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

Abstract

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.

Challenges of Precision Medicine for Atherosclerotic Cardiovascular Disease Based on Human Genome Information

“…Accumulated evidence suggests that LDL cholesterollowering therapy may not need to be so intensive in patients who are diagnosed and start treatment at an early phase. In our experience, a homozygous FH patient whose LDL cholesterol level was not adequately lowered but who started treatment at 13 years of age had a better prognosis than his older brother, with nearly the same genetic and environmental background, who started his treatment at 23 years of age 39) . The patients' genetic status can help us to determine how and when to treat them.…”

Triglycerides on the Rise!

“…We already know that LDL cholesterol is one of the causal factors for cardiovascular disease (CVD) 1) . In fact, we are using statins, ezetimibe, and a PCSK9 inhibitor to achieve further reduction in LDL cholesterol, more than ever 1) .…”

“…We already know that LDL cholesterol is one of the causal factors for cardiovascular disease (CVD) 1) . In fact, we are using statins, ezetimibe, and a PCSK9 inhibitor to achieve further reduction in LDL cholesterol, more than ever 1) . On the other hand, serum triglycerides have also been suggested to be an important causal factor for CVD 2) ; however, awareness regarding this issue is still inadequate in local communities and in hospital settings 3) .…”

Familial Hypercholesterolemia: A Narrative Review on Diagnosis and Management Strategies for Children and Adolescents

“…Low-density lipoprotein (LDL) cholesterol has been identified as the causative factor for atherosclerotic cardiovascular disease (ASCVD) based on a variety of evidence obtained from epidemiology, 1 human pathology, 2 human genetics, 3 and clinical trials. 4–7 Familial hypercholesterolemia (FH), an inherited hyper-LDL cholesterolemia, has often been associated with tendon and cutaneous xanthomas and premature ASCVD.…”