Ezetimibe in Renal Transplant Patients with Hyperlipidemia Resistant to HMG-CoA Reductase Inhibitors

Abstract

Hyperlipidemia affects the majority of renal transplant patients. Multiple risk factors contribute to elevated serum cholesterol including the use of certain immunosuppressant agents. HMG-Co A reductase inhibitors have become the preferred class of cholesterol-lowering medication with an increasing body of evidence to support their safety, efficacy, and outcomes in both the normal and renal transplant populations. New guidelines recommend lowering previous LDL-c goals as outcomes appears to continually improve. As a result, ezetimibe has been added to patients with persistently elevated triglycerides and/or LDL-c in individuals who possessed a renal transplant and were deemed to be on a maximum safe dose of statin agent. After the addition of ezetimibe, total cholesterol, LDL-c, and triglycerides fell by 21%, 31%, and 13%, respectively. Creatinine phosphokinase, liver enzyme serum levels, and renal function were not affected to any level of clinical significance with the addition of ezetimibe. Large interpatient variability of measurable immunosuppressant levels was seen but no serious adverse events were attributed to a change in levels.

Lipid abnormalities exist in greater than 70% of renal transplant recipients (¹). Genetic factors, inflammation, comorbidities such as diabetes, and chronic renal disease all contribute to the high prevalence of hyperlipidemia. In addition, the majority of immunosuppressant medications (corticosteroids, calcineurin inhibitors, and mammalian target of rapamycin [mTOR] inhibitors) contribute to elevations in serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and/or triglyceride levels.

Hyperlipidemia remains a significant risk factor for cardiovascular disease in the general population, and has also been associated with cardiovascular events and premature graft loss in renal transplant patients (^{2, 3}). Cardiovascular disease is the leading cause of death in the end-stage and renal transplant populations (⁴). Reducing circulating lipid levels in renal transplant recipients may improve patient survival. Lipid reductions might improve allograft longevity by preserving heart function and minimizing vascular atherosclerosis thereby maximizing forward flow.

Treatment of hyperlipidemia in renal transplant patients has historically occurred with consternation. HMG-Co A reductase inhibitors, often referred to as statins, lowers TC and LDL-C but in theory should interfere with calcineurin and mTOR inhibitor metabolism as they share a common elimination via the cytochrome P-450 3A4 pathway. In reality, statins appear to have a variable effect on cyclosporine levels, reducing the bioavailability and therefore measurable levels of cyclosporine in some studies (⁵) while increasing the level to a non-significant degree in other studies (⁶). In contrast, the serum statin levels are significantly elevated (as much as a 20-fold increase (⁷)) in the presence of cyclosporine. These findings suggest a more intricate interaction than the cytochrome P-450 complex alone and may involve inhibition of statin transport in the liver. Because cyclosporine is highly bound to lipoproteins, reduction in lipoproteins by statins has been shown to increase the free serum levels of cyclosporine by 30% (⁵). Increasing free serum levels improves renal clearance of cyclosporine which might partially explain the resultant diminished serum cyclosporine levels in the presence of a statin. Unfortunately to date, the great majority of published data lacks an adequate control group (both patients with normal kidney function on immunosuppression and renal transplant recipients not on calcineurin inhibitors).

In addition to their hepatic clearance, statins are renally eliminated to varying degrees with serum levels increased by chronic renal insufficiency. Patients with a renal transplant by definition have renal insufficiency. Rare but deleterious side effects of statins such as myalgias, rhadomyolysis and liver enzyme serum elevations are expected to have a higher prevalence in the renal transplant population due to the aforementioned elevation of statin serum levels and reductions in glomerular filtration rate inherent to the transplanted state.

In an attempt to meet increasingly lofty lipid lowering goals, strategies that combine different pharmacologic agents that block the absorption and decrease production of cholesterol in a complementary manner are sound. Fenofibrates primarily affect triglycerides for which statins have limited activity. Unfortunately, the use of fenofibrates with statins especially in the presence of calcineurin inhibitors is relatively contraindicated due to unacceptably high rates of myalgias and rhabdomyolysis.

