|Year : 2010 | Volume
| Issue : 6 | Page : 1021-1029
|Ezetimibe as a potential treatment for dyslipidemia associated with chronic renal failure and renal transplant
Mohamed H Ahmed1, Atif A Khalil2
1 Division of Acute Medicine, The James Cook University Hospital, Marton Road, Middlesbrough, United Kingdom
2 Nephrology Department, Royal Liverpool and Broadgreen University Hospitals, Liverpool, United Kingdom
Click here for correspondence address and email
|Date of Web Publication||4-Nov-2010|
| Abstract|| |
Individuals with chronic renal disease (CKD) are prone to have accelerated process of atherosclerosis. Importantly, cardiovascular disease is the main cause of morbidity and mortality in kidney transplant recipients. Recent studies suggest a potential benefit of the lipid lowering medications in preventing cardiovascular events in the CKD and the transplant populations. In particular, statin was shown to be effective in reducing low density lipoprotein (LDL)-cholesterol. However, refractory dyslipidemia and difficulty in lowering LDL to target were reported with the CKD and the kidney transplant patients. The second United Kingdom Heart and Renal protection study (UKHARP-II) showed that the addition of ezetimibe to simvastatin was safe and effective in treating dyslipidemia in CKD. Furthermore, the combination of ezetimibe and statin was also effective and safe in treating dyslipidemia in kidney transplant recipients. The Study of Heart and Renal Protection (SHARP) trial will evaluate the effects of lowering LDL-C with ezetimibe 10 mg and simvastatin 20 mg daily versus placebo in 9,000 patients with chronic kidney disease. The current evidence suggests that the addition of ezetimibe to satin is effective and safe in treating dyslipidemia in the CKD and the kidney transplant patients. Future clinical trials are needed to determine whether ezetimibe will reduce cardiovascular risk in the CKD patients.
|How to cite this article:|
Ahmed MH, Khalil AA. Ezetimibe as a potential treatment for dyslipidemia associated with chronic renal failure and renal transplant. Saudi J Kidney Dis Transpl 2010;21:1021-9
Patients with chronic kidney disease (CKD) are considered to be at significantly increased risk of cardiovascular disease (CVD), especially those with end-stage renal disease (ERSD) treated with dialysis or renal transplantation even if their graft function within normal range. This is largely accounted for by the tendency to have increased prevalence of an abnormal lipid profile.  It is estimated that 339 per million individuals with end-stage renal disease (ERSD) in USA require dialysis annually, , and around 10-15% of population of UK have CKD.  With the escalated epidemic of type 2 diabetes, the incidence of ESRD is likely to increase across the globe.
|How to cite this URL:|
Ahmed MH, Khalil AA. Ezetimibe as a potential treatment for dyslipidemia associated with chronic renal failure and renal transplant. Saudi J Kidney Dis Transpl [serial online] 2010 [cited 2014 Apr 19];21:1021-9. Available from: http://www.sjkdt.org/text.asp?2010/21/6/1021/72286
Moreover, individuals with early CKD are more likely to die of CVD than to develop ESRD.  In fact, among those who survive to ESRD, the allcause CVD mortality in patients with ESRD is many fold-higher than in the general population.
The CKD Patients have increased risk of CVD due to increased prevalence of hypertension, dyslipidemia and diabetes. Other non-traditional risk factors include, hypothyroidism, excessive alcohol consumption, chronic liver disease, left ventricular hypertrophy, cardiomyopathy, proteinuria, medications induced dyslipedemia, and uremic toxins.
It is well established that there increase in risk of CVD in association with CKD in stage 3, 4, 5 and renal transplantation. A pooled analysis of four community-based studies was carried by Weiner et al. The cohorts used were the Atherosclerosis Risk in Communities Study (ARIC), the Cardiovascular Health Study (CHS), the Framingham Heart Study (FHS), and the Framingham Offspring Study (Offspring). All these four studies have meticulous ascertainment of CVD events during the follow-up periods, and the results suggest that the presence of moderate CKD (GFR < 60 and >15 mL/min/1.73 m 2 ) carries 19% excess risk of CVD. The risk associated with CKD seems to be stronger in blacks than in whites.  Interestingly, in a retrospective study in patient with mild and moderate CKD, approximately 0.5 to 1% developed ESRD over 5 years follow-up, while 19 to 24% of these patients died mostly of cardiovascular complications in the same period.  This further support the evidence that patients with CKD should be considered at high risk for CVD.
