Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide.1 The relationship between coronary heart disease (CHD) and elevated low-density lipoprotein cholesterol (LDL-C) levels is well established.2 Several large-scale trials, in both primary and secondary prevention settings, have shown that lowering LDL-C levels using statins substantially reduces cardiovascular mortality.3,4 More importantly, this reduction correlates with the LDL-C level achieved; ‘lower is better’.3,4 The need for effective LDL-C-lowering therapy is increasingly important as LDL-C goals become more stringent. The updated National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines recommend an optional goal of <1.8mmol/l (<70mg/dl) for very high-risk patients,4 and the American Heart Association/American College of Cardiology (AHA/ACC) recommended that this LDL-C goal is a ‘reasonable’ option for patients with CHD.5 Is it therefore ‘unreasonable’ not to achieve this target? Guidelines for the prevention of CVD issued by the Joint British Societies (JBS2) also define the optimal LDL-C treatment target for high-risk patients as <2.0mmol/l (<77mg/dl).6
Despite the established efficacy of statins, the number of patients on statin monotherapy who achieve and maintain LDL-C levels recommended by current guidelines is suboptimal.7,8 In the Statin Therapies for Elevated Lipid Levels Compared Across Doses to Rosuvastatin (STELLAR) trial, rosuvastatin 10mg, atorvastatin 20mg, simvastatin 20mg and pravastatin 20mg achieved the LDL-C goal of <2.6mmol/l (<100mg/dl) in 53%, 44%, 14% and 3% of patients, respectively.9 At their top doses, rosuvastatin 40mg, atorvastatin 80mg, simvastatin 80mg and pravastatin 40mg daily achieved this LDL-C goal in 80%, 70%, 53% and 8% of patients, respectively.9 Therefore, not all patients reach their LDL-C goals, even with the highest doses of potent statins. It follows that even fewer will reach the LDL-C goal of <1.8mmol/l (<70mg/dl) with statin monotherapy. Furthermore, titration to higher statin dosages has its limitations because of increasing adverse side effects and decreased compliance.10–12
As in other branches of medicine, combination therapy with drugs that have different or complementary mechanisms of action is an option to achieve LDL-C treatment goals.13 Thus, it has been proposed that adding bile acid sequestrants or niacin to ongoing statin treatment could help achieve lipid targets.5 However, both of these agents are limited by significant rates of treatment discontinuation.14
It was recently reported that more than two-thirds and one-half, respectively, of patients treated with these agents stop treatment by the end of one year.14 Fibrates also have a significantly higher rate of discontinuation than statins and there is a potential for increased side effects when co-administered with a statin.13,14 Furthermore, the AHA/ACC 2006 recommendations do not include statin and fibrate combinations for LDL-C reduction but do mention fibrate monotherapy for the reduction of non-high-density lipoprotein cholesterol (HDL-C).5 Thus, the options for safe and well-tolerated combination therapy with lipid-lowering drugs were limited until the advent of ezetimibe.15 This drug is specifically mentioned in the AHA/ACC guidelines.5 Ezetimibe acts by selectively inhibiting intestinal cholesterol absorption16–18 by interacting with the transporter Niemann-Pick C1-like 1 protein (NPC1L1).19 Ezetimibe may also act on the class B type 1 scavenger receptor (SR-BI) in the intestine.20
Reducing the cholesterol absorbed from the intestine results in a decreased hepatic cholesterol pool.21–23 The liver then upregulates LDL receptor expression, trapping more LDL particles from the circulation and resulting in a fall in plasma LDL-C levels.21-23 Therefore, the complementary actions of statins and ezetimibe offer a potent treatment option via inhibition of both cholesterol absorption and production.15 Moreover, combining the two drugs reduces side effects and upregulation of cholesterol absorption associated with high doses of statins and the ezetimibe-induced compensatory rise in hepatic cholesterol synthesis.18,24,25 Furthermore, discontinuation rates of ezetimibe are comparable to those of statins, thus ensuring optimal compliance compared with other available therapeutic options.14 It follows that the availability of a single tablet (Inegy or Vytorin) that includes ezetimibe 10mg and different doses of simvastatin (10, 20, 40 and 80mg) may improve compliance. This is especially true for patients taking a large number of drugs.