A new molecule, ezetimibe (Zetia), shows promise as an adjunct to statins. Ezetimibe targets the small intestine where it blocks the absorption of cholesterol whereas HMG CoA reductase inhibitors affect the liver's ability to manufacture cholesterol. Ezetimibe and statins have been found to be complementary in their action with profound reductions in TC and LDL-C when used in combination in the general population (^8–14). Unfortunately, the original Food and Drug Administration (FDA) approved package insert for ezetimibe reports an average of 3.4 fold increase in the area under the curve (up to 7.9 times) of ezetimibe in the presence of cyclosporine (¹⁵). Caution is imparted within the package insert when using ezetimibe concomitantly with calcineurin inhibitors. Others have reported significant increases in the serum levels of cyclosporine in addition to the aforementioned increase in ezetimibe serum concentrations.

Ezetimibe has been prescribed to several of our renal transplant recipients who were unable to achieve National Cholesterol Educational Panel (NCEP) Adult Treatment Panel III (ATP III) cholesterol goals on maximally tolerated doses of statins (¹⁷). We report the results of our retrospective analysis that assessed the safety and efficacy of ezetimibe in the renal transplant patients at our transplant center who received this medication in addition to statin therapy.

METHODS

Utilizing the computerized patient record system at Vanderbilt University Medical Center, we identified all renal transplant patients who were prescribed ezetimibe. The following variables were collected on each patient: age, gender, date of transplantation, fasting cholesterol panel (TC, LDL-C, high density lipoprotein cholesterol (HDL-C) and triglycerides) before and after ezetimibe therapy, liver function tests, creatine kinase (CK), serum creatinine and maintenance immunosuppressant regimen. The glomerular filtration rate (GFR) in cc/min/1.73 m² was calculated using the Modification of Diet in Renal Disease (MDRD) equation (¹⁸). The primary outcomes were the percentage decreases in TC and LDL-C after at least 1 month of treatment with ezetimibe. Secondary outcomes were the number of patients who reached a TC less than 200 mg/dL, LDL-C less than 100 mg/dL and/or triglycerides less than 200 mg/dL. Statistical analysis was made by Student's t test and analysis of covariance. Statistical significance was set at a P value <0.05.

RESULTS

We identified 21 patients who had received a renal transplant at our transplant center who were prescribed ezetimibe after failing to reach NCEP ATEP III goals on statin therapy (Table 1). 13 (62%) patients were female and 8 (38%) were male. The average age was 49 years (range 31–67 years). 9 (43%) patients were on cyclosporine, 3 (14%) patients were on tacrolimus, 7 (33 %) patients were on sirolimus and 1 (5%) patient was on both cyclosporine and sirolimus for maintenance immunosuppression. A single patient who had received his renal transplant in 1973 was only on low dose prednisone and azathioprine immunosuppression.

TABLE 1: Baseline patient characteristics and lipid levels before and after ezetimibe

The average serum creatinine in these patients was 1.7 mg/dL (range 0.5–3.7 mg/dL). Thus the majority of patients had moderate renal insufficiency based upon the calculated GFR by the MDRD equation (average GFR was 53 mg/min/1.73 m², range 18–138 mg/min/1.73 m²).

The mean fasting TC, LDL-C, HDL-C and triglycerides prior to ezetimibe therapy was 255 mg/dL (range 182–365 mg/dL), 127 mg/dL (range 55–208 mg/dL), 64 mg/dL (range 40–101 mg/dL) and 333 mg/dL (range 77–994 mg/dL) respectively. The length of time between the fasting cholesterol panel measurement before and after ezetimibe treatment was on average 94 days (range 35–270 days).

The average reduction in lipid levels with ezetimibe therapy was TC by 21%, LDL-C by 31% and triglycerides by 13% (P<.05) (Fig. 1). The average HDL-C levels also fell in the patients taking ezetimibe (6% reduction, average absolute decrease of 4 mg/dL), though this was not statistically significant. In the subset of 7 patients with triglycerides >400 mg/dL prior to ezetimibe therapy (average 581 mg/dL, range 459–994 mg/dL), we observed an average decrease of 35% which translated to an absolute reduction of 205 mg/dL (range 55–524 mg/dL).

