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

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

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

Clinical implications for treating atherosclerosis

  • In the United States, atherosclerosis causes three-fourths of all cardiovascular deaths, but controlling hypercholesterolemia can greatly reduce cardiovascular risk.
  • Statins can significantly improve a patient’s lipid profile, primarily by reducing levels of low-density lipoprotein cholesterol
    (LDL-C).
  • Studies incorporating various imaging techniques indicate that it is possible to slow, halt, or reverse the progression of atherosclerosis with statin therapy.
  • It is important to initiate statin therapy in patients with elevated LDL-C levels before further atherosclerotic progression leads to clinical events.
  • Atherosclerotic regression is most likely to occur in patients who have attained low LDL-C levels and who have also increased their high-density lipoprotein cholesterol (HDL-C).

 

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 hypercholesterolemiais 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%).10Figure 1depicts 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

The atherosclerotic process
Atherosclerosis is a gradual, lifelong disease that can begin in childhood or adolescence, although symptoms typically develop later in life. It is caused by the interplay between the accumulation of cholesterol-rich lipids within the arterial wall, oxidative stress, and chronic inflammation. In the initiating step of atherosclerosis, modified or oxidized low-density lipoprotein (LDL) particles damage the endothelium, a thin layer of cells lining the interior of the arterial wall. This initial injury triggers an inflammatory and immune response with increased production of chemoattractant molecules, cytokines, and cell adhesion molecules (Figure A). As a result, the endothelium becomes more adherent and permeable to circulating monocytes and T-lymphocytes, and it acquires increased thrombotic and vasoactive properties.  Monocytes that adhere to the surface of endothelial cells are transported into the arterial wall, where they are converted into macrophages. Activated macrophages and leukocytes then release a variety of mediators that collectively increase inflammation and oxidative stress within the vessel wall.a

Figure A: Inflammation and the development of the atherosclerotic plaque

HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.

Fatty streaks are formed when macrophages ingest oxidized LDL and become foam cells, filled with lipid. As atherosclerosis develops, fatty streaks evolve into mature plaques with lipid-rich necrotic cores encased by a weakened fibrous cap (Figure B). The atherosclerotic process can be accelerated by several comorbid conditions and risk factors, such as hypercholesterolemia, hypertension, tobacco smoking, diabetes, obesity, and aging, which promote atherosclerosis through their effects on cholesterol levels and vascular inflammation. Over time, some atherosclerotic plaques may grow larger, causing stenosis of the major arteries. Other plaques are not critically stenotic but become unstable, most likely due to inflammation, and they may ultimately rupture, causing arterial thrombosis and acute coronary events (Figure B).

Figure B: Rupture of the atherosclerotic plaque leading to thrombosis


 
Reference
a.) Libby A, et al. J Am Coll Cardiol. 2006;48(9 suppl A):A33-A46.

Figure 1 Least-squares mean percentage change from baseline in LDL-C, HDL-C, and triglycerides with 10-mg statin doses from the STELLAR trial


*Significantly (P<.002) different versus rosuvastatin 10 mg.
HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; STELLAR, Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin.
Adapted from Jones PH, et al. Am J Cardiol. 2003;92:152-160.

Figure 2 Least-squares mean percentage change from baseline in LDL-C with statin doses from the STELLAR trial

LDL-C, low-density lipoprotein cholesterol; STELLAR, Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin

Least-squares mean percentage change from baseline in low-density lipoprotein cholesterol (LDL-C) with statin doses from the STELLAR trial.  In 22 pair-wise comparisons, rosuvastatin was significantly different (P < .002) versus equivalent or higher doses of comparators using an analysis of variance.
Reprinted from Lewis SJ. Am J Med. 2009;122(suppl 1A):s38-s50. Copyright 2009 with permission from Elsevier.

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) .

Acknowledgments
The author would like to acknowledge the editorial and medical illustration assistance of Jennifer Moon, PhD, and the Editorial Office of the Dean, Weill Cornell Medical College, which received funding from AstraZeneca to help in the preparation of this e-newsletter.

Disclosures
Dr Gotto is a consultant for AstraZeneca, KOWA Pharmaceuticals America, Inc., Merck & Co., Inc., and Roche Pharmaceuticals, and he is on advisory boards for DuPont and Novartis Pharmaceuticals Corp. He serves on corporate boards for Aegerion Pharmaceuticals, Inc, Arisaph Pharmaceuticals, Inc., and Vatera Capital LLC.