Furthermore, patients with stage 5 CKD (patients on dialysis) have extremely high morbidity and mortality from CVD. Johnson et al studied all adult Australian and New Zealand patients commencing dialysis between January 1, 1997 and December 31, 2007. The aim of the investigation was to compare the rates, causes, and timing of cardiovascular (CV) death in incident peritoneal dialysis (PD) and hemodialysis (HD) patients. Of the 24,587 patients who commenced dialysis (first treatment PD n = 6521; HD n = 18,066) during the study, 5669 (21%) died from CV causes [PD 2044 (28%) versus HD 3625 (21%)]. The incidence rates of CV mortality in PD and HD patients were 9.99 and 7.96 per 100 patient-years, respectively (incidence rate ratio PD versus HD, 1.25; 95% confidence interval 1.12 to 1.32). PD was consistently associated with an increased hazard of CV death compared with HD after 1 yr of treatment. This increased risk in PD patients was largely accounted for by an increased risk of death due to myocardial infarction.  In addition, Parfery et al showed that the prevalence of coronary heart disease in HD patients is 40% and
CVD mortality is 10 to 30 times higher than that in the general population despite stratification by gender, age, race and the presence of diabetes.  In addition, kidney transplantation is associated with a higher risk for morbidity and mortality largely as a consequence of CVD, , on account of the high prevalence of abnormal lipid profiles, 40% of renal transplant experience CVD complications.  Although myocardial infarction occurs in transplant patients, congestive heart failure is more common. 
Beside the traditional risk factors, other factors can also arise de novo from the unintended effects of immunosuppression (diabetes, hypertension, uremia and anemia). 
High cholesterol, LDL, triglyceride and low HDL are known as risk factors for CVD in general population. Besides the metabolic changes associated with CKD, dialysis and kidney transplantation are known to induce significant dyslipidemia. Given the current evidence of the benefit of lipid lowering medication in reducing CVD in the general population, it is possible to similarly suggest that treatment with lipid lowering medications are potentially beneficial in the CKD patients.  In a large post hoc analysis of large three trials, pravastatin treatment was shown to reduce the decline in renal function in patients with moderate CKD (GFR 30-60 mL/ min. Importantly pravastatin reduced CVD in diabetic patients irrespective of their stage of CKD. 
Interestingly, the ALERT (Assessment of Lescol in Renal Transplantation) study demonstrated that fluvastatin significantly reduces cardiac deaths and myocardial infarction in renal transplant recipients without compromising the renal graft function.  These studies demonstrated that CKD patients would derive benefit from the lipid lowering medications.
| Dyslipidemia in CKD Patients|| |
A. Dyslipidemia in moderate CKD
The key features of dyslipidemia in mild and moderate CKD patients are elevated triglycerides (TG) and lipoprotein (a) Lp (a), lower highdensity lipoprotein cholesterol (HDL-C), with normal (or low) total cholesterol (TC), and normal (or low) low-density lipoprotein cholesterol (LDL-C). 
