review of the medical records of all adult renal transplant recipients on ezetimibe for the treatment of hyperlipidemia from November 2002 through July 2004 at the University of Utah Hospitals and Clinics. Patients were included if they were over 18 years of age, had a history of hyperlipidemia and were treated with ezetimibe as monotherapy or combination therapy. The study protocol was approved by the institutional review board. A total of 34 patients met the inclusion criteria for the review and were included in the analysis presented. Statin therapy was the first-line therapy for the treatment of hyperlipidemia in all patients. Criterion for ezetimibe combination therapy was if the fasting lipid profile did not meet the National Kidney Foundation–Kidney Disease Outcomes Quality Initiative (NKF–K/DOQI) or the NCEP III lipid guideline goals for high-risk patients after 6 weeks on another agent or reaching the maximum dose of the agent before achieving a goal of TC < 200 mg/dL, LDL < 100 mg/dL, high-density lipoproteins (HDL) > 60 mg/dL and triglycerides (TG) of < 150 mg/dL. Monotherapy was initiated with ezetimibe if the patient did not tolerate the first-line agent. None of the patients reached their lipid goal with the first-line agents alone. Ezetimibe was initiated in all patients at 10 mg daily.

From the hospital medical records, the following data were collected: patient demographics (e.g. age, sex, gender), ezetimibe regimen (dose and administration), serum creatinine (SCr) both pre- and post-ezetimibe initiation, immunosuppression regimen (agents, dose, calcineurin inhibitor trough levels), in addition fasting lipid profiles (baseline and at 1–6 months post-ezetimibe initiation), cholesterol treatment regimens (dose and administration), incidence of adverse drug reactions, liver function tests (LFT) levels both pre- and post-ezetimibe therapy and creatinine kinase (CK) pre- and post-ezetimibe treatment.

Basic descriptive statistics were used to evaluate the data collected from the chart review. A computerized statistical software package [Microsoft Excel 2003 (Microsoft Corp., Redmond, WA) with Analyse-it + General Statistics add-on software, version 1.71 (Analyse-it Software, Ltd., Leeds, United Kingdom; 2003)] was used for calculations. Wilcoxon signed rank test was used to compare the SCr pre-ezetimibe to that post-ezetimibe. This test was utilized to also test CyA and TAC levels both pre- and post-ezetimibe. A p-value of p < 0.05 was considered as significant.

Results

Thirty-four adult renal transplant recipients currently receiving ezetimibe were included in this study. The majority of patients received a living-related transplant (47%), had hypertension (82%) and had received hemodialysis (HD) prior to transplantation (53%). The median age of patients treated with ezetimibe was 53 years. The mean time to follow-up was 3.1 months and the median time from transplantation to initiation of ezetimibe therapy was 3.6 years. The most common immunosuppressive therapy consisted of CyA, azathioprine and prednisone (44%); followed by TAC, mycophenolate mofetil (MMF) and prednisone (Table 1).

Table 1. Patient demographics and immunosuppressive regimens–n (%)
  1. CyA = cyclosporine; TAC = tacrolimus; MMF = mycophenolate mofetil; study medication = prednisone or placebo; CAD = coronary artery disease; HTN = hypertension.

Mean age (Years)53 (20–77)
Gender–n (%)
 Female13 (38%)
 Male22 (62%)
Transplant type–n (%)
 Deceased donor14 (41%)
 Living related donor16 (47%)
 Living unrelated donor4 (12%)
Dialysis prior to transplant–n (%)
 Hemodialysis18 (53%)
 Peritoneal4 (12%)
 None11 (32%)
 Unknown1 (3%)
Cardiovascular disease–n (%)
 CAD8 (24%)
 HTN28 (82%)
Diabetes–n (%)8 (24%)
Immunosuppressive regimens
 CyA, azathioprine3 (8.8%)
 TAC, MMF2 (5.8%)
 CyA, azathioprine, prednisone15 (44%)
 MMF, prednisone1 (3%)
 TAC, MMF, prednisone6 (17.6%)
 CyA, MMF, prednisone1 (3%)
 TAC, MMF, Study medication4 (11.8%)
 Sirolimus, prednisone, CyA1 (3%)
 CyA, MMF1 (3%)

Ezetimibe monotherapy was utilized in 8 patients who had previously failed statin therapy because of a statin-related adverse event. Of these patients, 4 were on CyA, 3 were on TAC and 1 was on sirolimus. The reasons for statin discontinuation were: myalgias (3 patients), nausea/vomiting (2 patients), non-compliance (1 patient) and elevated CK levels (2 patients).

