There are many risk factors for cardiovascular disease such as hypertension, smoking, dyslipidaemia, diabetes mellitus and obesity. In the US or Europe the most important risk factor is dyslipidaemia; however, in Japan it is traditionally hypertension. This is because cholesterol levels are lower in Japan than in Western countries. In the Japanese, even when cholesterol levels are very high, the incidence of cardiovascular events is very low. However, this traditional understanding of cardiovasular events in Japan is no longer necessarily the reality.1,2 This is because the incidence of cardiovascular events linearly and markedly increases along with the increases in serum cholesterol levels (see Figure 1), and serum cholesterol levels in the Japanese have increased to levels commonly found in the US. These facts strongly indicate that Japanese people need to seriously consider the management of serum cholesterol levels and the treatment of dyslipidaemia.
Cholesterol Levels and Coronary Heart Disease Risk
Disorders of lipoprotein metabolism, especially elevated low-density lipoprotein (LDL) cholesterol and low high-density lipoprotein (HDL) cholesterol levels, play an important role in the development of coronary atherosclerosis and, subsequently, myocardial infarction. Recent clinical studies such as The Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT), Treating to New Targets (TNT) and Incremental Decrease in Clinical End-points Through Aggressive Lipid Lowering (IDEAL) trials have tested the hypothesis of ‘the lower, the better’ and have shown that a more aggressive statin regimen, which achieved lower LDL cholesterol levels, was associated with improved clinical outcomes. Indeed, the ESTABLISH study also demonstrated the beneficial effect of early statin treatment on atherosclerotic lesions in Japanese patients with acute coronary syndrome (ACS).3 They found that early aggressive lipid-lowering treatment with atorvastatin for six months significantly reduced the plaque volume in patients with ACS, and that the percentage change in plaque volume showed a significant positive correlation with the percentage reduction of LDL, even in patients with low baseline LDL cholesterol. However, even the highest-dose regimes of the statins are limited and fail to achieve the optimal target for LDL cholesterol levels of >70mg/dl in a substantial proportion of patients. Therefore, we need to consider how best to control serum cholesterol to the levels indicated in guidelines for the treatment of dyslipidaemia.
Balance of Cholesterol Synthesis and Absorption
To control serum cholesterol levels we need to know how cholesterol is absorbed from the intestine and how it is produced in the liver. Hydroxymethylglutarly co-enzyme A (HMG-CoA) reductase is the key enzyme for the synthesis of cholesterol, and the inhibitor of HMG-CoA reductase stain blocks the production of cholesterol in the liver. This suggests that while decreased hepatic synthesis of cholesterol by statin is a critical step in lowering serum cholesterol levels, another important source of cholesterol, i.e. intestinal absorption, may be upregulated when hepatic cholesterol synthesis is inhibited by statins. This supports the idea that the intestinal cholesterol blockade by ezetimibe represents a crucial target to successfully lower LDL cholesterol beyond the levels that are currently achieved with statin therapy alone. Furthermore, oxidised cholesterol is deleterious to the vessels and endothelium. As oxidised cholesterol in the body is generated only by the absorption from the intestine, it is important to block the uptake of cholesterol from the intestine. As ezetimide is chemically produced to block cholesterol uptake, it is essential to consider using ezetimide to lower serum cholesterol levels and prevent cardiovascular events.
We need to know how ezetimibe works to reduce serum cholesterol levels in the clinical setting. Ezetimibe is chemically produced to block the route of cholesterol uptake, Niemann-Pick C1 Like 1 (NPC1L1). NPC1L1 is an intestinal cholesterol transporter and the molecular target of ezetimibe. The efficacy and safety of ezetimibe in patients with primary hypercholesterolaemia were evaluated in multicentre double-blind studies. In a pooled analysis of the 1,719 patients from the studies, ezetimibe significantly reduced mean LDL cholesterol by 18.2%, and resulted in a statistically significant increase in serum HDL cholesterol levels and reduction in the serum thyroglobulin (TG) levels.4 Furthermore, the current study in patients with primary hypercholesterolaemia showed that ezetimibe significantly reduced the mean values of the serum large LDL cholesterol levels and the serum small dense LDL cholesterol levels by 17.2 and 42.9%, respectively (see Figure 2).5 The in vivo kinetics study of ApoB-48 and ApoB-100 in men with primary hypercholesterolaemia showed that ezetimibe significantly increased the LDL cholesterol, intermediate-density lipoprotein and LDL apoB-100 fraction catabolic rates. These results indicate that the LDL-cholesterol- lowering effect of ezetimibe is caused by an increase in the catabolism of apoB-100-containing lipoproteins.6
Co-administration of Ezetimibe with Statins to Achieve Recommended Levels
Although statins are widely used to decrease plasma cholesterol levels, in a realistic clinical situation the effects of a statin are sometimes not satisfactory. In this case, one must consider using ezetimibe to lower cholesterol to the recommended levels. The Ezetimibe Add-on to Statin for Effectiveness (EASE) Trial examined the effectiveness and safety of ezetimibe 10mg added to the ongoing statin therapy in patients with hypercholesterolaemia who had LDL cholesterol levels exceeding the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) goals. Ezetimibe added to statin therapy significantly reduced the LDL cholesterol level by an additional 25.8% in the total population compared with an additional 2.7% reduction with placebo plus statin.7 Regardless of sex, race, age, statin and dose subgroup, the addition of ezetimibe resulted in an improvement in lipid parameters and high-sensitivity C-reactive protein (hs-CRP). In each risk category subgroup, more than 70% of patients treated with ezetimibe added to statin reached their target LDL cholesterol level (see Figure 3).