Hypertriglyceridemia is an early feature in CKD and this may occur even if serum creatinine is within normal range. This will be further exaggerated after fatty meals resulting in marked post-prandial hyperlipidemia.  Experimental studies have shown an increase in remnants of chyliomicron and triglyceride rich lipoprotein (VLDL) with a marked decrease in their catabolism. This decrease in catabolism was attributed to related toxic effect of uremia on enzymes responsible for lipid catabolism and possibility of insulin resistance in CKD. , Secondary hyperparathyroidism may partially contribute to hypertriglyceridemia.  Lipoprotein (a) represents an LDL-Like particle distinguished from LDL by presence of apolipoprotein (a), which is highly homologous to plasma protease zymogen plasminogen and promotes thrombogenesis. Interestingly, there is an association between the increase in plasma lipoprotein Lp (a) and the risk of developing coronary heart disease. , Despite the fact that the plasma levels of LDL-c may be low or normal, this small dense atherogenic particle contributes to atherosclerosis.  Experimental and epidemiological studies demonstrated that CKD is associated with low plasma levels of HDL-c, which has antiatherogenic effects (reverse transport of cholesterol, antioxadative, anti-inflammatory, and antithrombotic). 
B. Dyslipidemia in advanced CKD dialysis patients
PD is associated with increased plasma levels of TC, LDL-C (typically small-dense particles that are readily oxidized), apolipoprotein B, TG, and lipoprotein (a), and decreased HDL-C and apolipoprotein (a). Furthermore, HD is associated with near-normal LDL-C, increased oxidized LDL-C, TG, very-LDL-C (VLDL-C) and lipoprotein (a), the presence of TG-rich VLDL-C, and decreased HDL-C. , The pathophysiological mechanisms that underlie the alterations in lipoprotein metabolism in HD patients is the same as in CKD stage 2-4. Interestingly, the type of membrane (high flux poly-sulfone or cellulose triacetate) used in dialysis may alter lipoprotein metabolism. ,, In contrast, continuous ambulatory peritoneal dialysis (CAPD) usually exhibit a more atherogenic lipid profile characterized by higher total LDL-C and apo-B and excess TG. 
C. Dyslipidemia in renal transplant patient
In renal transplant patients, the pattern of dyslipidemia is unique and is characterized by elevated plasma levels of TC, LDL-C, VLDL-C, and TG in addition to markedly reduced HDLC. , Moreover, various anti-graft rejection agents, differ in their manipulation to the lipid synthesis pathways resulting in an immunosuppressive agents related dyslipidemia. Corticosteroids can induce hypercholesterolemia through manipulation of lipoprotein metabolism by multiple indirect pathways that possibly triggered by ACTH suppression.  Cyclosporine, a calcineurin inhibitor (CNI), is associated with dose dependent in-creased total and LDL cholesterol concentrations along with reduced HDL plasma levels. , Importantly, tacrolimus, azathioprine and mycophenolate mofetil usually induce only minor changes in serum lipid profile. A number of studies have shown that conversion of cyclosporine to one of these drugs is followed by significant decrease in the levels of total and LDL-c. , Rapamycin induces post transplantation dyslipidemia characterized by significantly raised triglycerides plasma levels. , Dyslipidemia per se is also assumed to contribute to chronic allograft dysfunction and this may further justify the need to use lipid lowering medications.  It is possible to conclude that direct and indirect factors are involved in dyslipidemia associated with CKD and kidney transplantation.
| Pharmacology of Ezetimibe|| |
Ezetimibe inhibits intestinal uptake of cholesterol with a half life of approximately of 22 hours. Approximately 78% of the dose is excreted in the feces predominantly as ezetimibe, with the balance found in the urine mainly as ezetimibe-glucuronide.  It has no effect on the activity of the major drug metabolizing enzymes (CYP450). Niemann-Pick C1 like1 (NPC1L1), highly expressed in jejunum of different species and only human liver, is the main transporter of intestinal cholesterol. Mice deficient in NPC1L1 showed a significant > 70 % reduction in cholesterol absorption, and further reduction in cholesterol levels with ezetimibe administration was not achievable. It was concluded that ezetimibe reduces intestinal absorption of biliary and dietary cholesterol through inhibiting the action of NPC1L1. Ezetimibe (10 mg/day) inhibits cholesterol absorption by an average of 54% in hypercholesterolemic individuals and by 58% in vegeterians. However, it lowers LDL-c by 15-25% from baseline and this can be seen after 12-24 weeks of treatment. Furthermore, it can be used as monotherapy or in combination with statin to treat hyperlipidemia. 