References

  1. Libby P, Ridker PM. Inflammation and atherothrombosis: from population biology and bench research to clinical ractice. J Am Coll Cardiol. 2006;48(9 Suppl A):A33-46.
  2. Rosamond W, Flegal K, Furie K, Go A, Greenlund K, et al. Heart Disease and Stroke Statistics 2008 Update: A Report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2008;117:e25-e146.
  3. Ford ES, Ajani UA, Croft JB, Critchley JA, Labarthe DR, et al. Explaining the decrease in U.S. deaths from coronary disease, 1980-2000. N Engl J Med. 2007;356:2388-2398.
  4. Grundy SM, Cleeman JI, Merz CNB, Brewer HB, Clark LT, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227-239.
  5. Ohashi R, Mu H, Wang X, Yao Q, Chen C. Reverse cholesterol transport and cholesterol efflux in atherosclerosis. QJM 2005; 98(12):845-856.
  6. Ibanez B, Vilahur G, Badimon JJ. Plaque progression and regression in atherothrombosis. J Thromb Haemost. 2007;5(Suppl 1):292-299.
  7. Miller M. High-density lipoprotein cholesterol in coronary heart disease risk assessment. In Ballantyne C, ed. Clinical Lipidology: A Companion to Braunwald's Heart Disease. Philadelphia: Saunders, 2009:119-129.
  8. Fruchart JC, Sacks F, Hermans MP, Assmann G, Brown WV, et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in patients with dyslipidemia. Am J Cardiol. 2008;102(10 Suppl):1K-34K.
  9. Brown BG, Zhao XQ, Sacco DE, et al. Lipid lowering and plaque regression. New insights into prevention of plaque disruption and clinical events in coronary disease. Circulation. 1993;87:1781-1791.
  10. Gotto AM. Contemporary Diagnosis and Management of Lipid Disorders. 4th ed. Newtown, PA: Handbooks in Health Care, 2008.
  11. Jones PH, Davidson MH, Stein EA, et al. Comparison of the efficacy of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR trial). Am J Cardiol. 2003;92:152-160.
  12. McKenney JM, Jones PH, Adamczyk MA, et al. Comparison of the efficacy of rosuvastatin versus atorvastatin, simvastatin, and pravastatin in achieving lipid goals: results from the STELLAR trial. Curr Med Res Opin. 2003;19:689-698.
  13. Armitage J. The safety of statins in clinical practice. Lancet 2007;370(9601):1781-90.
  14. Lee SH, Chung N, Kwan J, Kim DI, Kim WH, Kim CJ, et al. Comparison of the efficacy and tolerability of pitavastatin and atorvastatin: an 8-week, multicenter, randomized, open-label, dose-titration study in Korean patients with hypercholesterolemia. Clin Ther. 2007;29(11):2365-73.
  15. Ridker PM, Danielson E, Fonseca FAH, Genest J, Gotto AM Jr, Kastelein JJP, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ, for the JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195-2207.
  16. Waters D, Higginson L, Gladstone P, Boccuzzi SJ, Cook T, Lespérance J. Effects of cholesterol lowering on the progression of coronary atherosclerosis in women. A Canadian Coronary Atherosclerosis Intervention Trial (CCAIT) substudy. Circulation. 1995;92:2404-2410.
  17. Blankenhorn DH, Azen SP, Kramsch DM, Mack WJ, Cashin-Hemphill L, Hodis HN, DeBoer LW, Mahrer PR, Masteller MJ, Vailas LI, Alaupovic P, Hirsch LJ, MARS Research Group. Coronary angiographic changes with lovastatin therapy. The Monitored Atherosclerosis Regression Study (MARS). Ann Intern Med. 1993;119:969-976.
  18. Brown G, Albers JJ, Fisher LD, Schaefer SM, Lin JT, Kaplan C, Zhao XQ, Bisson BD, Fitzpatrick VF, Dodge HT. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med.19908;323:1289-1298.
  19. Herd JA, Ballantyne CM, Farmer JA, Ferguson JJ 3rd, Jones PH, West MS, Gould KL, Gotto AM Jr. Effects of fluvastatin on coronary atherosclerosis in patients with mild to moderate cholesterol elevations (Lipoprotein and Coronary Atherosclerosis Study [LCAS]). Am J Cardiol. 1997;80:278-286.
  20. Pitt B, Mancini GB, Ellis SG, Rosman HS, Park JS, McGovern ME. Pravastatin limitation of atherosclerosis in the coronary arteries (PLAC I): reduction in atherosclerosis progression and clinical events. PLAC I investigation. J Am Coll Cardiol. 1995;26:1133-1139.
  21. de Groot E, Jukema JW, van Boven AJ, Reiber JH, Zwinderman AH, Lie KI, Ackerstaff RA, Bruschke AV. Effect of pravastatin on progression and regression of coronary atherosclerosis and vessel wall changes in carotid and femoral arteries: a report from the Regression Growth Evaluation Statin Study. Am J Cardiol. 1995;76:40C-46C.
  22. Raggi P, Taylor A, Fayad Z, et al. Atherosclerotic plaque imaging: contemporary role in preventive cardiology. Arch Intern Med. 2005;165:2345-2353.
  23. Temple R. Are surrogate markers adequate to assess cardiovascular disease drugs? JAMA. 1999;282:790-795.
  24. Corti R, Fayad ZA, Fuster V, Worthley SG, Helft G, Chesebro J, Mercuri M, Badimon JJ. Effects of lipid-lowering by simvastatin on human atherosclerotic lesions: a longitudinal study by high-resolution, noninvasive magnetic resonance imaging. Circulation. 2001;104:249-252.
  25. Underhill HR, Yuan C, Zhao X-Q, et al. Effect of rosuvastatin therapy on carotid plaque morphology and composition in moderately hypercholesterolemic patients: a high-resolution magnet resonance imaging trial. Am Heart J. 2008;155:584.e1-584.e8.
  26. Crouse JR III, Raichlen JS, Riley WA, et al, for the METEOR study group. Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR trial. JAMA. 2007;297:1344-1353.
  27. Nissen SE, Tuzcu EM, Schoenhagen P, et al, for the REVERSAL Investigators. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291:1071-1080.
  28. Nissen SE, Nicholls SJ, Sipahi I, et al, for the ASTEROID investigators. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. 2006;295:1556-1565.
  29. Nicholls SJ, Tuzcu EM, Sipahi I, et al. Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis. JAMA. 2007;297:499-508.
  

