Ezetimibe for the Treatment of Uncontrolled Hypercholesterolemia in Patients with High-Dose Statin Therapy After Renal Transplantation
*Corresponding author: Frank Pietruck, firstname.lastname@example.org
We investigated prospectively the efficacy of ezetimibe in addition to statin therapy in stable renal transplant patients in whom hypercholesterolemia was not sufficiently treated. Eighteen renal transplant patients received 10 mg ezetimibe once daily in addition to high-dose statin therapy for uncontrolled hypercholesterolemia. Total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, Tacrolimus (Tac)- and Cyclosporine A (CsA) blood levels, creatinine, urea, liver enzymes, electrolytes and creatinkinase (CK) were measured before initiation of ezetimibe therapy, after 7 days, 6 weeks and 3 months. Cholesterol concentrations decreased significantly (p < 0.005) from 264 ± 46 mg/dL at baseline to 205 ± 48 mg/dL after 1 week to 202 ± 48 mg/dL after 6 weeks and 212 ± 40 mg/dL after 3 months (reduction after 3 months 21 ± 10%). LDL-concentrations decreased significantly (p < 0.005) from 178 ± 41 mg/dL at baseline to 129 ± 35 mg/dL after 1 week to 123 ± 25 after 6 weeks and to 117 ± 40 mg/dL after 3 months (reduction after 3 months 37 ± 14%). Two patients stopped ezetimibe therapy due to nausea and muscle pain without CK elevation. Significant changes of CsA and Tac blood levels, liver and muscle enzymes were not observed. Ezetimibe seems to be an effective therapy for uncontrolled hypercholesterolemia in renal transplant patients when combined with high-dose statin therapy.
Premature cardiovascular morbidity and mortality are still the major problems in the long-term after renal transplantation and death with a functioning transplant is a common complication. The relative age-specific death rates due to cardiovascular disease are 5–10 times greater than in the general population (1–3) and also graft loss due to chronic allograft nephropathy is associated with hypercholesterolemia (4,5). Hypercholesterolemia as a major contributor of cardiovascular disease is very common in patients after renal transplantation. Although a large clinical trial (ALERT study) and epidemiological data have supported that cholesterol lowering reduces cardiovascular events in this population (6–8), there are significant difficulties in reaching the cholesterol target levels as recommended by the American Heart Association (AHA) (9–11) by therapy with statins alone (12). Therapy with statins is often limited due to pharmacologic interactions (e.g. Cs/Tac etc.) or side effects (13,14). Statins inhibit the enzyme 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase thereby reducing endogenous cholesterol synthesis. Ezetimibe is a new agent with a different way of action selectively blocking absorption of dietary and biliary cholesterol by the small-intestine enterocyte brush-border (15). The addition of ezetimibe to a statin therapy has resulted in reduction of approximately 10–15% of the cholesterol levels (16). Limited experience exists about ezetemibe therapy in patients after solid organ transplantation (17). It was the aim of this study to investigate prospectively the efficacy of ezetimibe in addition to statin therapy in stable renal transplanted patients in whom hypercholesterolemia was not sufficiently treated as defined by the AHA with statin therapy alone.
Renal transplant recipients with hypercholesterolemia and high-dose statin therapy were included into this prospective study. Inclusion criteria were: stable renal transplant function after more than 6 months following transplantation, uncontrolled hypercholesterolemia with respect to the criteria of the ‘American Heart Association (AHA)’ and the National Education Program (NCEP) (9–11) despite high-dose statin therapy, stable statin therapy for at least 3 months before inclusion in the study and informed consent of the patient. Exclusion criteria were: uncontrolled malignant and infectious disease, active liver disease (AST or ALT > 2 × the upper norm), signs of rhabdomyolysis (creatinkinase (CK) > 2 × the upper norm), therapy with fibrates of cholestyramine and pregnancy.
After the inclusion into the study, all patients received additionally 10 mg ezetimibe once a day. There were no changes in the dose of statin therapy during the study period. All patients had been given instructions prior to institution of statin therapy focusing on lifestyle changes, low-fat diet and body-weight reduction in appropriate patients. New dietary recommendations were not given prior or within the study period. The study visits were scheduled before initiation of ezetimibe therapy, after 7 days, after 6 weeks and after 3 months. Total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, tacrolimus (Tac)- and cyclosporine A (CsA) blood concentrations, creatinine, urea, electrolytes and CK were measured on all scheduled visits and serum aminotransferases before initiation of ezetimibe therapy and after 3 months. The protocol was approved by the local ethical committee and informed consent was obtained from all patients.