Three patients (9%) had elevations in CK while taking a statin agent. One patient had an increase in CK on atorvastatin, but was switched to pravastatin for a brief period of time without further elevations and then eventually discontinued pravastatin secondary to elevations in CK. Another patient developed a rash on atorvastatin and was switched to rosuvastatin, on which they developed elevated CK and rhabdomyolysis. In addition, a patient was on combination therapy with colesevelem instead of a statin agent secondary to prior CK elevations while on a statin.

Twenty-six patients (76%) were placed on combination therapy with ezetimibe. Of the patients receiving combination therapy, 1 patient was on fluvastatin, 1 patient was on colesevelam, 8 patients were on pravastatin, 1 patient was on lovastatin, 11 patients were on atorvastatin and 4 patients were on simvastatin. The 1 patient receiving colesevelam had previously failed the statin agents (atorvastatin and simvastatin), niacin and fenofibrate.

After treatment with either ezetimibe monotherapy or combination therapy, the fasting lipid profiles were significantly improved (Table 2). Ezetimibe therapy also resulted in no significant change in SCr, LFT's or calcineurin inhibitor (CNI) levels. The average SCr prior to ezetimibe therapy was 1.40 ± 0.39 mg/dL and after treatment was 1.48 ± 0.49 mg/dL (P = NS). This difference was not statistically significant. The average aspartate amino transferase (AST) prior to ezetimibe therapy was 21.7 ± 7.64 U/mL and after treatment was 22.5 ± 6.9 U/mL. The average alanine aminotransferase (ALT) prior to ezetimibe therapy was 28.2 ± 11.1 U/mL and after treatment was 28.3 ± 13.5 U/mL. These differences were not statistically significant. The average CyA blood trough level prior to ezetimibe was 167 ± 58.1 ng/mL and 157 ± 44.2 ng/mL post-ezetimibe therapy (P = NS). The average TAC level prior to ezetimibe was 9.50 ± 2.95 ng/mL and after ezetimibe therapy the average level was 9.08 ± 2.67 ng/mL (P = NS).

Table 2. Ezetimibe monotherapy and combination therapy results on lipids
Cholesterol (mg/dL)MonotherapyCombination therapyMean lipid profile (monotherapy and combination therapy)
Pre-ezetimibePost-ezetimibep-valuePre-ezetimibePost-ezetimibep-valuePre-ezetimibePost-ezetimibep-value
  1. TC = total cholesterol; TG = triglyceride; LDL = low-density lipoproteins; HDL = high-density lipoproteins.

TC301 ± 172.9209 ± 47.70.1301230 ±36183 ±51.3<0.0001247 ±95.7189 ±51.60.0003
TG543 ± 891188 ± 89.80.3034244 ± 209.6188 ±180.80.0029314 ±492.5188 ± 163.40.1052
LDL149 ± 52.5120 ± 36.20.0357123 ±29.991 ± 42.20.0012114 ± 38.295 ± 42.7<0.0001
HDL54 ± 14.752 ± 10.50.835264 ± 2558 ± 20.20.012360 ± 23.457 ± 18.50.0326

One patient was switched from CyA to TAC due to CNI toxicity after ezetimibe was initiated. Another patient had his CyA dose decreased when diltiazem, a potent cytochrome 3A4 (CYP3A4) inhibitor, was initiated. Only one patient discontinued ezetimibe therapy due to tremors, diarrhea and myalgias. This patient had previously failed statin, colestid and niacin therapy secondary to diarrhea. Ezetimibe monotherapy or combination therapy was well tolerated in all the other patients.

