Safety and effect of very low levels of low-density lipoprotein cholesterol on cardiovascular events.

Larosa JC, Pedersen TR, Somaratne R, Wasserman SM.
Am J Cardiol. 2013 Apr 15;111(8):1221-9. doi: 10.1016/j.amjcard.2012.12.052.

Background

More-aggressive lipid-lowering therapy more effectively reduces the incidence of cardiovascular (CV) events than does a less-aggressive lipid-lowering strategy. Questions remain about the validity of LDL-cholesterol (LDL-C) targets, because trials generally did not focus on assessing the merits and safety of achieving one specific LDL-C level versus another. It is important to know whether the residual CV risk observed in trials can be reduced by further lowering of LDL-C. We here summarise this review article on current evidence from clinical trials on the effect of very low LDL-C concentration (<50 mg/dl) in subjects at risk of CV events.

Human LDL cholesterol levels: normal versus optimal

Total cholesterol and LDL-C levels change over the course of life. Data from human gestation, early life and animal studies give interesting insight into what might be considered ‘physiological lipid levels’. The current Western diet containing large quantities of grains and farm animal meat high in saturated fat, appears to contribute importantly to increasing LDL-C levels and the incidence of atherosclerosis. Individuals who consume a typical Western diet have an average total cholesterol level of about 200 mg/dl. Considering the high rate of atherosclerosis in Western populations, this can hardly be called ‘normal’. Comparative studies show that ‘normal’ Western total cholesterol and LDL-C levels are higher than those seen in non-Western or Western vegetarian populations.

Safety of very low LDL-C levels

These observations generally support the safety of lower LDL-C than those recommended in treatment guidelines. However, some epidemiologic and clinical studies have caused concern that very low LDL-C levels may increase risk of cancer, hemorrhagic stroke and non-CV death.
Nevertheless, most studies found no association between cholesterol and cancer, or it was attributable to preclinical cancer. Also, an association between low cholesterol and a reduced risk of prostate cancer has been described. It is furthermore suggested that malignancies may lower cholesterol levels by an as yet unknown mechanism.
A possible link between statin use and cancer risk has also been studied, but large meta-analyses of clinical and observational studies did not find evidence of an increased cancer incidence among statin users or an excess risk of cancer associated with more-intensive regimens versus standard regimens.
Concerns about increased incidence of hemorrhagic stroke in individuals with low cholesterol originated from a limited number of clinical trial observations, although no relation was found between hemorrhagic stroke and baseline LDL-C or the most recent on-treatment LDL-C level. Similarly, meta-analyses did not find evidence that lowering LDL-C in patients with low baseline LDL-C increase non-CV mortality.
A recent meta-analysis of large statin trials did however suggest a slightly increased risk of diabetes in patients receiving statin therapy, which could not be explained by a change in LDL-C levels. Another meta-analysis showed that the risk of diabetes was enhanced after more-intensive statin therapy as compared to less-intensive statin therapy.  
Some of the observed increased incidences  of some adverse events in statin-treated patients did not correlate with on-treatment LDL-C levels and might not result from the achieved LDL-C levels per se.
In light of the safety of very low LDL-C levels, individuals with familial hypobetalipoproteinemia (FHBL) are interesting to consider. Subjects with homozygous FHBL as a result of a mutation in the APOB gene have extremely low to undetectable levels of apolipoprotein B (apoB) and very low LDL-C levels and total cholesterol. The clinical picture of people with homozygous FHBL is extremely variable. Those with FHBL might be at an increased risk of fatty liver disease,  but long-term effects are not known.
FHBL can also be caused by  loss-of-function mutations in the PCSK9 gene, which codes for a protein that inhibits clearance of LDL-C  by inducing degradation of hepatic LDL-receptors. PCSK9 mutation carriers are apparently without any adverse health issues.

Effects of very low LDL-C levels on CV risk

Several studies indicate that achieving LDL-C levels lower than those recommended in treatment guidelines (targeting 50-70 mg/dl) further reduces CV risk. Some studies revealed the lowest rate of major CV events in patients with on-treatment LDL-C levels <64 mg/dl as opposed to patients with higher LDL-C concentrations.
Thus, studies indicate clear clinical benefits of attaining very low levels of LDL-C (<50 mg/dl), mostly in secondary prevention. However, they do not provide information on whether pharmacotherapeutic LDL-C lowering should be initiated in at-risk patients with low baseline LDL-C levels. An observational study that followed non-statin-treated patients with acute coronary syndrome and LDL-C<80 mg/dl at hospital admission, described lower 6-month incidence of death, reinfarction or stroke in patients who were discharged with statin-therapy, as compared to those not taking statins. On-treatment LDL-C levels were not reported. Other studies also suggest reduced mortality upon statin-treatment in patients with low LDL-C levels.
A retrospective study in Korean patients did show a reduced 1-year risk of cardiac death, coronary revascularisation and major adverse cardiac events in patients treated with statins versus a non-statin group, but statin treatment did not affect the composite of all-cause death, recurrent myocardial infarction or percutaneous coronary intervention.

Conclusion

Individuals with very low LDL-C concentrations are generally healthy and have low CV risk. No clear increased risk of cancer has been identified in humans with very low LDL-C, neither in statin-treated persons attaining a very low level of LDL-C. Data is sparse but LDL-C < 50 mg/dl does not appear to be inherently unsafe, as long is some LDL-C is still present. Future studies will need to shed further light on which patients might benefit from further LDL-C lowering beyond recommended levels in current guidelines as well as on possible risks. Moreover, the benefit of primary prevention beyond current recommendations remains to be explored.

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