Konstantinos Tziomalos Department of Clinical Biochemistry (Vascular Prevention Clinic), Royal Free Hospital, Royal Free University College Medical School, London , Dimitri P Mikhailidis Department of Clinical Biochemistry (Vascular Prevention Clinic), Royal Free Hospital, Royal Free University College Medical School, London

Originally printed in:
» European Cardiovascular Disease 2007 - Issue 1 - June 2007

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 lipidlowering 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.