The Low-density Lipoprotein Cholesterol Cholesterol Verdict - Lower is Better

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The debate among cardiologists over whether ‘lower is better’ with regards to serum levels of low-density lipoprotein cholesterol (LDL-C) has raged for years. Three recently completed statin trials – REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering), PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Prevention and Infection Therapy- Thrombolysis in Myocardial Infarction 22) and ALLIANCE (Aggressive Lipid Lowering Initiation Abates New Cardiac Events) – have provided unambiguous evidence that LDL-C levels substantially lower than 100mg/dL (2.6 mmol/L) are associated with a reduced risk of cardiovascular events and with plaque regression, particularly in patients with pre-existing heart disease. The findings from these benchmark studies will likely lead to a re-evaluation of existing cholesterol guidelines and prompt more aggressive management of patients with atherosclerotic disease. To this end, the use of the more efficacious statins in clinical practice holds promise for yielding greater LDL-C reductions in patients with coronary heart disease risk factors and facilitating achievement of lipid targets while minimising the occurrence of adverse events.


The debate among cardiologists over whether ‘lower is better’ with regards to serum levels of LDL-C has raged for years. Some investigators have argued that there is a threshold below which further LDL-C reductions will provide no added benefit, while others have maintained that such a cut-off point, if it does exist, lies far below current National Cholesterol Education Program (NCEP)1 or Joint European2 treatment targets. While 2002’s landmark Heart Protection Study3 suggested that there was no threshold for benefit from lowering LDL-C in individuals with baseline levels in the ‘normal’ range (<120mg/dL [3.1mmol/L]), the overall concept awaited definitive proof. Now, three recently completed statin trials have provided the evidence to reach a verdict and finally put the debate to rest: lower LDL-C is indeed better, particularly in patients with pre-existing heart disease. The findings from these benchmark studies will likely lead to a reevaluation of existing cholesterol guidelines and prompt substantial changes in the management of patients with atherosclerotic disease.

Atherosclerosis Progression After Intensive Lipid Lowering├é┬á – The REVERSAL Trial
REVERSAL4 was the first large, randomised trial to compare the rate of coronary artery disease progression associated with two distinct statin regimens. This imaging study used intravascular ultrasound (IVUS) to measure plaque progression in 502 patients with stable coronary disease treated either with a moderate LDL-C-lowering regimen (40mg pravastatin daily) or an intensive regimen (80mg atorvastatin daily). After 18 months of treatment, high-dose atorvastatin was shown to reduce the primary end-point, atheroma volume, by a mean of 0.4%, compared with an increase of 2.7% in the pravastatin group (p = 0.02). LDL-C levels, which averaged 150.2mg/dL (3.9mmol/L) at baseline, were lowered to a mean of 110mg/dL (2.8mmol/L) in the pravastatin 40mg group, compared with 79mg/dL (2.0mmol/L) among atorvastatin 80mg recipients (p < 0.001). The authors suggested that LDL-C lowering alone could not explain the superior outcome in the atorvastatin group, and that other factors (e.g. reductions in levels of triglycerides and/or C-reactive protein [CRP]) may have played a contributing role.

Figure 1: Comparison of Percentage of LDL-C Reduction and Change in Atheroma Volume in the REVERSAL Trial


The solid line indicates the relationship between mean change in LDL-C and change in atheroma volume from linear regression analysis; the dashed lines indicate the upper and lower 95% confidence limits for the mean values. Adapted with permission from Nissen et al.4



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