Ezetimibe is approved for monotherapy as well as in co-administration with statins for the treatment of hyper-cholesterolaemia.26-37 Monotherapy lowers plasma LDL-C by about 18%.26–28 However, the greatest effectiveness of ezetimibe results from its use in co-administration with statins.28–37 When added to a statin, ezetimibe can achieve an additional 21% to 30% reduction in LDL-C.28–37 In the Examination of Potential Lipid-modifying Effects Of Rosuvastatin in Combination with Ezetimibe versus Rosuvastatin Alone (EXPLORER) trial, ezetimibe (10mg/day) co-administered with rosuvastatin (40mg/day) produced a fall in LDL-C of as much as 69.8%.34
More importantly, this additional reduction in LDL-C results in a higher proportion of patients achieving treatment goals.28,37 In the Ezetimibe Add-on to Statin for Effectiveness (EASE) trial, 71.0% of patients treated with ezetimibe added to statin reached their respective NCEP ATP III LDL-C targets compared with 20.6% of those treated with placebo plus statin (p<0.001).37 Furthermore, ezetimibe (10mg/day) co-administered with a starting dose of a statin results in an LDL-C lowering that is equivalent to using the maximum dose of the statin alone.28–37 This enhancing effect is seen with all statins evaluated.28–37 In contrast, the addition of ezetimibe to maximal-dose simvastatin, atorvastatin, or rosuvastatin provided relatively smaller additional LDL-C reductions (between 7% and 13%).29,33,34 Thus, higher-dose statin therapy is not essential in co-administration with ezetimibe, considering the efficacy and safety of the low-dose co-administration.15 It should also be mentioned that ezetimibe and simvastatin in a single tablet was more effective than rosuvastatin in LDL-C lowering at the usual starting, next highest and maximum doses in hypercholesterolaemic patients.38 Similar results were observed when ezetimibe and simvastatin in a single tablet was compared with atorvastatin monotherapy in patients with type 2 diabetes and hypercholesterolemia.39
In heterozygous familial hypercholesterolaemia (FH) patients, LDL-C levels were reduced significantly more by ezetimibe plus atorvastatin co-administration therapy than by doubling the dose of atorvastatin (-22.8% versus -8.6%; p<0.01).40 Moreover, ezetimibe co-administered with atorvastatin or simvastatin also produced clinically important LDL-C reductions in homozygous FH patients.41
It is of interest that a meta-analysis of five diet, three bile acid sequestrant, one surgery and 10 statin trials, with 81,859 participants, showed a relationship between LDL-C lowering and reduction in cardiovascular events.42 Therefore, it seems that LDL-C reduction by different methods results in clinical benefit.
In addition to its potent LDL-C lowering effect, ezetimibe may exert other cardioprotective actions.43 Thus, ezetimibe monotherapy usually, but not always, results in a modest, but statistically significant, increase in HDL-C and decrease in triglycerides.26,27,30,37,44–46
Furthermore, patients with raised serum C-reactive protein (CRP) levels are at a higher risk of cardiovascular events.47 In this context, decreases in CRP levels up to 62% were reported with atorvastatin 80mg plus ezetimibe.33 Similarly, an additional fall in CRP levels was seen with ezetimibe co-administered with simvastatin compared with statin monotherapy.34,48,49
Conclusions
Current lipid treatment guidelines present new challenges to health professionals because of the more aggressive plasma LDL-C goals recommended in patients at very high risk of CVD.5,6,50 Given the inherent limitations of statin monotherapy, ezetimibe co-administered with a statin, which inhibits cholesterol absorption and production, represents a valuable aid in our efforts to achieve lipid goals. However, clinical trials are needed in order to evaluate the potential of ezetimibe to reduce cardiovascular morbidity and mortality. There is currently a comprehensive clinical programme of trials, including ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression), SEAS (Simvastatin and Ezetimibe in Aortic Stenosis), SHARP (Study of Heart and Renal Protection) and IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), which will enrol 21,000 patients to address this question.