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

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

Clinical implications for treating atherosclerosis

  • In the United States, atherosclerosis causes three-fourths of all cardiovascular deaths, but controlling hypercholesterolemia can greatly reduce cardiovascular risk.
  • Statins can significantly improve a patient’s lipid profile, primarily by reducing levels of low-density lipoprotein cholesterol
    (LDL-C).
  • Studies incorporating various imaging techniques indicate that it is possible to slow, halt, or reverse the progression of atherosclerosis with statin therapy.
  • It is important to initiate statin therapy in patients with elevated LDL-C levels before further atherosclerotic progression leads to clinical events.
  • Atherosclerotic regression is most likely to occur in patients who have attained low LDL-C levels and who have also increased their high-density lipoprotein cholesterol (HDL-C).

 

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 hypercholesterolemiais 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%).10Figure 1depicts 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

The atherosclerotic process
Atherosclerosis is a gradual, lifelong disease that can begin in childhood or adolescence, although symptoms typically develop later in life. It is caused by the interplay between the accumulation of cholesterol-rich lipids within the arterial wall, oxidative stress, and chronic inflammation. In the initiating step of atherosclerosis, modified or oxidized low-density lipoprotein (LDL) particles damage the endothelium, a thin layer of cells lining the interior of the arterial wall. This initial injury triggers an inflammatory and immune response with increased production of chemoattractant molecules, cytokines, and cell adhesion molecules (Figure A). As a result, the endothelium becomes more adherent and permeable to circulating monocytes and T-lymphocytes, and it acquires increased thrombotic and vasoactive properties.  Monocytes that adhere to the surface of endothelial cells are transported into the arterial wall, where they are converted into macrophages. Activated macrophages and leukocytes then release a variety of mediators that collectively increase inflammation and oxidative stress within the vessel wall.a

Figure A: Inflammation and the development of the atherosclerotic plaque

HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.