FIGURE 1.: Serum lipid levels before and after treatment with ezetimibe.

Out of 18 patients with initial TC >200 mg/dL, 11 (61%) patients achieved a fasting TC <200 mg/dL with the addition of ezetimibe. Of the 12 patients with initial LDL-C >100 mg/dL, 10 (83%) patients achieved a fasting LDL-C of <100 mg/dL with the addition of ezetimibe.

Serum drug levels of the immunosuppressants were measured before and after the introduction of ezetimibe. Rapamycin (n=7) increased an average of 6% overall with a range of −23% to +40% and an absolute change in measure drug levels between −1.8 ng/ml and +3.9 ng/ml. Cyclosporine (n=9) increased an average of 4% overall with a range of −19% to +62% with a range in absolute measurable levels between −61 ng/ml and +34 ng/ml. Tacrolimus (n=3) decreased an average of 24% with a range of −46% to 7% with an absolute range of measurable levels between −4.3 ng/ml to 0.5 ng/ml.

DISCUSSION

All patients were either on pravastatin (n=15) 40 mg to 80 mg daily or atorvastatin (n=6) 40 mg to 80 mg daily (physician preference determined the choice of statin) without reaching lipid lowering goals before ezetimibe was added. Despite maximally tolerated doses of HMG-CoA reductase inhibitors, the addition of ezetimibe resulted in significant reductions of LDL-C, TC and triglycerides in the large majority of patients regardless of primary concomitant immunosuppressant type. The patients who experienced the largest LDL-C reductions may represent a particular subset of individuals who hyperabsorb cholesterol rather than manufacture cholesterol de novo (¹⁹). These individuals would be expected to respond well to ezetimibe. Since cyclosporine and presumably tacrolimus as well as rapamycin interact with ezetimibe, the magnitude of cholesterol lowering may also partially be the result of elevated ezetimibe serum levels. In the original eztimibe trials on patients with normal native kidney function, HDL levels increased on therapy 2% points above the placebo group (¹⁵). In our study, HDL levels dropped by 4 mg/dl or 6% on average. This result was not statistically significant and probably occurred by chance as a result of the relative small statistical power of the study. In addition, the HDL/LDL ratio statistically increased over preezetimibe levels suggesting an overall improvement in cholesterol profile.

We still advocate maximizing statin use as first line therapy in the renal transplant population before adding eztimibe. Since eztimibe has yet been shown to provide positive hard cardiovascular outcomes data, statins should be maintained due to their proven benefits. Anti-inflammatory effects may be greater with statin therapy as demonstrated in a recent comparison of C-reactive protein reductions versus eztimibe (²⁰). Lastly, statins may reduce chronic allograft nephropathy (²¹) and due to mild immunosuppression provided by statin agents, acute rejection rates maybe lowered (²²).

No adverse events were reported by the patients nor discerned on laboratory measurements (liver functions, serum creatinine). Changes in measurable immunosuppressant levels were unpredictable but did not lead to adverse outcomes as any nephrotoxicity (monitored as a change in renal function) nor acute rejection could be attributed to the addition of ezetimibe. Due to the demonstrated large inter-patient variability, we recommend close monitoring of serum immunosuppressant levels after the addition of ezetimibe. Changes in CPK levels were not clinically significant as myalgias and muscle complaints were not reported. Although these results are promising, it would be hard to conclude with any certainty that the use of ezetimibe is safe in renal transplantation. Our data, in addition to other small studies (²³) will increase the overall experience with ezetimibe in transplantation and hopefully reveal trends in lipid reduction and adverse events if they exist. Larger multi-center trials would be required to truly establish the efficacy and safety of ezetimibe in this specialized population.

In summary, we report a significant reduction in TC and LDL-C in our renal transplant patients who were prescribed ezetimibe to treat hyperlipidemia. We also observed a significant fall in triglycerides in our patients while on ezetimibe when their preezetimibe therapy levels were greater than 400 mg/dL. Ezetimibe maybe an effective adjunct to statin therapy and its role in cardiovascular risk reduction may become apparent with time.