Background: Low-density Lipoprotein Cholesterol (LDL-C) is a major Cardiovascular (CV) risk
factor. Accumulating evidence supports a linear association between LDL-C levels and CV risk. However, the
lower limit of LDL-C that might offer CV benefits without any safety concerns is still a topic of debate.
Objective: The purpose of this review is to present the safety of reducing LDL-C to low levels as it comes from
major lipid-lowering drug studies, and to discuss data on several safety events that have been associated with low
Methods: A comprehensive literature search was performed to identify available data from clinical studies evaluating
the association of low LDL-C with safety outcomes.
Results: Several large trials have evaluated the safety or reducing LDL-C to levels lower than 50 mg/dl or even
lower than 25 mg/dl, more commonly with the use of a combination of statins with ezetimibe or proprotein convertase
subtilisin kexin 9 inhibitors. In almost all trials, CV benefits were observed with LDL-C levels of 50
mg/dl or less compared with higher levels. In terms of safety, reduction of LDL-C to such levels was not associated
with any significant adverse event. Of importance, cancer and hemorrhagic stroke incidences were not increased
in patients attaining LDL-C lower than 40-50 mg/dl. Data regarding the impact of lowering LDL-C with
neurocognitive disorders are contradictory; nevertheless, most studies stand in favor of neurocognitive safety with
LDL-C reductions to low levels.
Conclusion: Achieving an LDL-C of 40-50 mg/dl seems to be safe, and importantly might offer CV beneficial
effects. Data for attaining levels below 25 mg/dl is limited, however in favor of such reductions.