Publish in this journal
Journal Information
Vol. 71. Issue 7.
Pages 591-592 (July 2018)
Download PDF
More article options
Vol. 71. Issue 7.
Pages 591-592 (July 2018)
Scientific letter
DOI: 10.1016/j.rec.2017.04.009
Full text access
The Zero-LDL Hypothesis. Towards Extremely Low LDL Concentrations
La hipótesis del LDL cero. Hacia concentraciones de LDL extremadamente bajas
Luis Masana
Unidad de Medicina Vascular y Metabolismo, Hospital Universitario Sant Joan, Universitat Rovira i Virgili, Instituto de Investigación Sanitaria Pere Virgili (IISPV), Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Reus, Tarragona, Spain
Article information
Full Text
Download PDF
Full Text
To the Editor,

Recent clinical data show that very low low-density lipoprotein (LDL) cholesterol (LDL-C) levels are associated with an even lower incidence of arteriosclerosis-related diseases. The Cholesterol Treatment Trialists’ Collaboration meta-analyses have shown a continuous linear correlation between LDL reduction and cardiovascular benefit.1 The IMPROVE-IT trial provided scientific evidence of incremental benefits down to an LDL-C concentration of 1.3 mmol/L (50mg/dL).2 Proprotein convertase subtilisin kexin type 9 inhibitors have quickly been adopted in this field and have provided physicians with new scenarios. Patients with LDL-C values<0.4 mmol/L (15mg/dL) are occasionally seen, while concentrations below 1.3 mmol/L (50mg/dL) are common. The LDL-C concentrations<0.4 mmol/L (15mg/dL) show no concerns in safety analyses; on the contrary, these concentrations are associated with even higher cardiovascular benefit. The recently reported GLAGOV trial data confirm a benefit to atherosclerotic plaque level by lowering LDL concentrations closer to 0.52 mmol/L (20mg/dL).3

Can we live with these extremely low LDL-C levels? In other words, what is the physiological function of LDL?

Low-density lipoprotein is the final step of the lipoprotein metabolism cascade and is considered the vehicle by which cholesterol is delivered to peripheral tissues through LDL receptors (LDL-R). However, a few points must be taken into consideration. First, all mammalian cells have the capacity to synthesize their own cholesterol. Additionally, in the adrenal glands, where cholesterol is needed for hormone synthesis, the cells capture external cholesterol from high-density lipoprotein (HDL), rather than LDL, through scavenger receptor B1. Interestingly, the main organ receiving LDL particles is the liver. Approximately 3 out of 4 LDL particles finish their metabolic life in the liver. The hepatic LDL/LDL-R system is, along with HDL, the main pathway to excrete cholesterol with bile into the feces, which is almost the only mechanism to get rid of cholesterol. When the LDL-LDL-R pathway is not efficient enough, LDL accumulates and infiltrates the artery wall, inducing atheroma plaque formation. Familial hypercholesterolemia patients, who are characterized by an abnormally low number of LDL-R, are an example of this process.

Low LDL-C plasma concentrations due to an increased catabolic rate are the result of a highly efficient LDL/LDL-R pathway. For the first time in history, we are facing the impact of highly efficient therapies that increase the activity of this pathway, thereby leading to extremely low LDL-C levels.

Do we need LDL-C at all? The question is a provocative one.

Low LDL levels due to increased catabolism should not be compared with those due to low production rates, as in hypobeta- and abetalipoproteinemia, which are diseases characterized by severe symptoms because of apolipoprotein B deficiency.

Which other functions could be altered by very low LDL-C concentrations? LDL proteomic studies show that, in contrast to HDL, this particle carries–almost exclusively–proteins linked to its own metabolism (apolipoprotein B:100 [85%] and other apolipoproteins).4 Some vitamins, such as vitamin E, are associated with the lipoprotein system. LDL-vitamin E has 2 functions: accessing peripheral tissues through the LDL/LDL-R system, and protecting the LDL particle itself from oxidation. An increased LDL-R activity results in a more efficient delivery of vitamin E. On the other hand, the vitamin E:LDL-C ratio is not modified by proprotein convertase subtilisin kexin type 9 inhibitors, thereby maintaining its antioxidant function.

LDL transports toxic substances, such as endotoxin lipopolysaccharide, in special situations such as septicemia. By increasing LDL-R activity, LDL-associated lipopolysaccharide plasma clearance is accelerated, which has been associated with a better prognosis.5

Regarding LDL-mediated peripheral delivery, we should take into account lessons from homozygous familial hypercholesterolemia patients. Homozygous familial hypercholesterolemia is a zero-LDL/LDL-R functional pathway situation; however, no clinical effects due to impaired LDL-mediated peripheral delivery have been reported. There have been no reports of metabolic or immune alterations, either during fetal development or in patients achieving advanced ages6 and normal pregnancies have been described. This suggests a negligible effect of the LDL/LDL-R system on molecular transport to peripheral tissues.

We are not recommending achieving a zero-LDL level, but are rather advising that extremely low LDL plasma concentrations due to increased LDL-R activity should not be considered harmful. This is not a science fiction statement, as LDL concentrations<0.4 mmol/L (15mg/dL) are frequently seen, and no adverse effects have been reported, only benefits.

In summary, by increasing LDL-R activity, the LDL/LDL-R system is improved, and thus, very low LDL-C levels must be considered a marker of optimal LDL/LDL-R system efficiency. Although extremely low LDL-C concentrations secondary to increased LDL-R activity should not be viewed with concern, extreme caution should be taken before extrapolating these data to the overall population until more extensive safety data are available.


Lectures and advisory fees from Amgen, Sanofi, and MSD.

J. Fulcher, R. O’Connell, M. Voysey, et al.
Efficacy and safety of LDL-lowering therapy among men and women: Meta-analysis of individual data from 174 000 participants in 27 randomised trials.
Lancet., 385 (2015), pp. 1397-1405
C.P. Cannon, M.A. Blazing, R.P. Giugliano, et al.
Protocol - Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes.
N Engl J Med., 372 (2015), pp. 2387-2397
S.J. Nicholls, R. Puri, T. Anderson, et al.
Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated PatientsThe GLAGOV Randomized Clinical Trial.
JAMA., 316 (2016), pp. 2373-2384
J. Godzien, M. Ciborowski, E.G. Armitage, et al.
A single in-vial dual extraction strategy for the simultaneous lipidomics and proteomics analysis of HDL and LDL fractions.
J Proteome Res., 15 (2016), pp. 1762-1775
K.R. Walley.
Role of lipoproteins and proprotein convertase subtilisin/kexin type 9 in endotoxin clearance in sepsis.
Curr Opin Crit Care., 22 (2016), pp. 464-469
R.M. Sánchez-Hernández, F. Civeira, M. Stef, et al.
Homozygous Familial Hypercholesterolemia in Spain: Prevalence and Phenotype-Genotype Relationship.
Circ Cardiovasc Genet., 9 (2016), pp. 504-510
Copyright © 2017. Sociedad Española de Cardiología
Revista Española de Cardiología (English Edition)

Subscribe to our newsletter

Article options
es en

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?