Statin therapy: New data suggest effects on plaque volume and stability

Antonio M. Gotto, Jr, MD, DPhil
Weill Cornell Medical College
New York, NY

Currently in the United States, atherosclerosis is implicated in nearly three-fourths of all cardiovascular-related deaths. However, age-adjusted death rates from coronary heart disease (CHD) have decreased both in men and women over the past 30 years.¹ A recent study indicated that approximately half of the decrease in mortality since 1980 is due to improved medical and surgical treatments, and approximately half is due to improved control of population risk factors, including hypercholesterolemia.² Numerous clinical trials have shown unequivocally that managing hypercholesterolemia, specifically by reducing levels of LDL-C, results in reduced cardiovascular risk and improved clinical outcomes.³

Affecting the progression of atherosclerosis
LDL particles deposit cholesterol into the arterial wall, whereas HDL particles remove cholesterol from the arterial wall and transport it to the liver for excretion, in a process known as reverse cholesterol transport.⁴ Atherosclerosis is not an inevitably progressive process, as was thought in the past. Rather, the balance of transport between LDL and HDL in the subendothelial space determines the rate of disease progression, and it is possible to stop plaque formation and to induce regression.⁵

High levels of LDL-C and low levels of HDL-C are both independent predictors of atherosclerotic cardiovascular disease. A large body of evidence demonstrates that there is a log-linear relationship between LDL-C levels and the relative risk for CHD, such that each 30 mg/dL decrease in LDL-C confers an approximate 30% decrease in risk.³ Levels of HDL-C are inversely related to CHD risk. Evidence from 5 large prospective studies in the United States suggests that each 1 mg/dL increase in HDL-C is associated with an approximate 3% reduction in CHD, although a causal relationship between HDL-C levels and atherosclerotic disease has not yet been definitively established.⁶ Atherogenic dyslipidemia, which is characterized by low HDL-C, elevated triglycerides, and LDL particles that are small and dense, is common in patients with the metabolic syndrome and type 2 diabetes, and it is believed to exacerbate the atherosclerotic process and increase cardiovascular risk.⁷

Therapeutic lifestyle changes, including dietary modification, aerobic exercise, and smoking cessation, are the first line of therapy for patients with hypercholesterolemia. Pharmacologic therapy, with statins in particular, has been shown to significantly improve lipid profiles in patients who need further intervention after a trial of lifestyle therapy. If hypercholesterolemia is left untreated, atherosclerotic disease will continue to progress. Improving a patient’s lipid profile with aggressive statin treatment has been shown to slow the progression of atherosclerosis and, in some cases, can even lead to atherosclerotic plaque regression, both of which can significantly reduce the patient’s risk of suffering a cardiovascular event.⁸

The primary effect of statin therapy is LDL-C reduction. Statins share a common mechanism of action (inhibition of the rate-limiting enzyme in cholesterol synthesis, HMG CoA reductase), but they differ in terms of chemical structures and efficacy of lipid reduction. The response to statin therapy is variable and in part genetically determined, but LDL-C reductions can be expected to range from 20% to 63%. Elevations in HDL-C are typically more modest, with an approximate 5% to 15% increase. Triglycerides can be reduced by 10% to 37%.⁹

The available statins include atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. In the 6-week Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin (STELLAR) trial, 2431 adults with hypercholesterolemia were randomized to 1 of the 4 most commonly prescribed statins at varying doses. At starting doses of 10 mg/day, treatment with rosuvastatin resulted in significantly greater reductions in LDL-C (46%), as compared with atorvastatin (37%), simvastatin (28%), and pravastatin (20%).¹⁰ Figure 1 depicts the comparative effects on lipid parameters of the 10-mg starting doses, whereas Figure 2 illustrates the mean percent change from baseline in LDL-C levels with varying doses of statins.^10,11

Recommended therapeutic doses, which typically reduce LDL-C by 30% to 45%, are atorvastatin 10 to 20 mg, fluvastatin 40 to 80 mg, lovastatin 40 mg, pitavastatin 1 to 4 mg, pravastatin 40 mg, rosuvastatin 10 mg, and simvastatin 20 to 40 mg.^12,13 All of the statins are well tolerated and have a similar safety profile, with standard doses occasionally causing myopathy and transient, reversible increases in liver enzymes; these risks increase at higher doses but still remain very low.¹²

The efficacy of rosuvastatin in reducing LDL-C may make it particularly useful in high-risk patients who need to achieve low LDL-C targets. In addition, results from the recent Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) suggest that individuals without hypercholesterolemia, but with elevated levels of the inflammatory marker C-reactive protein, can also experience significant cardiovascular benefit with treatment to achieve very low LDL-C levels (median, 55 mg/dL), with no increase in adverse events.¹⁴

Effects of statins on atherosclerotic progression
Beginning in the late 1980s, clinical trials utilizing various imaging techniques have demonstrated that it is possible to halt atherosclerotic progression and, in some cases, induce regression. Early trials with quantitative coronary angiography have demonstrated an attenuation of atherosclerotic plaque progression; these include the Canadian Coronary Atherosclerosis Intervention Trial (CCAIT) and the Monitored Atherosclerosis Regression Study (MARS) with lovastatin; the Familial Atherosclerosis Treatment Study (FATS) with lovastatin, niacin, and a bile acid resin; the Lipoprotein and Coronary Atherosclerosis Study (LCAS) with fluvastatin; and the Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC I) and the Regression Growth Evaluation Statin Study (REGRESS) with pravastatin.^15-20 In general, these early studies demonstrated that even relatively small changes in coronary blockage with statin therapy could result in unexpectedly large reductions in adverse coronary events.⁸