Fatty streaks are formed when macrophages ingest oxidized LDL and become foam cells, filled with lipid. As atherosclerosis develops, fatty streaks evolve into mature plaques with lipid-rich necrotic cores encased by a weakened fibrous cap (Figure B). The atherosclerotic process can be accelerated by several comorbid conditions and risk factors, such as hypercholesterolemia, hypertension, tobacco smoking, diabetes, obesity, and aging, which promote atherosclerosis through their effects on cholesterol levels and vascular inflammation. Over time, some atherosclerotic plaques may grow larger, causing stenosis of the major arteries. Other plaques are not critically stenotic but become unstable, most likely due to inflammation, and they may ultimately rupture, causing arterial thrombosis and acute coronary events (Figure B).

Figure B: Rupture of the atherosclerotic plaque leading to thrombosis


 
Reference
a.) Libby A, et al. J Am Coll Cardiol. 2006;48(9 suppl A):A33-A46.

Figure 1 Least-squares mean percentage change from baseline in LDL-C, HDL-C, and triglycerides with 10-mg statin doses from the STELLAR trial


*Significantly (P<.002) different versus rosuvastatin 10 mg.
HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; STELLAR, Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin.
Adapted from Jones PH, et al. Am J Cardiol. 2003;92:152-160.

Figure 2 Least-squares mean percentage change from baseline in LDL-C with statin doses from the STELLAR trial

LDL-C, low-density lipoprotein cholesterol; STELLAR, Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin

Least-squares mean percentage change from baseline in low-density lipoprotein cholesterol (LDL-C) with statin doses from the STELLAR trial.  In 22 pair-wise comparisons, rosuvastatin was significantly different (P < .002) versus equivalent or higher doses of comparators using an analysis of variance.
Reprinted from Lewis SJ. Am J Med. 2009;122(suppl 1A):s38-s50. Copyright 2009 with permission from Elsevier.

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) .

Acknowledgments
The author would like to acknowledge the editorial and medical illustration assistance of Jennifer Moon, PhD, and the Editorial Office of the Dean, Weill Cornell Medical College, which received funding from AstraZeneca to help in the preparation of this e-newsletter.

Disclosures
Dr Gotto is a consultant for AstraZeneca, KOWA Pharmaceuticals America, Inc., Merck & Co., Inc., and Roche Pharmaceuticals, and he is on advisory boards for DuPont and Novartis Pharmaceuticals Corp. He serves on corporate boards for Aegerion Pharmaceuticals, Inc, Arisaph Pharmaceuticals, Inc., and Vatera Capital LLC.