Discussion

This study demonstrates that ezetimibe is effective in lowering cholesterol either as monotherapy or combination therapy. None of the patients receiving statin monotherapy were able to achieve the lipid goals stated in the NCEP ATP III and NKF–K/DOQI guidelines with a statin alone (17,18). However, treatment with ezetimibe, either as monotherapy or combination therapy, significantly reduced the fasting lipid profile to therapeutic goals. The mean reduction in the lipid profile for those patients on monotherapy was 30.6% in TC, 65.3% in TG, 19.4% in LDL and 2.1% in HDL. Similarly, the mean reduction in the combination therapy group was 20.4% in TC, 23% in TG, 26.5% in LDL and 9.1% in HDL. Thus, lipid levels were significantly lowered with an average reduction in TC of 23.3%, TG 40.2%, LDL 16.8% and HDL 4.8% after a mean 3.1 months of therapy (Figure 1). Therefore, the use of ezetimibe, either as monotherapy or combination therapy, is effective in achieving goal lipid levels in renal transplant recipients.

Figure 1.

Effect of ezetimibe mono- therapy or combination therapy on lipids in transplant recipients.

The clinically significant reduction in the lipid profile was much greater than that previously reported in the literature (13). This variance was thought to be explained by the interaction between CyA and ezetimibe, which results in an increase in the AUC and Cmax of ezetimibe. However, on further analysis it was determined that the reduction in the lipid profile did not vary based on whether the patient received CyA or TAC nor whether the patient received monotherapy or combination therapy (P = NS).

In our review, the use of ezetimibe did not alter CyA or TAC blood trough levels and did not result in serious adverse events. However, it has been reported that the mean AUC and Cmax values of total ezetimibe were increased 3.4-fold and 3.9-fold, respectively, in renal transplant recipients on CyA and ezetimibe. In addition, a 12-fold greater exposure to total ezetimibe and a mean 15% increase in cyclosporine AUC have been shown in renal transplant recipients receiving these medications in combination (14).

The use of ezetimibe in our study resulted in only one patient with fluctuations in his CNI levels after the initiation of ezetimibe and was explained by the addition of diltiazem, a potent inhibitor of CYP 3A4. There were no other significant changes in CNI levels. Another patient had tremors, myalgias and diarrhea after the initiation of ezetimibe. This patient previously had not tolerated statin agents, niacin or colestid. No other patient experienced an adverse reaction to the ezetimibe therapy.

Ezetimibe is a selective inhibitor of the intestinal absorption of cholesterol at the brush border. Thus, complementing the statin agents' mechanism of action (13,15,19–20). Combination therapy with a statin and ezetimibe has been shown to be effective in reducing cholesterol in the non-transplant population (18–20). Because of the limitation in the use of statin agents at higher doses in transplant recipients, the use of ezetimibe either as combination therapy or monotherapy may prove to be very useful in the transplant population.

Our study had several limitations. The most significant being a retrospective study with a small number of patients, followed for a short period of time. The retrospective nature of this study limits a thorough assessment of potential adverse drug reactions and drug interactions in the renal transplant population. As mentioned previously, there have been a few reports of CyA and ezetimibe interacting and causing an increase in the mean AUC and Cmax of ezetimibe as well as an increase in the mean AUC of CyA (13). In addition, the study was further limited by the lack of a full pharmacokinetic profile. Further studies need to be conducted to determine the significance of ezetimibe therapy in the renal transplant population. This includes the assessment of the effect of ezetimibe on morbidity and mortality in the renal transplant population.

In conclusion, ezetimibe is safe and effective for the treatment of dyslipidemia in renal transplant recipients as either monotherapy or combination therapy. Our results show that the use of this agent may help this patient population reach their lipid goals and with minimal adverse reactions. The use of ezetimibe, with or without statin therapy, effectively lowered TC, TG and LDL without a significant change in HDL. In addition, concomitant use of ezetimibe with a CNI did not alter the CNI blood trough levels. However, more studies are needed in order to determine the long-term safety and efficacy of ezetimibe use, with and without statins, as well as, the long-term effects on the cardiovascular and allograft outcomes in the renal transplant population.

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