Safety and effectiveness of ezetimibe in liver transplant recipients with hypercholesterolemia

Abstract

Hypercholesterolemia is a common problem among transplant recipients. Despite package-insert warnings about the potential side effects of the use of statins in patients with chronic liver disease, they are often prescribed for liver transplant recipients. Unlike statins, ezetimibe acts through inhibition of enterohepatic recirculation of lipids. We report the effectiveness and safety of ezetimibe among liver transplant recipients because this has been evaluated previously only in kidney and heart transplant patients. A consecutive cohort of 25 liver graft recipients with serum low-density lipoprotein (LDL) levels Ͼ 100 mg/dL (2.5 mmol/L) after a mean (Ϯstandard deviation) of 55 Ϯ 21 months following liver transplantation received ezetimibe (10 mg orally every day) for at least 6 months. Serum lipid profiles, liver and renal function tests, and dosages and blood levels of the immunosuppression drugs at baseline, 3 months, and 6 months were prospectively collected. The overall mean age was 58 Ϯ 12 years, and 56% were males. Statin therapy and fibrates were already being used in 32% and 20% of recipients for elevated LDL and/or triglycerides, respectively. The immunosuppression regimen included cyclosporine in 48% of subjects, tacrolimus in 32%, sirolimus in 48%, and mycophenolate mofetil in 44%; only 12% were on oral prednisone with a maximum daily dose of 5 mg. After ezetimibe was started, an 18% reduction in LDL values was observed [at baseline, 147 Ϯ 35 mg/dL (3.8 Ϯ 0.9 mmol/L), and at 6 months, 120 Ϯ 31 mg/dL (3.1 Ϯ 0.8 mmol/L); P ϭ 0.010]. After 6 months, an additional 32% achieved the target LDL level of Ͻ100 mg/dL. None of the remaining variables, including immunosuppression drug levels, varied significantly during ezetimibe therapy. None of the subjects required adjustments in their pharmacological dosages. One discontinued ezetimibe 3 months later because of cost, 2 subjects had minimal nausea, 1 subject had myalgias without a rise in creatine phosphokinase, and 1 subject had a transient elevation (3-5 times) in liver enzymes from baseline with increases in the total and indirect bilirubin levels. In conclusion, among liver transplant recipients, hypercholesterolemia can be effectively treated with ezetimibe with few side effects and no interaction with immunosuppressive regimens. Liver Transpl 15:504-508, 2009. © 2009 AASLD. Received August 5, 2008 accepted November 16, 2008. After orthotopic liver transplantation (OLT) in the adult population, between 16% and 43% of recipients will develop hypercholesterolemia, and 40% will develop hypertriglyceridemia, with the majority suffering from mixed hyperlipidemia.

Dyslipidemia after allogeneic hematopoietic stem cell transplantation: evaluation and management

“…Gemfibrozil has been shown to increase statin levels 1.9-to 5.7-fold by inhibition of glucuronidation, making fenofibrate a better choice if a fibrate must be added to a statin. 47,48 However, fenofibrate can cause a reversible increase in serum creatinine levels and has been associated with reversible renal allograft dysfunction in some renal transplantation patients. 40,45,53 …”

“…40 However, safe use of this agent has been reported in solid organ transplantation patients. 47,48 It is less potent than the statins and does not have proven benefit in CHD outcomes, so it is considered a second-line agent for LDL reduction.…”

Increased NPC1L1 and serum cholesterol in a chronic rejection rat

“…Characterization of the NPC1L1 pathway revealed that ezetimibe specically binds to NPC1L1 and inhibits its sterol transport function, and it is now widely used in combination therapy with statins for management of hypercholesterolemia in the general population [20]. In liver, cardiac and kidney transplant patients, hypercholesterolemia could be e ectively treated with ezetimibe with few side e ects [21][22][23]. e present study suggests that the signi cantly increased expression of NPC1L1 might promote intestinal cholesterol absorption, which might contribute to hypercholesterolemia involved in the development of CR; however, other important aspects of cholesterol metabolism were not studied simultaneously.…”

Long-term Medical Management of the Liver Transplant Recipient: What the Primary Care Physician Needs to Know

“…Data on transplant patients are limited for other lipid-lowering agents, including ezetimibe, but in a small study of OLT and other organ recipients, these agents appeared to be safe and effective. 39 Niacin has not been systematically studied in OLT recipients, but it can be used for management of mixed hyperlipidemia, based on data from renal and cardiac transplant recipients. Caution must be observed to ensure that bile acidbinding agents such as cholestyramine, if used, are taken at least 2 hours separate from other medications, particularly immunosuppressants.…”