Cholesterol attached to LDL particles leaves the liver to be transported in the bloodstream to tissues throughout the body. Along the way, this is expected to contribute to development of atherosclerosis in blood vessel walls via deposition of excessive cholesterol in some locations. Patients with homozygous familial hypercholesterolemia, who exhibit loss of function mutations in the LDL receptor and enormously elevated LDL cholesterol in blood, demonstrate that past a certain point there is a dramatic acceleration of atherosclerosis resulting from too much transported cholesterol. Untreated, these patients typically die in their 30s from heart attack or stroke.
What about the rest of the population with a more normal varied range of LDL cholesterol levels, however? The consensus on lowering LDL cholesterol as the dominant approach to reduce atherosclerotic cardiovascular disease risk is not without its challengers. Physicians note that most of the aged patients who present with a first heart attack or stroke do not have elevated LDL cholesterol. Epidemiologists note that the data suggests that the mechanisms of atherosclerosis vary considerably across the population. People respond very differently to cholesterol levels and pharmacological strategies to reduce them. This is one of the reasons why very large trials are needed to see effect sizes resulting from lowered LDL cholesterol.
Today’s open access paper is an example of the body of literature that challenges the consensus on the practice of setting targets for LDL cholesterol levels, and the relevance of LDL cholesterol to disease. A reasonable view of the situation is that some fraction of the population does suffer when LDL cholesterol is too high, and thus does benefit from the therapeutic strategy of lowering LDL cholesterol – but at present there is no good way to identify in advance whether any given individual is in that group. The underlying biochemistry is not fully understood, and outcomes arise only slowly over time, a situation in which producing greater understanding is necessarily expensive, and thus few groups are willing to make the effort.
Over the past two decades, the strategy for managing cardiovascular disease (CVD) risk with lipid-lowering therapy has changed significantly. LDL-cholesterol (LDL-C) targets in guidelines have been progressively lowered from 100 mg/dL (2.6 mmol/L) or less to 70 mg/dL (1.8 mmol/L) or less for high-risk patients and 55 mg/dL (1.4 mmol/L) or less for very high-risk patients. The reduction in target LDL-C levels was stated as justified based on the appearance that intensive lipid-lowering therapy offered additional cardiovascular benefits compared to the standard regimens.
The establishment of low LDL-C targets in CVD prevention was based on the premise that there is a linear relationship between LDL-C levels and CVD risk. However, this premise faces several challenges: (1) The supposed direct correlation between LDL-C levels and atherosclerosis progression is questionable; (2) The systematic reviews that provided the foundation for this assumption have several limitations, including extrapolation of results for LDL-C levels beyond observed data; (3) Potential bias due to the ecological fallacy stemming from meta-regression results based on study-level rather than patient-level analyses; (4) Inconsistent findings from trials specifically designed to investigate the relationship between LDL-C targets and CVD risk; (5) Research documenting greater longevity of elderly individuals with familial – as well as non-familial – hypercholesterolemia contradicts the premise that lower LDL-C levels are ideal.
In this paper, we address these challenges point by point, providing evidence to support each argument. We also point out that LDL-C is a hybrid measure composed of heterogeneous particles, with varying atherogenicity depending on the size of the particles. Finally, we address evidence that pleiotropic effects of lipid-lowering therapies, particularly statins, may contribute to cardiovascular benefits, independent of LDL-C reduction. This paper, therefore, presents evidence to challenge current LDL-C targets of 70 mg/dL or less in patients at high CVD risk.