Finally, 18 renal transplant patients (10 men and 8 women) were eligible for participation in this prospective study. The mean age was 55 ± 11 years (range: 41–71) and the time after transplantation was 7 ± 5 years (range: 1–18). Patients received either fluvastatin 80 mg (n = 14) or fluvastatin 40 mg (n = 1) or pravastatin 40 mg (n = 2) or simvastatin 80 mg (n = 1). The immunosuppressive therapy was based on a calcineurin inhibitor therapy (CsA, 11 patients [mean daily dose 200 ± 42 mg], Tac, 6 patients [mean daily dose 4.6 ± 2.3 mg]) except for 1 patient treated with sirolimus. All patients additionally received prednisone (7.5 ± 1.0 mg/day). Seven patients were on a triple drug therapy, with 5 patients receiving mycophenolate mofetil (MMF) and 2 patients receiving azathioprine (AZA).
Complete data were available from 16 of 18 patients as 2 patients stopped ezetimibe therapy due to nausea (n = 1) and muscle pain without CK elevation (n = 1) after 10 and 4 weeks, respectively. Both patients received 80 mg fluvastatin and CsA in addition. These patients had total cholesterol concentrations of 221 mg/dL and 243 mg/dL before ezetimibe therapy, 192 mg/dL and 183 mg/dL during and 242 mg/dL and 227 mg/dL 2 weeks following cessation of ezetimibe therapy. LDL concentrations were 183 mg/dL and 142 mg/dL before ezetimibe therapy, 123 mg/dL and 98 mg/dL during and 150 mg/dL and 126 mg/dL 2 weeks following cessation of ezetimibe therapy. Symptoms resolved few days after stopping ezetimibe.
In the 16 patients who completed the study, total cholesterol and LDL-concentration decreased significantly (p < 0.005 each) from baseline to 1 week, after 6 weeks and after 3 months (reduction after 3 months: total cholesterol 21 ± 10%, LDL-cholesterol 37 ± 14%) (Table 1). While all 16 patients had LDL-cholesterol >130 mg/dL before ezetimibe therapy, only 5 patients were above 130 mg/dL after 3 months. The decrease in total cholesterol and LDL-cholesterol was comparable in patients receiving CsA (n = 11) or Tac (n = 6) (total cholesterol: CsA: 267 ± 44 mg/dL (baseline) to 222 ± 36 mg/dL (3 months); Tac: 248 ± 33 mg/dL (baseline) to 189 ± 31 mg/dL (3 months); LDL-cholesterol: CsA: 181 ± 49 mg/dL (baseline) to 119 ± 49 mg/dL (3 months); Tac: 172 ± 25 mg/dL (baseline) to 111 ± 24 mg/dL (3 months). Triglyceride concentrations and HDL-concentrations did not change significantly during ezetimibe therapy (Table 1). Creatinine and urea concentrations remained stable throughout the study period and there was no case of renal graft failure in association with ezetimibe therapy (Table 1). Significant changes of CsA and Tac trough concentrations were not observed after initiation of ezetimibe. For safety reasons, myoglobin, CK and liver enzymes were measured (Table 1). Although some patients with slight elevations of CK without clinical symptoms were included into the study, CK remained stable. Myoglobin and ALT-concentrations remained also stable during the study period.