Administration of ezetimibe plus statins is a unique therapeutic strategy for the treatment of dyslipidemia in high-risk patients for CVD. The role of ezetimibe in preventing CVD will be revealed upon the completion of IMPROVE-IT trial. The definitive IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), randomizing 18,000 patients with acute coronary syndrome and comparing simvastatin with or without ezetimibe, is currently under way with completion planned for 2012. The study will determine whether an LDL-C level of approximately 1.3 mmol/L with the combination of ezetimibe and simvastatin can reduce CVD events compared with an LDL-C level of approximately 1.8 mmol/L with simvastatin alone. Ezetimibe has shown a potential benefit to ameliorate renal function and reduce proteinuria in CKD patients.
| Ezetimibe and Hyperlipidemia in Stage 3 and 4 CKD Patients|| |
The second United Kingdom Heart and Renal protection study (UK-HARP-II) is a randomized controlled study of the biochemical safety and efficacy of adding ezetimibe10 mg/d to simvastatin 20 mg/d as initial therapy in CKD patients. Two hundred and three patients (152 predialysis, 18 PD, and 33 HD patients) were randomly assigned to the administration of 20 mg/d simvastatin plus 10 mg/d ezetimibe or 20 mg/d mg simvastatin plus placebo. After 6 months, allocation to simvastatin monotherapy was associated with a 31 mg/dL (0.8 mmol/L) decrease in non-fasting LDL cholesterol levels compared with baseline. Allocation to simvastatin plus ezetimibe produced an additional 18 mg/dL (0.47 mmol/L) decrease in LDL cholesterol levels, representing an incremental 21% reduction over that achieved with simvastatin monotherapy (P< 0.0001). Though, there were no statistically significant effects of the addition of ezetimibe to simvastatin on triglyceride or highdensity lipoprotein cholesterol levels. Ezetimibe was not associated with an excess risk of abnormal liver function tests, elevated creatine kinase levels or impaired absorption of fat-soluble vitamins.
Moreover, there were no serious adverse events or significant toxicity caused by the drugs used in the study.  Nakamura et al showed that the addition of ezetimibe to statin therapy in non diabetic CKD patient resulted in a significant reduction in proteinuria.  The same authors attributed the reno-protective effect of ezetimibe to its ability to lower serum levels of asymmetric dimethylarginine (ADMA), which plays a role in the progression of atherosclerosis and CKD in high-risk patients. Furthermore, ezetimibe was also shown to be associated with reduction in markers of renal tubular injury [8-hydroxydeoxyguanosine (8-OHdG) and l-fatty acid binding protein (l-FABP)] in 10 non diabetic individuals.  This may suggest that ezetimibepleiotropic actions may in part contribute to its renopotective actions in addition to lowering LDL-C.
The SHARP trial (Study of Heart and Renal Protection) will evaluate the effects of lowering LDL-C with ezetimibe 10 mg and simvastatin 20 mg daily versus placebo in 9,000 CKD patients. The study will assess the effect of this combination therapy on the time to the first major vascular event (i.e., heart attack, stroke, or revascularization) and on progression to ESRD as well as assessing safety and tolerability in the different treatment arms. The SHARP and (UK-HARP-II) will add more to our understanding of dyslipidemia with CKD.
| Ezetimibe Use in Stage 5 CKD Patients|| |
The benefit of lipid lowering medications in patients on dialysis is likely to be revealed by future clinical trials. However, the current evidence suggests that the use of statin in dialysis patients is not associated with the same cardiovascular benefit seen in non-dialysis patients. For instance, the 4D trial (Die Deutsche Diabetes Dialyse Studie) was a prospective randomized controlled clinical trial in 1200 HD type 2 diabetes patients on 20 mg atorvastatin/ placebo for 4 years. Atorvastatin treatment was associated with nonsiginifcant 8% relative risk reduction on primary end point of cardiac death, non fatal myocardial infarction or stroke. Importantly, atorvastatin treatment was associated increased risk of fatal stroke.  In patients undergoing HD in the AURORA Study (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular HD: An Assessment of Survival and Cardiovascular Events), the initiation of treatment with rosuvastatin lowered the LDL cholesterol level but had no significant effect on the composite primary end point of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.  Interestingly, The second United Kingdom Heart and Renal protection study (UK-HARP-II) included 18 patients on PD and 33 patients on HD with significant reduction in LDL-c. It is not yet clear whether the administration of ezetimibe in these particular patients will reveal the protective cardiovascular benefit of statin. The SHARP trial may answer the question about the use of statins and ezetimibe in HD patients.
