LDL lowering and atherosclerosis

To prepare the ground for our argument, we need to revisit the biology of atherogenesis. Plaque development in the vessel wall depends always on the accumulation of lipid material in the subendothelial space, a phenomenon that directly or indirectly triggers all other aspects of lesion growth, including macrophage recruitment, foam cell formation, and the inflammatory response in the artery wall. After more than 90 years of studies on atherosclerosis, it is clear that the pathology of the lesion is dependent on cholesterol accumulation, and that no alternative pathways to the initiation of atherogenesis are in place [17,18]. This means that, even in subjects whose main CHD risk factors are not related to lipids, the atherogenic pressures are translated into a 'permissive' environment that allows lipid accumulation in the vessel wall. In other words, a diabetic hypertensive patient with a LDL level of 115 mg/dl and a HDL level of 34 mg/dl has increased risk because insulin resistance, hyperglycemia, and high blood pressure affect the endothelium, the intima, and the rest of the vessel wall so that the environment becomes permissive for lipid deposition, which initiates the atherosclerotic process. In this scenario, lowering LDL and raising HDL are clinically beneficial because they affect the plasma and tissue concentration of the 'initiators' of atherogenesis even if the 'permissive' factors are not modified. This hypothesis finds support in the data of clinical trials such as the United Kingdom Prospective Diabetes Study (UKPDS) [19,20], the Scandinavian Simavastatin Survival Study (4S) [21,22], the Cholesterol and Associated Events (CARE) study [7], or the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) study [23], which together show that the strongest intervention to reduce the risk of heart attacks in diabetics may not be an improved glucose control or a more aggressive lowering of blood pressure, but rather a LDL reduction of 28-38%. The advantage of LDL lowering applies to the most common high risk phenotypes, because one of the most striking results of the major statin trials is the larger clinical benefits observed in individuals who have other risk factors in addition to the hypercholesterolemia (ie pre-existing CHD, smoking, hypertension, diabetes, or family history of CHD). Statins may, in this line of thinking, be seen as anti-atherogenic agents that will impact on the overall CHD risk even when the LDL component of the risk profile is not the most prominent problem in the patient.

LDL goals in high risk patients

This information brings us to the central point of our argument; that is, the most important objective in LDL lowering for high risk patients is the percentage change from baseline rather than the reaching of any predefined on-treatment goal. This view is corroborated by a large amount of clinical trial data showing, first, that on-treatment LDL levels do not predict CHD rates whereas baseline LDL levels do [24]. Second, the correlation between LDL reduction and CHD risk reduction within each study is at best curvilinear even in high risk, high cholesterol populations where the average on-treatment LDL is still significantly distant from the NCEP goal of 100 mg/dl [10]. Finally, the same percentage LDL reduction appears to be more effective in subjects with higher baseline LDL (and whose on-treatment LDL stays higher than 100 mg/dl) compared with those with a lower baseline LDL (and whose on-treatment LDL adjusts below 100 mg/dl) [7,21,25]. With regard to the last point, Cullen and Assmann propose the scenario in which higher doses of statins would be needed in high risk patients with 'average cholesterol' rather than in average risk patients with high cholesterol [26]. Since statin treatment produces the same relative reduction in cholesterol levels irrespective of baseline concentrations, it follows that to accomplish the same absolute reduction in cholesterol (eg 40 mg/dl), more aggressive intervention must be given to produce a cholesterol decrease from 200 to 160 mg/dl (20% reduction) than to decrease it from 260 to 220 mg/dl (15% reduction). It is interesting to note that when the correlation between LDL reduction and coronary events is analyzed on a large scale, including statin and non-statin trials, less additional clinical benefits are expected from cholesterol reductions larger than 15%, indicating that this relationship is governed by a law of diminishing returns [15,27]. Considering that each doubling of statin dose reduces LDL only by an additional 6-7% [28,29], the cost-effectiveness of high dose statin treatment in the long-term care of patients with common hypercholesterolemia remains to be evaluated. On the contrary, it is clear that high risk patients with high cholesterol (eg subjects with familial hypercholesterolemia) should be treated with the most aggressive regimens available and that they represent the best targets for the new 'superstatins' now in the experimental phase, which can reportedly reduce LDL cholesterol approximately 65-70% [30].