More recent imaging studies have utilized more sophisticated techniques, including B-mode ultrasonography, intravascular ultrasound (IVUS), electron-beam computed tomography (EBCT), and high-resolution magnetic resonance imaging (MRI). Measures of carotid intima-media thickness (CIMT) can be obtained with B-mode ultrasonography, whereas IVUS provides cross-sectional visualization of the interior of a blood vessel, including the size and dimensions of atheromas. EBCT scans document the degree of calcification within the coronary arteries, and cardiac MRI can provide still and moving images of the heart and large arteries. Although advances in imaging have yielded valuable data on the progression of atherosclerosis, the use of these techniques in lipid-lowering clinical trials remains somewhat controversial.²¹ While reductions in LDL-C have been clearly linked to improved clinical outcomes, the relationship between vascular and clinical end points is still unclear.²²

Evidence from recent imaging studies suggests that statin therapy may beneficially affect plaque volume and composition within the arterial wall, possibly leading to increased plaque stability and a decreased likelihood of thrombotic events. For example, one small MRI trial found that treatment with simvastatin for 1 year resulted in significant reductions in vessel wall thickness and vessel wall area, with no change in lumen area, in both carotid and aortic arteries.²³ Similarly, a small high-resolution MRI study of rosuvastatin found no significant change in plaque volume over a 2-year period and demonstrated a significant decrease in the mean proportion of the vessel wall composed of lipid-rich necrotic core.²⁴ The larger Measuring Effects on Intima-Media Thickness: an Evaluation of Rosuvastatin (METEOR) study, which enrolled 984 low-risk individuals with evidence of subclinical atherosclerosis, found that rosuvastatin reduced the rate of progression of carotid plaques over 2 years, although it did not induce regression.²⁵

IVUS trials examining the effects of intensive statin therapy on coronary atheroma burden have provided the strongest evidence that statins can slow or reverse the progression of atherosclerosis within the vessel wall. The Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial enrolled approximately 600 patients with evidence of at least 20% narrowing of a coronary artery and compared treatment with atorvastatin 80 mg/day vs pravastatin 40 mg/day. After 18 months of treatment, results indicated a nonsignificant halt in atherosclerotic progression in the atorvastatin group and a significant 2.7% progression in the pravastatin group, with significant between-group comparisons favoring intensive therapy.²⁶ A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden (ASTEROID) was one of the first major trials to demonstrate either atherosclerotic regression or a significant halting of progression. In this trial, 349 individuals with coronary atherosclerosis received rosuvastatin 40 mg/day. After 24 months, mean LDL-C had been reduced to 60.8 mg/dL, and mean HDL-C increased by 15%. All 3 end points measuring atheroma burden (change in percent atheroma volume, change in atheroma volume in most diseased 10-mm segment at baseline, and change in normalized total atheroma volume for the entire artery) demonstrated significant regression of atherosclerosis.²⁷

A post-hoc analysis by Nicholls et al attempted to quantify the relationship between LDL-C, HDL-C, and atheroma burden. It combined data from REVERSAL, ASTEROID, and 2 similar IVUS trials involving treatment with statins for 18 or 24 months, the ACAT Intravascular Atherosclerosis Treatment Evaluation (ACTIVATE) and Comparison of Amlodipine vs Enalapril to Limit Occurrence of Thrombosis (CAMELOT) studies. This analysis concluded that substantial atherosclerotic regression (≥5% reduction in atheroma volume) was most likely to occur in patients who had achieved LDL-C levels below 87.5 mg/dL and who had increases in HDL-C greater than 7.5%.²⁸ This analysis suggests that substantial reductions in LDL-C combined with increases in HDL-C are likely to confer the greatest benefit, although it is not yet fully understood how atherosclerotic regression associated with these changes in lipids might affect clinical outcomes.

Approved indications for statins in treating atherosclerosis
In general, all of the statins are indicated to improve a patient’s lipid profile, but their specific US Food and Drug Administration (FDA)–approved indications vary. Lovastatin, fluvastatin, and pravastatin are indicated for slowing coronary atherosclerosis in patients with CHD (ie, secondary prevention) (prescribing information for lovastatin [Mevacor], Merck, 2008; fluvastatin [Lescol], Novartis, 2006; and pravastatin [Pravachol], Bristol-Myers Squibb, 2007). Rosuvastatin is indicated for slowing the progression of atherosclerosis both in patients with and without CHD (ie, primary and secondary prevention) (prescribing information for rosuvastatin [Crestor], AstraZeneca, 2009). Currently, simvastatin, atorvastatin, and pitavastatin are not FDA-approved for the treatment of atherosclerosis (prescribing information for simvastatin [Zocor], Merck, 2008; atorvastatin [Lipitor], Pfizer, 2009; pitavastatin [Livalo], Kowa, 2009) .