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.