| Ezetimibe as Potential Treatment for Dyslipidemia in Kidney Transplant Recipients|| |
Dyslipidemia is an important multifactorial complication that is unlikely to spare any but few kidney transplant recipients. Cardiovascular disease is the leading cause of death in kidney transplant recipients. Generally speaking, the recommendation is that lipid lowering medications will be initiated in case lipid profile target could not be achieved through life style modifications. Statins, the first-line therapy, are often insufficient. Ezetimibe may be effective in combination with statin therapy. Administration of ezetimibe 10 mg and simvastatin 10 mg for 6 months in 77 kidney transplant recipients with dyslipidemia was associated with a significant reduction in the levels of total cholesterol (34.6%), triglyceride (16.0%), and low-density lipoprotein cholesterol (LDL-C) (47.6%), and 82.5% of the patients reached the target LDL-C level of < 2.6 mmol/L (100 mg/dL). No significant change in the trough calcineurin inhibitor levels or allograft function occurred, and no serious adverse effects were observed. Fourteen patients (18.2%) discontinued treatment; eight patients (11.7%) developed muscle pain or weakness without an increase in creatinine kinase levels, and two patients (2.6%) developed elevated liver transaminase levels. Importantly, no significant change was observed in both proteinuria and highly sensitive C-reactive protein (hsCRP) levels.  Recently, administration of ezetimibe in combination with maximum statin doses in 27 stable kidney transplant patients with uncontrolled hypercholesterolemia was assessed. A combination therapy resulted in median reductions in total cholesterol of 29% (interquartile range [IQR] 12-39; P = 0.0001) and 28% (IQR 9-38; P = 0.0001); in low-density lipoprotein cholesterol of 34% (IQR 16-61; P = 0.0001) and 44% (IQR 24-56; P = 0.0001); and in triglycerides of 14% (IQR 4-31; P = 0.01) and 19% (IQR 1-37; P = 0.006) at 3 and 6 months post-ezetimibe therapy, respectively. There were no significant differences in high-density lipoprotein cholesterol, renal function, proteinuria, creatine kinase, amylase, liver function, body mass index, or drug levels. There were no adverse drug reactions that required treatment withdrawal. 
Furthermore, in 18 kidney transplant patients, the addition of ezetimibe to maximum statin doses was not only associated with significant improvement in dyslipidemia, but also no significant changes of blood levels of tacrolimus and cyclosporine.  However, ezetimibe total area under the curve was 3.4 fold higher in transplant patients receiving cyclosporine. The clinical significance of this interaction is not known besides the impact of higher exposure of ezetimibe.  It is important to mention that myopathy was reported with the use of ezetimibe as monotherapy or in association with statin.  Interestingly, ezetimibe is also being shown to have the potential to ameliorate the decline of renal function after kidney transplantation. Turk et al studied the effect of addition of ezetimibe (10 mg/day) for 12 months in 56 patients with statin-resistant hypercholesterolemia (total cholesterol > 200 mg/dL) after kidney transplantation. A group receiving statin therapy (n = 28) served as controls in this prospective study. Total cholesterol and LDL cholesterol concentrations decreased significantly in the ezetimibetreated patients but remained stable in the control group. The mean creatinine clearance remained stable in the ezetimibe-treated patients, but decreased significantly in the control group. 
