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THE EFFECT OF ELEVATED LDL LEVELS ON CARDIOVASCULAR DISEASE
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States; it accounts for approximately 75% of deaths among the general population.1 Consequently, the modification of risk factors for cardiovascular disease has become an essential tool in the prevention of CVD. The preeminent role of elevated low-density lipoprotein (LDL) cholesterol levels in the pathogenesis of CVD has emerged from many clinical trials.2,3,4 More evidence is available in the area of cardiovascular protection by statins than in any other area of modern medicine. During the past decade, almost 80,000 patients have participated in randomized, double-blind, placebo-controlled clinical trials that have confirmed the protective benefit of lowering LDL levels with statins. This newsletter reviews the major clinical trials that have contributed to the wider understanding of the importance of LDL levels in the development of atherosclerotic disease.
RECENT CLINICAL TRIALS
The major divergence of the National Cholesterol Education Program’s Adult Treatment Panel III (ATP III) from ATP II is the emphasis of an elevated LDL level as the primary target of cholesterol management, in addition to newer targets for persons with multiple risk factors.5 Evidence that stringent lipid control results in improved cardiovascular outcomes has led to aggressive lipid level goals. Since the publication of ATP III, many major clinical trials with statin therapy have been published, including the Heart Protection Study (HPS),6 the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER),7 Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT),8 Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA),9 the Pravastatin or Atorvastatin Evaluation and Infection–Thrombolysis in Myocardial Infarction 22 trial (PROVE IT-TIMI 22),10 and the Treating to New Targets trial (TNT).11 With the exception of the ALLHAT-LLT trial, all of these trials demonstrate the effect of LDL level reduction on substantial reduction of CVD risk. More detailed descriptions of these trials can be found in eMedicine’s Lipid Feature Series 1, Issue 13.
Atherosclerosis improvements and regression: Benefits of low LDL levels
Mounting evidence indicates that statin therapy slows the progression of atherosclerosis and can induce the regression of atherosclerotic lesions. Some illustrative trials are reviewed here. A direct relationship exists between LDL level and changes in carotid intima-media thickness (CIMT) and plaque size.12,13 Kent et al demonstrated that lower LDL levels were associated with regression of CIMT. Sixty-one percent of patients who achieved the target LDL level (<70 mg/dL) showed regression of CIMT compared with only 29% of patients with LDL levels higher than 114 mg/dL.12
More recently, the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) study14 randomized 654 patients with previous history of coronary artery disease (CAD) to moderate lipid-lowering with pravastatin 40 mg/d or intensive treatment with atorvastatin 80 mg/d. Intravascular ultrasound (IVUS) was performed during baseline catheterization and repeated after 18 months of treatment. Efficacy parameters included changes in atheroma burden (as determined by IVUS), lipoprotein levels, and C-reactive protein (CRP) levels. Serum LDL levels were reduced from 150.2 mg/dL to 110 mg/dL in the moderate treatment group and to 79 mg/dL in the intensive treatment arm. Changes in atheroma burden showed a significantly lower progression rate in the intensive arm for all the 3 prespecified IVUS efficacy measures, while progression occurred in the moderate treatment cohort. However, plaque volume was unchanged in the intensive arm, indicating absence of progression.
The German Atorvastatin Intravascular Ultrasound Investigators (GAIN) showed that the greater reduction in LDL levels with intensive therapy also resulted in a smaller increase in plaque volume.15 After a 12-month follow-up period for 131 patients, atorvastatin reduced the progression of the plaque volume.
Both the REVERSAL and GAIN trials demonstrate that the magnitude of the LDL level reduction appears to be important.
Relationship of serum LDL concentrations to CHD risk: Lower is better
Clinical trials of statin therapy have confirmed the log-linear (curvilinear) relationship between LDL levels and CHD risk.16 Therefore, at any given LDL level, for a given milligram per deciliter change in the LDL level, the CHD relative risk change is the same as it would be at any other LDL level. This relationship has important clinical implications, especially for patients who may have low LDL levels but still have a relatively high absolute risk because of the presence of other CHD risk factors. These patients may benefit from further reductions in LDL levels.
The log-linear relationship between LDL levels and CHD risk was also supported by the HPS. This large, randomized, double-blind trial included 20,536 subjects. The results showed a consistent and early benefit of statin therapy in patients with CHD, including those with LDL levels lower than 116 mg/dL. The results suggest that reducing the LDL level from the baseline levels, even if they were relatively low at the start, further decreased the risk of CHD. Until this study, clinical trials had identified threshold LDL levels below which no further benefit of CHD risk occurred.
Regression trials, as described above, also confirm that the magnitude of the LDL level reduction and the absolute value of LDL remain important. Currently, several ongoing trials with simvastatin and rosuvastatin will hopefully elucidate whether aggressive LDL level reduction translates to slower progression of atherosclerosis and related events.
CONCLUSION
In the past decade, the understanding that an elevated LDL level is a prominent risk factor for CVD has generally been well recognized but has not yet been effectively translated into clinical practice. To combat the ever-increasing rates of CVD events, goals for the control of lipid levels and other risk factors must be achieved through the aggressive use of lifestyle modifications and appropriate medications. As more is learned about the underlying pathobiology of atherosclerosis, clinicians will better learn whether to aim for a specific percentage reduction in LDL level or to base treatment decisions on clinical risk level. Because the development of atherosclerosis is multifactorial and generally starts long before the development of the clinically evident disease, a global approach to CVD risk factor reduction is mandated in all patients; the ultimate target is CVD event reduction.
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