Atherosclerosis is a complex multifactorial process involving lipid accumulation, oxidation and modification, which together provoke chronic inflammation in the arteries leading to the development of fibrous plaques that can erode or rupture causing thrombosis or stenosis . Atherosclerosis develops progressively, over several decades, and starting in the early teens. The rate of progression varies according to the presence of risk factors, such as hypertension, diabetes mellitus, tobacco smoking, obesity and genetic predisposition, which affect low-density lipoprotein cholesterol (LDL-C) particles and the inflammatory response . Hypercholesterolemia constitutes a major risk factor for the development of atherosclerosis and coronary heart disease.

Evidence from randomized clinical trials has unequivocally shown that long-term lipid-lowering treatment with statins substantially reduces the risk of cardiovascular morbidity and mortality and the requirement for coronary intervention . Combined with the fact that these drugs are generally well tolerated and serious side effects are rare , statins have become the first-line treatment for lowering LDL-C . Statins are potent inhibitors of cholesterol biosynthesis through the reversible inhibition of 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA) reductase, but they have also shown cholesterol-independent effects . However, whether these “pleiotropic” effects have demonstrable clinical benefits is as yet unclear .

Reduction of LDL-C with statins, alongside improvements in diet, lifestyle and other modifiable risk factors, is a key aim in the primary and secondary prevention of cardiovascular disease . However, residual thromboembolic risk persists despite aggressive LDL-C reduction. Not all patients achieve the recommended LDL-C treatment targets, which according to the European Society of Cardiology guidelines are < 1.8 mmol/L (< 70 mg/dL) or a reduction > 50% from baseline when the target cannot be achieved, in very high cardiovascular risk patients . Furthermore, some patients are intolerant of statins, including at the doses required to achieve sufficient reduction in LDL-C. In such patients, the addition of other non-statin treatments can be used to lower LDL-C further . While nicotinic acid and bile acid sequestrants, such as cholestyramine, colestipol and colesevelam, improve the lipid profile, clinical outcome data with these drug combinations have either not been performed, or have failed to demonstrate additive atherothrombotic protection over statin monotherapy .

Ezetimibe is an alternative non-statin lipid-lowering medication that corresponds to an essential pathophysiological mechanism in the progression of atherosclerosis. Ezetimibe reduces blood cholesterol concentrations by inhibiting activity of the Niemann-Pick C1-Like 1 (NPC1L1) receptor, thereby impeding absorption of cholesterol in the small intestine, which in turn reduces hepatic stores of cholesterol and increases cholesterol clearance from the blood . Data from one genetic study have suggested that the effect on coronary heart disease risk of reducing LDL-C is mediated by the separate and combined effects on NPC1L1 and HMG-CoA reductase genetic polymorphisms; both have approximately the same effect when measured per unit lower LDL-C concentration . Furthermore, the reductions in risk of coronary heart disease in this study were linearly additive. These findings led the authors to hypothesize that the cardiovascular benefits of LDL-C lowering are independent of the mechanism by which it is reduced. In a second genetic study, naturally occurring human mutations (nonsense, splice-site, or frameshift mutations) that disrupt NPC1L1 function were used to infer the potential effects of ezetimibe in terms of reducing the risk of coronary heart disease. The mean LDL-C in heterozygous carries of these mutations was 0.31 mmol/L (12 mg/dL) lower than that in non-carriers ( P = 0.04) and was associated with a relative reduction of 53% in the risk of developing coronary heart disease ( P = 0.008). These data support the hypothesis that drugs, such as ezetimibe, that disrupt NPC1L1 function will lower the risk of coronary heart disease .

The first indication of clinical benefits of the addition of ezetimibe to a statin were shown in the randomized, double blind Study of Heart and Renal Protection (SHARP) , the objective of which was to determine the safety and efficacy of reducing LDL-C in 9270 patients with chronic kidney disease and no known history of myocardial infarction or coronary revascularization. Initially, patients were randomly assigned to simvastatin 20 mg plus ezetimibe 10 mg daily, simvastatin 20 mg, or placebo. Patients were followed-up for a median of 4.9 years. The primary outcome (first occurrence of non-fatal myocardial infarction or coronary death, non-haemorrhagic stroke, or any arterial revascularization procedure) was reduced by 17% (95% confidence interval 6–26%) with the combination (11.3% for simvastatin plus ezetimibe vs. 13.4% for placebo; rate ratio 0.83, 95% confidence interval 0.74–0.94; P = 0.0021). The results from this study therefore showed that lowering LDL-C with simvastatin plus ezetimibe safely reduced the risk of major atherosclerotic events in a broad range of patients with chronic kidney disease, including those on dialysis.

The long-awaited results of the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) were published recently . This multicentre, randomized, double blind, active-control trial, which involved 18,144 moderate- to high-risk stabilized patients with an acute coronary syndrome, was designed to test the hypothesis that the addition of ezetimibe 10 mg to simvastatin 40 mg would translate into a reduction in cardiovascular outcomes relative to simvastatin monotherapy. Mean LDL-C concentrations were 2.4 mmol/L (93.8 mg/dL) at baseline, decreasing to 1.4 mmol/L (53.2 mg/dL) in the simvastatin–ezetimibe group and 1.8 mmol/L (69.9 mg/dL) in the simvastatin monotherapy group. Consistent values were obtained over the entire course of the trial for median time-weighted average LDL-C. After 7 years of follow-up, the addition of ezetimibe to simvastatin reduced the risk of cardiovascular events (cardiovascular death, myocardial infarction, rehospitalization for unstable angina, coronary revascularization, or stroke) by 6.4% (32.7% vs 34.7% ; absolute risk difference, 2.0 percentage points; hazard ratio 0.936, 95% confidence interval, 0.89–0.99; P = 0.016). This result was driven by a statistically significant reduction in the risk of myocardial infarction (13.1% vs 14.8%, P = 0.002) and any stroke (4.2% vs 4.8%, P = 0.05). IMPROVE-IT was therefore the first study to report an incremental clinical benefit from the combination of ezetimibe and simvastatin after an acute coronary syndrome. The data also reinforced the concept that “lower is better” for LDL-C, with an incremental benefit in patients treated below the target of 1.8 mmol/L (< 70 mg/dL).

Taken together, this new evidence lends support to the move from a pure statin LDL-C lowering risk-stratified strategy to a high-intensity treat-to-target strategy involving combination therapy with a statin and ezetimibe, as recommended in the European guidelines on cardiovascular disease prevention . In response to the publication of these new findings, the American College of Cardiology/American Heart Association guidelines continue to advocate a net benefit approach to atherosclerotic cardiovascular disease reduction, but which now extends to non-statin drugs, including ezetimibe and other LDL-C lowering drugs currently in development . The findings from IMPROVE-IT also demonstrate a need to investigate, in future large randomized trials, the potential cardiovascular benefits of reducing the LDL-C target to 1.3 mmol/L (< 50 mg/dL) or below.