The addition of ezetimibe to statin therapy should be considered for patients who are not achieving their LDL cholesterol treatment goals. Failure to achieve LDL cholesterol levels durng titration of statin therapy may be explained by the rule of six. Doubling of the dose results in an additional reduction in LDL cholesterol concentration of only about 6%. Patients with an inadequate response to statin therapy or who require more LDL cholesterol lowering may benefit from ezetimibe co-administered with a statin.
Summary and the Future Direction of Ezetimibe
Ezetimibe is a selective intestinal cholesterol transport inhibitor that inhibits the absorption of dietary and biliary cholesterol from the proximal intestine without affecting the absorption of fat-soluble vitamins. Ezetimibe was found to inhibit intestinal cholesterol absorption by an average of 54% in hypercholesterolaemia patients8 and by 58% in vegetarians (see Figure 4).9
Ezetimibe monotherapy reduced LDL cholesterol by 18% in patients with primary hypercholesterolaemia. When ezetimibe was added to ongoing statin treatment, a further 25% reduction in LDL cholesterol was found in patients with primary hypercholesterolaemia.10 Ezetimibe in co-administration with statins allows more patients to achieve their LDL cholesterol goals. Furthermore, a retrospective analysis found an inverse linear relationship between the initial LDL cholesterol response to statins and subsequent response to ezetimibe. A poor initial response to statin therapy predicted a favourable response to the addition of ezetimibe and vice versa.11
Combination lipid-lowering therapy is needed to meet the current LDL cholesterol goals recommended by the NCEP-ATP III and the Japanese Atherosclerosis Society (JAS) guidelines. Inhibition of both cholesterol synthesis and absorption using a statin plus ezetimibe provides a greater LDL cholsterol response than statin titration therapy alone. Ongoing trials are evaluating the ability of ezetimibe with statins to reduce carotid intima-media thickness in patients with hereditary familial hypercholesterolaemia, slow the progress of calcific aortic stenosis, reduce cardiovascular morbidity in patients with chronic kidney disease and reduce cardiovascular death or major coronary events in patients with ACS (see Table 1). These outcomes are awaiting the incremental effect of adding ezetimibe to statins.
Finally, in Japan we need to seriously consider the control of serum cholesterol levels in adherence to the guidelines, otherwise cardiovascular disease will further increase in Japan despite decreasing in Western countries. We need to evaluate the effects of ezetimibe in patients with dyslipidaemia in Japan using small- and large-scale clinical trials.
- Okamura T, Kadowaki T, et al., What cause of mortality can we predict by cholesterol screening in the Japanese general population?, J Intern Med, 2003;253(2):169–80.
- Stamler J, Wentworth D, Neaton JD, Is the relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded?, Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT), JAMA, 1986;256(20):2823–8.
- Okazaki S, Yokoyama T, et al., Early statin treatment in patients with acute coronary syndrome: demonstration of the beneficial effect on atherosclerotic lesions by serial volumetric intravascular ultrasound analysis during half a year after coronary event: the ESTABLISH Study, Circulation, 2004;110(9):1061–8.
- Knopp RH, et al., Evaluation of the efficacy, safety and tolerability of ezetimibe in primary hypercholesterolaemia: a pooled analysis from two controlled phase III clinical studies, Int J Clin Pract, 2003;57:363–8.
- Kalogirou M, et al., Effect of ezetimibe monotherapy on the concentration of lipoprotein subfractions in patients with primary dyslipidaemia, Curr Med Res Opin, 2007;23:1169–76.
- André J, et al., Effect of Ezetimibe on the In Vivo Kinetics of ApoB-48 and ApoB-100 in Men With Primary Hypercholesterolaemia, Arterioscler Thromb Vasc Biol, 2006;26: 1101–6.
- Pearson TA, et al., A community-based, randomised trial of ezetimibe added to statin therapy to attain NCEP ATP III goals for LDL cholesterol in hypercholesterolemic patients: the ezetimibe add-on to statin for effectiveness (EASE) trial, Mayo Clin Proc, 2005;80:587–95.
- Sudhop T, et al., Inhibition of intestinal cholesterol absorption by ezetimibe in humans, Circulation, 2002;106:1943–8.
- Clarenbach JJ, et al., The lipid-lowering effect of ezetimibe in pure vegetarians, J Lipid Res, 2006;47:2820–24.
- Gagne C, et al., Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary Hypercholesterolaemia, Am J Cardiol, 2002;90:1084–91.
- Pisciotta L, et al., Effect of ezetimibe co-administered with statins in genotype-confirmed heterozygous FH patients, Atherosclerosis, 2007;192:e116–22.