Review
Safety and Effect of Very Low Levels of Low-Density Lipoprotein Cholesterol on Cardiovascular Events

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Based on the cardiovascular (CV) outcomes data derived predominantly from 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (statin) trials, guidelines have set low-density lipoprotein (LDL) cholesterol targets at successively lower levels over time. Recent data have demonstrated that more-intensive statin therapy (and, consequently, lower LDL cholesterol level) is more effective at reducing CV events than less-intensive statin therapy. Although the average LDL cholesterol level for a United States adult is 119 mg/dl, within the “normal” range (90 to 130 mg/dl) per the United States National Cholesterol Education Program–Adult Treatment Panel III guidelines, data from fetal studies, diet studies, contemporary hunter-gatherer populations, and other mammals have suggested that the “normal” physiologic range for LDL cholesterol in humans is likely 50 to 70 mg/dl. Low LDL cholesterol levels have been sporadically associated with an increased risk of cancer, hemorrhagic stroke, and other complications in population studies and clinical trials. However, statin clinical trials have generally not demonstrated correlations between on-treatment LDL cholesterol levels and safety. Clinical data have suggested a linear relation between LDL cholesterol lowering and CV risk reduction, supporting a favorable risk/benefit ratio for attaining very low levels of LDL cholesterol to minimize the risk of CV events. In conclusion, clinical trial evidence demonstrating the efficacy and safety of LDL cholesterol lowering to a very low level is essential to ascertain the benefits and risks in reducing the residual risk of vascular disease.

Section snippets

Human LDL Cholesterol Levels: Normal Versus Optimal

Data from the early period in life (from gestation to adolescence) and from populations that consume a non-Western diet have provided useful insight into what could be considered the “physiologic lipid levels” in humans. Total cholesterol and LDL cholesterol change as humans age (Table 1).10, 11, 12, 13, 14 During late gestation in utero, the total cholesterol and LDL cholesterol levels reach approximately 55 and 30 mg/dl, respectively, and these levels increase during breastfeeding.10, 11 A

Safety of Very Low LDL Cholesterol Levels

Although these observations generally support the safety of lower LDL cholesterol levels than specified in the current treatment guidelines from North America, Europe, and Australia/New Zealand, some epidemiologic and clinical trial data have led to concern that very low levels of LDL cholesterol might increase the risk of cancer,26, 27 hemorrhagic stroke,27, 28, 29 and non-CV death.7, 27

Data from the Framingham Study were used to examine the relation between lipoprotein levels and non-CHD

Effects of Very Low LDL Cholesterol Levels on CV Risk

The potential of LDL cholesterol reduction to reduce the risk of CV events has been clearly established in secondary prevention, placebo-controlled, statin trials.2, 4, 67, 68 Furthermore, data from more recent trials have favored more-intensive statin therapy instead of less-intensive therapy with respect to a reduction in CV events.7, 69 These findings demonstrate that lowering LDL cholesterol beyond current guidelines imparts incremental clinical benefit in high-risk patients. Studies of

Conclusion

Humans with very low levels of LDL cholesterol (e.g., those with certain forms of FHBL) are generally healthy and have a low risk of CV events. Although the risk of cancer death was greater among those who did not develop atherosclerosis compared to those who did, this was probably because those protected from atherosclerotic death will succumb to other diseases. Cancer risk was not increased in statin-treated subjects attaining a very low level of LDL cholesterol. Furthermore, on the basis of

Acknowledgment

We thank Rick Davis, MS, RPh, Complete Healthcare Communications, Chadds Ford, Pennsylvania (whose work was funded by Amgen, Inc.), and Meera Kodukulla, PhD, Amgen, Inc. (Thousand Oaks, California), for assistance with the writing of our report.

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