The Ezetimibe

The Ezetimibe/Simvastatin Single Pill in the Management of Hypercholesterolaemia

Akira Yik-Tian Wu, MBBS (Monash), FRACP, FAMS

oduction

Therapy with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors or statins has been shown to be effective in lowering low-density lipoprotein cholesterol (LDL-C) levels, which are linked to cardiovascular morbidity and mortality. Previous pivotal trials with simvastatin have demonstrated that reductions in LDL-C resulted in a decrease in acute coronary events and improved survival.^1,2 However, a significant number of patients still fail to achieve LDL-C goals.³ There is evidence to suggest that greater reductions in LDL-C can further protect patients from cardiovascular events.^2,4 The strategy of increasing the doses of statins is effective but is complicated by an increase in the incidence of adverse reactions.⁵ To limit toxicity and maintain anti-atherosclerotic benefits, one approach is to combine a moderate dose of a statin and another lipid-lowering drug, such as ezetimibe. This review will focus on simvastatin and ezetimibe in a single pill.

Pharmacology

Ezetimibe and simvastatin are lipid-lowering compounds with complementary mechanisms of action. Simvastatin is a potent inhibitor of HMG-CoA reductase, which catalyzes the conversion of HMG-CoA to mevalonate, an early and the rate-limiting step in cholesterol biosynthesis.⁶ Simvastatin has been shown to lower LDL-C, apolipoprotein B and plasma triglyceride, and to moderately increase high-density lipoprotein cholesterol (HDL-C). Evidence from clinical and basic research studies showed that simvastatin treatment may lower C-reactive protein (CRP) levels and pro-inflammatory activities.^7,8 Ezetimibe inhibits the absorption of biliary and dietary cholesterol from the small intestine.⁹ Ezetimibe localizes at the wall of proximal jejunum and binds to Niemann-Pick C1 Like 1 (NPC1L1) with higher affinity. NPC1L1 is a sterol transporter that is involved in the intestinal uptake of cholesterol and phytosterols. The inhibition of cholesterol absorption leads to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood.

In a 2-week clinical study involving 18 hypercholesterolaemic patients, ezetimibe inhibited intestinal cholesterol absorption by 54%, compared with placebo.¹⁰ Co-administration of ezetimibe and statins results in inhibition of biliary and dietary cholesterol absorption by ezetimibe and the complementary inhibition of a compensatory increase in hepatic cholesterol synthesis by the statins. The combination of these two lipid-lowering agents has been shown to result in synergistic reductions in plasma cholesterol levels. In addition, no plasma pharmacokinetic interaction was seen with these drug combinations.¹¹

Pharmacokinetics

The peak plasma concentrations of simvastatin 10 mg and simvastatin 10 mg plus ezetimibe 10 mg are 2.6 and 2.5 ng/mL, respectively, and the area under time–concentration curves are 7.5 and 8.1 ng·h/mL, respectively. In a clinical study of 58 healthy subjects given placebo, simvastatin 10 mg or with ezetimibe 0.25, 1 or 10 mg once daily for 14 days, no pharmacokinetic interaction between simvastatin and ezetimibe was noted. In another study of 24 patients with LDL-C levels > 130 mg/dL, the co-administration of ezetimibe and simvastatin produced greater reductions in LDL-C than administration of simvastatin alone. Side effects were mild between the groups in both studies.¹²

Simvastatin and ezetimibe are predominantly metabolized by cytochrome P450 enzyme systems and by glucuronidation, respectively, in the liver and also in the small intestine for the latter with subsequent biliary excretion. Since ezetimibe undergoes extensive enterohepatic recirculation, there is minimal systemic exposure. As ezetimibe is not metabolized by cytochrome P450 enzymes, significant pharmacokinetic interactions with most medications do not occur.¹³

Clinical Trials

In published studies, ezetimibe monotherapy reduced LDL-C by 17–20% within 2 weeks.¹⁰ In patients with primary hypercholesterolaemia, ezetimibe/simvastatin therapy has been shown to be consistently more efficacious in LDL-C reduction than statin monotherapy and with comparable tolerability. Addition of ezetimibe 10 mg per day to a statin (atorvastatin, simvastatin, pravastatin, fluvastatin, cerivastatin or lovastatin) over 8 weeks resulted in an additional 25.1% reduction in LDL-C compared with a 3.7% reduction in the statin placebo group.¹⁴

In a 6-week study of patients with hypercholesterolaemia and type 2 diabetes mellitus, simvastatin (20–40 mg/day) plus ezetimibe (10 mg/day) significantly improved total cholesterol, LDL-C, HDL-C, triglycerides and high-sensitivity CRP levels in comparison with atorvastatin (10–40 mg/day).¹⁵ In another 6-week study in which 1,902 patients with hypercholesterolaemia were recruited, ezetimibe/simvastatin (10/10–80 mg) caused a greater reduction in LDL-C and significant elevation in HDL-C compared with atorvastatin (10–80 mg/day).¹⁶

The three pivotal ezetimibe/simvastatin trials are the ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) study, IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial), and SHARP (Study of Heart and Renal Protection) study (Table 1). The ENHANCE study examined the effect of ezetimibe on the progression of atherosclerosis, focusing on the carotid and femoral arterial intima-medial thickening as a surrogate marker of atherosclerosis. This 24-month trial compared ezetimibe/simvastatin (10/80 mg) with simvastatin monotherapy (80 mg) in 720 patients with familial hypercholesterolaemia. The ezetimibe/simvastatin combined treatment reduced LDL-C and CRP levels but failed to improve carotid and femoral intima-media thickness. The short duration of the study and the fact that most patients were already receiving statin therapy could have contributed to the lack of effect.¹⁷

IMPROVE-IT is a multicentre, randomized, double-blind, active-controlled study designed to determine whether ezetimibe/simvastatin (10/40 mg) improves cardiovascular outcomes compared with simvastatin monotherapy (40 mg) in patients after acute coronary syndrome. The study will recruit up to 18,000 moderate- to high-risk patients stabilized after acute coronary syndrome. Patients will be followed up for a minimum of 2.5 years.¹⁸ The results of the trial are still pending.