References

  1. Libby P, Ridker PM. Inflammation and atherothrombosis: from population biology and bench research to clinical ractice. J Am Coll Cardiol. 2006;48(9 Suppl A):A33-46.
  2. Rosamond W, Flegal K, Furie K, Go A, Greenlund K, et al. Heart Disease and Stroke Statistics 2008 Update: A Report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2008;117:e25-e146.
  3. Ford ES, Ajani UA, Croft JB, Critchley JA, Labarthe DR, et al. Explaining the decrease in U.S. deaths from coronary disease, 1980-2000. N Engl J Med. 2007;356:2388-2398.
  4. Grundy SM, Cleeman JI, Merz CNB, Brewer HB, Clark LT, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227-239.
  5. Ohashi R, Mu H, Wang X, Yao Q, Chen C. Reverse cholesterol transport and cholesterol efflux in atherosclerosis. QJM 2005; 98(12):845-856.
  6. Ibanez B, Vilahur G, Badimon JJ. Plaque progression and regression in atherothrombosis. J Thromb Haemost. 2007;5(Suppl 1):292-299.
  7. Miller M. High-density lipoprotein cholesterol in coronary heart disease risk assessment. In Ballantyne C, ed. Clinical Lipidology: A Companion to Braunwald's Heart Disease. Philadelphia: Saunders, 2009:119-129.
  8. Fruchart JC, Sacks F, Hermans MP, Assmann G, Brown WV, et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in patients with dyslipidemia. Am J Cardiol. 2008;102(10 Suppl):1K-34K.
  9. Brown BG, Zhao XQ, Sacco DE, et al. Lipid lowering and plaque regression. New insights into prevention of plaque disruption and clinical events in coronary disease. Circulation. 1993;87:1781-1791.
  10. Gotto AM. Contemporary Diagnosis and Management of Lipid Disorders. 4th ed. Newtown, PA: Handbooks in Health Care, 2008.
  11. Jones PH, Davidson MH, Stein EA, et al. Comparison of the efficacy of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR trial). Am J Cardiol. 2003;92:152-160.
  12. McKenney JM, Jones PH, Adamczyk MA, et al. Comparison of the efficacy of rosuvastatin versus atorvastatin, simvastatin, and pravastatin in achieving lipid goals: results from the STELLAR trial. Curr Med Res Opin. 2003;19:689-698.
  13. Armitage J. The safety of statins in clinical practice. Lancet 2007;370(9601):1781-90.
  14. Lee SH, Chung N, Kwan J, Kim DI, Kim WH, Kim CJ, et al. Comparison of the efficacy and tolerability of pitavastatin and atorvastatin: an 8-week, multicenter, randomized, open-label, dose-titration study in Korean patients with hypercholesterolemia. Clin Ther. 2007;29(11):2365-73.
  15. Ridker PM, Danielson E, Fonseca FAH, Genest J, Gotto AM Jr, Kastelein JJP, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ, for the JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195-2207.
  16. Waters D, Higginson L, Gladstone P, Boccuzzi SJ, Cook T, Lespérance J. Effects of cholesterol lowering on the progression of coronary atherosclerosis in women. A Canadian Coronary Atherosclerosis Intervention Trial (CCAIT) substudy. Circulation. 1995;92:2404-2410.
  17. Blankenhorn DH, Azen SP, Kramsch DM, Mack WJ, Cashin-Hemphill L, Hodis HN, DeBoer LW, Mahrer PR, Masteller MJ, Vailas LI, Alaupovic P, Hirsch LJ, MARS Research Group. Coronary angiographic changes with lovastatin therapy. The Monitored Atherosclerosis Regression Study (MARS). Ann Intern Med. 1993;119:969-976.
  18. Brown G, Albers JJ, Fisher LD, Schaefer SM, Lin JT, Kaplan C, Zhao XQ, Bisson BD, Fitzpatrick VF, Dodge HT. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med.19908;323:1289-1298.
  19. Herd JA, Ballantyne CM, Farmer JA, Ferguson JJ 3rd, Jones PH, West MS, Gould KL, Gotto AM Jr. Effects of fluvastatin on coronary atherosclerosis in patients with mild to moderate cholesterol elevations (Lipoprotein and Coronary Atherosclerosis Study [LCAS]). Am J Cardiol. 1997;80:278-286.
  20. Pitt B, Mancini GB, Ellis SG, Rosman HS, Park JS, McGovern ME. Pravastatin limitation of atherosclerosis in the coronary arteries (PLAC I): reduction in atherosclerosis progression and clinical events. PLAC I investigation. J Am Coll Cardiol. 1995;26:1133-1139.
  21. de Groot E, Jukema JW, van Boven AJ, Reiber JH, Zwinderman AH, Lie KI, Ackerstaff RA, Bruschke AV. Effect of pravastatin on progression and regression of coronary atherosclerosis and vessel wall changes in carotid and femoral arteries: a report from the Regression Growth Evaluation Statin Study. Am J Cardiol. 1995;76:40C-46C.
  22. Raggi P, Taylor A, Fayad Z, et al. Atherosclerotic plaque imaging: contemporary role in preventive cardiology. Arch Intern Med. 2005;165:2345-2353.
  23. Temple R. Are surrogate markers adequate to assess cardiovascular disease drugs? JAMA. 1999;282:790-795.
  24. Corti R, Fayad ZA, Fuster V, Worthley SG, Helft G, Chesebro J, Mercuri M, Badimon JJ. Effects of lipid-lowering by simvastatin on human atherosclerotic lesions: a longitudinal study by high-resolution, noninvasive magnetic resonance imaging. Circulation. 2001;104:249-252.
  25. Underhill HR, Yuan C, Zhao X-Q, et al. Effect of rosuvastatin therapy on carotid plaque morphology and composition in moderately hypercholesterolemic patients: a high-resolution magnet resonance imaging trial. Am Heart J. 2008;155:584.e1-584.e8.
  26. Crouse JR III, Raichlen JS, Riley WA, et al, for the METEOR study group. Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR trial. JAMA. 2007;297:1344-1353.
  27. Nissen SE, Tuzcu EM, Schoenhagen P, et al, for the REVERSAL Investigators. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291:1071-1080.
  28. Nissen SE, Nicholls SJ, Sipahi I, et al, for the ASTEROID investigators. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. 2006;295:1556-1565.
  29. Nicholls SJ, Tuzcu EM, Sipahi I, et al. Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis. JAMA. 2007;297:499-508.
  