Table 1. Lipid-profile, calcineurin-inhibitor blood levels, renal, liver and muscle parameters before initiation of ezetimibe therapy, after 7 days, 6 weeks and 3 months
|Cholesterol (mg/dL)||264 ± 46||205 ± 48**||202 ± 48**||212 ± 40**|
|LDL-cholesterol (mg/dL)||178 ± 41||129 ± 35**||123 ± 25**||117 ± 40**|
|HDL-cholesterol (mg/dL)||74 ± 24||70 ± 18||69 ± 25||69 ± 24|
|Triglycerides (mg/dL)||210 ± 90||220 ± 105||170 ± 78||199 ± 119|
|Creatinine (mg/dL)||1.48 ± 0.42||1.45 ± 0.49||1.46 ± 0.51||1.52 ± 0.42|
|Urea (mg/dL)||27 ± 12||26 ± 9||28 ± 15||28 ± 13|
|Creatinkinase (U/L)||86 ± 36||72 ± 19||76 ± 23||87 ± 32|
|Myoglobine (μg/L)||46 ± 9||43 ± 11||49 ± 16||49 ± 20|
|ALT (U/L)||27 ± 12|| ||29 ± 11|
|Tacrolimus (ng/mL)||7.4 ± 1.7||8.1 ± 1.2||7.1 ± 1.4||7.8 ± 1.3|
|Cyclosporine (ng/mL)||133 ± 32||122 ± 14||125 ± 12||130 ± 32|
The data obtained in this study demonstrate that ezetimibe added to high-dose statin therapy is effective in patients after renal transplantation. The efficacy of ezetimibe therapy was comparable in patients receiving CsA and Tac. In our study, ezetimibe reduced cholesterol by 21% and LDL cholesterol by 37% which compared well to the data reported by Puthenparumpil et al. (41% LDL reduction when combined with a statin (n = 22) and 24% when used as a monotherapy (n = 18)) also in renal transplant recipients although this study did only mention that not the maximal statin dosage was used but did not give details of dosage and the specific drug used for statin therapy (17). Koshman et al. also observed a supratherapeutic response (LDL reduction by 60%) in a heart transplant recipient when 40 mg of atorvastatin was combined with 10 mg of ezetimibe (18). In addition, the decrease observed in cholesterol- (–21%) and LDL-(–37%) concentrations was more pronounced than in nontransplanted patients (16,19). Another possible explanation for this pronounced decrease in total and LDL-cholesterol could be a failure of our patients to follow dietary recommendations as it is conceivable that ezetimibe is more effective in patients with high-cholesterol intake. A different explanation is a pharmacological interaction between CsA and ezetimibe leading to 2.3–12 fold higher exposures to ezetimibe in these patients (18,20). Such an increase of ezetimibe levels might increase therapeutic efficacy but also represents a potential safety concern. Our data further indicate that by adding ezetimibe to high-dose statin therapy, around 2 of 3 of patients with LDL-hypercholesterolemia can be shifted into the recommended target range of <130 mg/dL for patients after renal transplantation (13).
Despite the presumed higher exposure with ezetimibe of patients taking CsA, we did not observe severe side effects during the 3-month study period. In 2 patients with minor symptoms after initiation of ezetimibe, therapy was stopped with complete resolution of symptoms. However, our patient cohort was too small to draw definite conclusions about the safety of ezetimibe in transplant recipients.
The investigation of the drug ezetimibe has also brought some new light into the mechanism of cholesterol absorption. The newly discovered mechanism of a specific binding of ezetimibe to the Niemann-Pick C1-Like 1 (NPC1L1) protein was determined by using labeled ezetimibe glucuronide binding directly to a single site in brush border expressing NPC1L1. Therefore, NPC1L1 seems to be a critical mediator of cholesterol absorption and an essential component of the ezetimibe-sensitive pathway. Ezetimibe interferes with NPC1L1, reducing the intestinal uptake of cholesterol and other plant sterols (21). Finally, nearly 80% of ezetimibe is excreted in the feces. The major metabolic pathway for ezetimibe consists of glucuronidation to form ezetimibe-glucuronide in the intestine and liver with excretion of ezetimibe-glucuronide in the urine (20). Ezetimibe has a favorable safety profile lacking clinically relevant interactions with HMG-CoA reductase inhibitors (statins). Although small increases in CsA levels have been described to be caused by ezetimibe (20), we did not observe clinically relevant change in calcineurin-inhibitor blood concentrations, although we did not measure CyA 2-h blood concentrations.
In conclusion, ezetimibe seems to be an effective therapy for uncontrolled hypercholesterolemia in renal transplanted patients when combined with high-dose statin therapy. Further studies are needed to evaluate its safety in a larger cohort of transplant patients and the benefit of the additional reduction of cholesterol levels on cardiovascular morbidity and mortality over the long term.