Low-Density Lipoprotein Cholesterol Level cannot be too Low: Considerations from Clinical Trials, Human Genetics, and Biology

LDL cholesterol is by far the best established “causal” cardiovascular risk. It is distributed normally, and the mean value ranges around 100∼120 mg/dl. In terms of preventive cardiology, we now know very well that the lower the LDL cholesterol, the better. Clinical usefulness of aggressive LDL-lowering therapies using statin, ezetimibe, and proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors have been shown in primary and in secondary prevention settings. Additionally, the idea, based on recent randomized controlled trials (RCT), that the lower LDL cholesterol the better appears to be true for LDL as low as ∼ 30 mg/dl. According to those data, recent guidelines in Europe and in Japan suggest the lowering of LDL cholesterol level < 70 mg/dl for high-risk patients. However, the attainment rates of such “strict” goals seem to be quite low, probably because most cardiologists still have a sense of anxiety of “low” LDL cholesterol level. But “low” indicates no more than “lower” than the “average” range, which is not always implying the optimal range. Additionally, Mendelian randomization studies focusing on individuals exhibiting “low” LDL cholesterol suggest that “normal” LDL cholesterol levels might be too much for us. Moreover, LDL cholesterol levels of other primates are substantially lower than those in humans. In this review article, based on a series of evidence from clinical trials, human genetics, and biology, we provide the idea that we need to rethink what is the optimal range of LDL cholesterol level, instead of “normal” or “average” range.