The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study is a randomized, double-blind trial involving 1,873 patients with aortic stenosis who received either simvastatin/ezetimibe (10/40 mg) or placebo. During a median follow-up of 52.2 months, ezetimibe/simvastatin did not reduce the composite outcome of combined aortic valve events and ischaemic events but reduced the incidence of ischaemic cardiovascular events significantly. An increased incidence of cancer and deaths due to cancer were also observed in the ezetimibe/simvastatin group.¹⁹ However, subsequent analysis of cancer data from two larger trials (the SHARP study and IMPROVE-IT) failed to provide evidence of adverse effect of ezetimibe on rates of cancer.²⁰

The SHARP study is a randomized, controlled study designed to determine the effect of ezetimibe/simvastatin (10/20 mg) versus placebo on major atherosclerotic events in patients at high vascular risk with established chronic kidney disease. The study recruited 9,438 patients (mean age, 40 years) with stages 3 to 5 chronic kidney disease and with no history of coronary heart disease, previous acute myocardial infarction or revascularization, of whom one-third were already receiving dialysis therapy. The mean LDL-C level at entry was 108 mg/dL. After a median follow-up of 4.9 years, a risk reduction of 17% of major atherosclerotic events (coronary death, myocardial infarction, non-haemorrhagic stroke, or any revascularization) was observed in the ezetimibe/simvastatin group compared with the placebo group (P < 0.0022). The mean reduction of LDL-C in the ezetimibe/simvastatin group was 32 mg/dL.

Ezetimibe/simvastatin has no substantial effect on progression of kidney disease and did not increase the risk of myopathy, liver and biliary disorders, cancer, or non-vascular mortality.²¹

Safety

Statin therapy has been associated with a slight increase in the risk of transaminase elevations (1–2%), creatinine kinase elevations and peripheral neuropathy compared with placebo.^22,23 Simvastatin rarely causes myopathy and rhabdomyolysis resulting in acute renal failure (incidence, < 0.1%).²⁴

Similar prevalences of adverse events for the ezetimibe/simvastatin therapy and for the drugs alone have been shown.²⁵ Combined ezetimibe/simvastatin therapy was not associated with an increased incidence of rhabdomyolysis in comparison with placebo^26,27 or simvastatin alone.²⁸ In the SHARP trial, ezetimibe/simvastatin (10/20 mg) therapy did not increase the risk of myopathy, liver and biliary disorders, cancer or non-vascular mortality compared with placebo.²¹

The SEAS trial reported an increased incidence of cancer (11.1% vs 7.5%; P = 0.001) and more frequent deaths (4.1% vs 2.5%; P = 0.05) in the ezetimibe/simvastatin-treated patients compared with placebo. These cancers were not organ-specific and were not related to the degree of LDL-C reduction.¹⁹ Subsequent analysis of cancer data from two larger trials (the SHARP trial and IMPROVE-IT) failed to show an increase in cancer rate during ezetimibe/simvastatin treatment.²⁰ Post-marketing analysis of ezetimibe/simvastatin showed no increase in cancer-associated adverse events per million prescriptions in comparison with other drugs.²⁹

Precautions

The risk of myopathy is dose-related for simvastatin and is increased by high levels of HMG-CoA reductase activity in plasma. In a recent study, high-dose simvastatin (80 mg daily) was associated with significantly increased risk of myopathy.³⁰ A recent meta-analysis of five major trials revealed a 12% risk of developing new-onset diabetes associated with high-dose statin therapy.³¹ Some of the predisposing factors include advanced age, female gender, uncontrolled hypothyroidism, and renal impairment. The risk of myopathy is increased by concomitant administration of high doses of ezetimibe/simvastatin with potent inhibitors of CYP3A4 (eg, itraconazole, clarithromycin or nefazodone), fibrates (eg, gemfibrozil), cyclosporine, danazol, diltiazem, and amiodarone. In patients with creatinine clearance < 30 mL/min, dosages of ezetimibe/simvastatin above 10/10 mg per day should be implemented cautiously. Ezetimibe/simvastatin is contraindicated during pregnancy.^32,33

Conclusion

Intensive lowering of LDL-C, particularly in the high-risk population, continues to reduce cardiovascular risk. Ezetimibe/simvastatin single tablet inhibits biliary and dietary cholesterol absorption while also inhibiting a compensatory increase in hepatic cholesterol synthesis. Ezetimibe/simvastatin offers the advantages of enhancing the efficacy of LDL-C lowering over the constituent compounds without increasing the risk of adverse events. The recently announced SHARP trial confirms the significant risk reduction of atherosclerotic events in ezetimibe/simvastatin-treated patients with stages 3 to 5 chronic kidney disease.

References

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About the Author

Dr Wu is a Nephrologist and Physician at the Mount Elizabeth Medical Centre, Singapore. He is currently the President of the Singapore Hypertension Society.

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