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.

Keywords: Cholesterol; Genetics; LDL; Lipoproteins; PCSK9.

Fig. 1.

Clinical course of brothers with compound heterozygous FH A. Clinical course of older brother Picture of buttocks with huge xanthoma is illustrated on the left. Clinical course is illustrated in the middle. Blue line indicates total cholesterol level (mg/dl). Images obtained through intravascular ultrasound are illustrated in the right. B. Clinical course of younger brother Picture of buttocks with small xanthoma is illustrated on the left. Clinical course is illustrated in the middle. Blue line indicates total cholesterol level (mg/dl). Images obtained through intravascular ultrasound are illustrated in the right. UAP: unstable angina pectoris; CAG: coronary artery disease; PCI: percutaneous coronary intervention

Fig. 2.

Images of coronary computed tomography and carotid ultrasound in a patient with ABL A. Coronary computed tomography obtained in a patient with ABL. There are no stenotic lesions nor any calcifications identified in coronary arteries. B. Carotid ultrasound image obtained in a patient with ABL. There are no stenotic lesions or intima-media thickness in right common carotid artery. C. Carotid ultrasound image obtained in a patient with ABL. There are no stenotic lesions or intima-media thickness in left common carotid artery. ABL, abetalipoproteinemia; RCA, right coronary artery; LAD, Left anterior descending coronary artery; LCX, Left circumflex coronary artery

Fig. 3.

Precision medicine for FH When we encounter an individual whose LDL cholesterol level is ≥ 180 mg/dl, then we have to consider a clinical as well as genetic diagnosis of FH. Additionally, additional risk stratification can be considered based on their common genetic variations, and their imaging. According to this information, we can select the best approach for their LDL cholesterol reduction. FH: familial hypercholesterolemia; SNV: single nucleotide variation