Different studies clearly demonstrated that the use of ezetimibe as a monotherapy or in combination with statins in kidney transplant recipients was well tolerated and resulted in a significant reduction in cholesterol, LDL-cholesterol and triglyceride plasma levels. Moreover, such beneficial effect was not associated with any alteration in renal or liver function, increase in creatinine kinase, electrolyte disorders, or interaction with other medications. For instance, Puthenparumpil et al  conducted a non randomized, open-label, single-cohort evaluation of ezetimibe in 40 stable kidney transplant recipients with hypercholesterolemia. After 4 weeks of therapy the levels of total and LDL cholesterol were reduced by 23 ± 13% (P < 0.0001) and 33 ± 15% (P < 0.0001), respectively. The drug was equally effective in patients on cyclosporine (19), tacrolimus (13), or sirolimus (8), but more effective (P = 0.0006) when used in combination with a statin (41 ± 13% reduction in LDL, n = 22) compared with monotherapy (24% ± 13%, n = 18). There were no significant effects on serum creatinine, drug levels, body weight, or liver function tests. Furthermore, Buchanan et al carried retrospective review of 34 adult kidney transplant recipients receiving ezetimibe as a monotherapy or combination therapy. Monotherapy or combination therapy resulted in a mean reduction in total cholesterol of 23.3%, triglycerides 40.2%, lowdensity lipoproteins 16.8% and high-density lipoproteins 4.8% after 3.1 months of therapy. Ezetimibe as a combination or monotherapy is a safe and effective treatment option for dyslipidemia in renal transplant recipients without changes in CNI levels or renal function.  The administration of statin with ezetimibe was shown to be associated with a significant reduction in lipid levels. Panichi et al performed a pilot study to evaluate the safety and efficacy of atorvastatin and ezetimibe in five renal transplant patients with hypercholesterolemia and mild renal functional impairment receiving cyclosporine A. The medications were well-tolerated and no important clinical or laboratory abnormalities (muscle enzyme, creatinine clearance, and cyclosporine A concentration) were observed throughout the study period. The combination of ezetimibe plus atorvastatin produced the lowest lipid levels and significantly reduced CRP mean values and allowed all patients to attain target levels of LDL-C, total cholesterol and triglycerides.  Furthermore, Lopez et al  performed a prospective study of 25 kidney transplant recipients with dyslipidemia who started treatment with 10 mg of ezetimibe. Statins were co-administered in 96% of these patients. A significant reduction was noted in total cholesterol, low-density lipoprotein cholesterol, and triglycerides. No patient experienced changes in the hepatic profile, increased CPK and lactose dehydrogenase levels, or important adverse effects. Renal function remained stable, with no significant variations in plasma levels of the different immunosuppressive agents.
On the other hand, ezetimibe showed potential benefit in treating dyslipidemia associated with liver transplant. Al mutairi et al showed that in 25 liver graft recipients ezetimibe was an effective treatment for the hypercholesterolemia with few side effects and no interaction with immunosuppressive regimens.  This may suggest the need for further investigation to assess the safety and effectiveness of ezetimibe in liver transplant patients.
| Conclusion|| |
Ezetimibe/simvastatin combined therapy offers an effective means for lowering LDL plasma levels with similar safety, when compared with equivalent simvastatin monotherapy doses. The SHARP trial will evaluate the effects of lowering LDL-C with ezetimibe 10 mg and simvastatin 20 mg daily in CKD patients. The study will assess the effect of this combination therapy on the time to the first major vascular event (i.e., heart attack, stroke, or revascularization) and on progression to end-stage renal disease among pre-dialysis patients. The SHARP and (UK-HARP-II) will add more to our understanding of dyslipidemia with CKD. The current evidence suggest that in case of refractory dyslipidemia in CKD and kidney transplant patients, the addition of ezetimibe to statin is effecttive and safe in achieving LDL target [Figure 1].
|Figure 1 :Suggested algorithm for management of dyslipidemia in CKD and post- renal transplant.|
Click here to view
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Mohamed H Ahmed
Division of Acute Medicine, The James Cook University Hospital, Marton Road, Middlesbrough ,TS4 3BW
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