 

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

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

Clinical implications for treating atherosclerosis

  • In the United States, atherosclerosis causes three-fourths of all cardiovascular deaths, but controlling hypercholesterolemia can greatly reduce cardiovascular risk.
  • Statins can significantly improve a patient’s lipid profile, primarily by reducing levels of low-density lipoprotein cholesterol
    (LDL-C).
  • Studies incorporating various imaging techniques indicate that it is possible to slow, halt, or reverse the progression of atherosclerosis with statin therapy.
  • It is important to initiate statin therapy in patients with elevated LDL-C levels before further atherosclerotic progression leads to clinical events.
  • Atherosclerotic regression is most likely to occur in patients who have attained low LDL-C levels and who have also increased their high-density lipoprotein cholesterol (HDL-C).

 

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 hypercholesterolemiais 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%).10Figure 1depicts 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

The atherosclerotic process
Atherosclerosis is a gradual, lifelong disease that can begin in childhood or adolescence, although symptoms typically develop later in life. It is caused by the interplay between the accumulation of cholesterol-rich lipids within the arterial wall, oxidative stress, and chronic inflammation. In the initiating step of atherosclerosis, modified or oxidized low-density lipoprotein (LDL) particles damage the endothelium, a thin layer of cells lining the interior of the arterial wall. This initial injury triggers an inflammatory and immune response with increased production of chemoattractant molecules, cytokines, and cell adhesion molecules (Figure A). As a result, the endothelium becomes more adherent and permeable to circulating monocytes and T-lymphocytes, and it acquires increased thrombotic and vasoactive properties.  Monocytes that adhere to the surface of endothelial cells are transported into the arterial wall, where they are converted into macrophages. Activated macrophages and leukocytes then release a variety of mediators that collectively increase inflammation and oxidative stress within the vessel wall.a

Figure A: Inflammation and the development of the atherosclerotic plaque

HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.

Fatty streaks are formed when macrophages ingest oxidized LDL and become foam cells, filled with lipid. As atherosclerosis develops, fatty streaks evolve into mature plaques with lipid-rich necrotic cores encased by a weakened fibrous cap (Figure B). The atherosclerotic process can be accelerated by several comorbid conditions and risk factors, such as hypercholesterolemia, hypertension, tobacco smoking, diabetes, obesity, and aging, which promote atherosclerosis through their effects on cholesterol levels and vascular inflammation. Over time, some atherosclerotic plaques may grow larger, causing stenosis of the major arteries. Other plaques are not critically stenotic but become unstable, most likely due to inflammation, and they may ultimately rupture, causing arterial thrombosis and acute coronary events (Figure B).

Figure B: Rupture of the atherosclerotic plaque leading to thrombosis


 
Reference
a.) Libby A, et al. J Am Coll Cardiol. 2006;48(9 suppl A):A33-A46.

Figure 1 Least-squares mean percentage change from baseline in LDL-C, HDL-C, and triglycerides with 10-mg statin doses from the STELLAR trial


*Significantly (P<.002) different versus rosuvastatin 10 mg.
HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; STELLAR, Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin.
Adapted from Jones PH, et al. Am J Cardiol. 2003;92:152-160.

Figure 2 Least-squares mean percentage change from baseline in LDL-C with statin doses from the STELLAR trial

LDL-C, low-density lipoprotein cholesterol; STELLAR, Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin

Least-squares mean percentage change from baseline in low-density lipoprotein cholesterol (LDL-C) with statin doses from the STELLAR trial.  In 22 pair-wise comparisons, rosuvastatin was significantly different (P < .002) versus equivalent or higher doses of comparators using an analysis of variance.
Reprinted from Lewis SJ. Am J Med. 2009;122(suppl 1A):s38-s50. Copyright 2009 with permission from Elsevier.

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) .

Acknowledgments
The author would like to acknowledge the editorial and medical illustration assistance of Jennifer Moon, PhD, and the Editorial Office of the Dean, Weill Cornell Medical College, which received funding from AstraZeneca to help in the preparation of this e-newsletter.

Disclosures
Dr Gotto is a consultant for AstraZeneca, KOWA Pharmaceuticals America, Inc., Merck & Co., Inc., and Roche Pharmaceuticals, and he is on advisory boards for DuPont and Novartis Pharmaceuticals Corp. He serves on corporate boards for Aegerion Pharmaceuticals, Inc, Arisaph Pharmaceuticals, Inc., and Vatera Capital LLC.

References

  1. Libby P, Ridker PM. Inflammation and atherothrombosis: from population biology and bench research to clinical ractice. J Am Coll Cardiol. 2006;48(9 Suppl A):A33-46.
  2. Rosamond W, Flegal K, Furie K, Go A, Greenlund K, et al. Heart Disease and Stroke Statistics 2008 Update: A Report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2008;117:e25-e146.
  3. Ford ES, Ajani UA, Croft JB, Critchley JA, Labarthe DR, et al. Explaining the decrease in U.S. deaths from coronary disease, 1980-2000. N Engl J Med. 2007;356:2388-2398.
  4. Grundy SM, Cleeman JI, Merz CNB, Brewer HB, Clark LT, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227-239.
  5. Ohashi R, Mu H, Wang X, Yao Q, Chen C. Reverse cholesterol transport and cholesterol efflux in atherosclerosis. QJM 2005; 98(12):845-856.
  6. Ibanez B, Vilahur G, Badimon JJ. Plaque progression and regression in atherothrombosis. J Thromb Haemost. 2007;5(Suppl 1):292-299.
  7. Miller M. High-density lipoprotein cholesterol in coronary heart disease risk assessment. In Ballantyne C, ed. Clinical Lipidology: A Companion to Braunwald's Heart Disease. Philadelphia: Saunders, 2009:119-129.
  8. Fruchart JC, Sacks F, Hermans MP, Assmann G, Brown WV, et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in patients with dyslipidemia. Am J Cardiol. 2008;102(10 Suppl):1K-34K.
  9. Brown BG, Zhao XQ, Sacco DE, et al. Lipid lowering and plaque regression. New insights into prevention of plaque disruption and clinical events in coronary disease. Circulation. 1993;87:1781-1791.
  10. Gotto AM. Contemporary Diagnosis and Management of Lipid Disorders. 4th ed. Newtown, PA: Handbooks in Health Care, 2008.
  11. Jones PH, Davidson MH, Stein EA, et al. Comparison of the efficacy of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR trial). Am J Cardiol. 2003;92:152-160.
  12. McKenney JM, Jones PH, Adamczyk MA, et al. Comparison of the efficacy of rosuvastatin versus atorvastatin, simvastatin, and pravastatin in achieving lipid goals: results from the STELLAR trial. Curr Med Res Opin. 2003;19:689-698.
  13. Armitage J. The safety of statins in clinical practice. Lancet 2007;370(9601):1781-90.
  14. Lee SH, Chung N, Kwan J, Kim DI, Kim WH, Kim CJ, et al. Comparison of the efficacy and tolerability of pitavastatin and atorvastatin: an 8-week, multicenter, randomized, open-label, dose-titration study in Korean patients with hypercholesterolemia. Clin Ther. 2007;29(11):2365-73.
  15. Ridker PM, Danielson E, Fonseca FAH, Genest J, Gotto AM Jr, Kastelein JJP, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ, for the JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195-2207.
  16. Waters D, Higginson L, Gladstone P, Boccuzzi SJ, Cook T, Lespérance J. Effects of cholesterol lowering on the progression of coronary atherosclerosis in women. A Canadian Coronary Atherosclerosis Intervention Trial (CCAIT) substudy. Circulation. 1995;92:2404-2410.
  17. Blankenhorn DH, Azen SP, Kramsch DM, Mack WJ, Cashin-Hemphill L, Hodis HN, DeBoer LW, Mahrer PR, Masteller MJ, Vailas LI, Alaupovic P, Hirsch LJ, MARS Research Group. Coronary angiographic changes with lovastatin therapy. The Monitored Atherosclerosis Regression Study (MARS). Ann Intern Med. 1993;119:969-976.
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Statin therapy: New data suggest effects on plaque volume and stability
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