How Low Is Safe? The Frontier of Very Low (<30 mg/dL) LDL Cholesterol

Angelos D. Karagiannis; Anurag Mehta; Devinder S. Dhindsa; Salim S. Virani; Carl E. Orringer; Roger S. Blumenthal; Neil J. Stone; Laurence S. Sperling


Eur Heart J. 2021;42(22):2154-2169. 

In This Article


We reviewed genetic conditions associated with lifelong, very low LDL-C levels. Severe neurocognitive impairment and hepatic steatosis seen in abetalipoproteinemia and familial hypobetalipoproteinemia, respectively, are caused by mechanisms unrelated to very low LDL-C. Hundreds of healthy patients with PCKS9 loss-of-function mutations or familial combined hypolipidaemia living on lifelong low LDL-C for decades have been described.[55,57,113] On the contrary, individuals with PCSK9 loss-of-function mutations appear to be healthy, without any evidence of neurocognitive impairment, higher incidence of diabetes, cataracts, or stroke.[48,113] These individuals experience significantly fewer coronary events compared to control groups and cardiovascular event rates are lower than expected based on patients' serum LDL-C.[9,47,113] This may be attributed to lifelong low LDL-C conferring more robust atheroprotection than attaining lower LDL-C later in life. Moreover, it may be enhanced by pleiotropic, LDL-C-independent, anti-atherosclerotic effects that have been associated with PCSK9 loss of function/inhibition.[114] Even though all aforementioned genetic conditions and lipid-lowering agents are associated with low LDL-C, the mechanism through which lower LDL-C is achieved differs (Figure 4). Increased LDL-C clearance thanks to LDL-R up-regulation appears to have fewer side effects compared to decreased lipoprotein secretion/lipoprotein toxic intracellular accumulation or decreased lipoprotein production.

Figure 4.

Overview of the molecular players of the LDL-C pathway. Several genetic conditions and lipid-lowering agents can all result in very low LDL-C via different though mechanisms. It is important to know the specific molecular players affected by each medication or genetic condition to predict and avoid potential side effects.

We now possess the pharmacological armamentarium (statins, ezetimibe, PCSK9 inhibitors) to reduce LDL-C levels to an unprecedented extent. Recent guidelines for cholesterol management were updated to incorporate evolving evidence supporting the beneficial effects of aggressive LDL-C reduction[21,23] and it is likely a greater number of patients will achieve very low (<30 mg/dL) LDL-C. Clinicians, though, often feel uncomfortable encountering patients with very low LDL-C. Evidence to date supports the lack of significant correlation between very low LDL-C and major side effects. Whereas several studies have shown increased rate of diabetes, haemorrhagic stroke, haematuria, insomnia, hepatobiliary disorders, and cataract development among patients attaining very low LDL-C, the majority of studies have demonstrated no significant association. Whether this discrepancy is a result of confounders, selection bias, side effects related to a specific medication and not to lower LDL-C levels, inadequate sample sizes or insufficient Follow-up is yet to be clarified. Current data showing an overall safe profile of patient subgroups attaining very low LDL-C are post-randomization with therefore potential bias. Long-term exposure to very low LDL-C levels may be needed for real world statistical significance to become apparent. Observational studies and post marketing case reports would be useful to illuminate a possible association of very low LDL-C with a rare side effect in the long term. However, given inherent biases (due to non-blinding and non-randomization of patients) in observational studies, no causality can be inferred and, findings from non-randomized observational studies should be interpreted with caution and be further investigated in large-scale RCTs for confirmation.[11] Overall, a possible association of very low LDL-C with increased incidence of new-onset diabetes and haemorrhagic stroke necessitates further investigation.

Several new drugs have been approved or are under investigation for the management of hypercholesterolaemia and are anticipated to provide additional information on the safety of attaining very low LDL-C. Inclisiran, an siRNA PCSK9 inhibitor, has been shown to reduce LDL-C by 50% when administered subcutaneously every 6 months; lower LDL-C persists over an 18-month period, and 16% of patients receiving inclisiran attained LDL-C < 25 mg/dL (supplementary).[115] Furthermore, ORION-4 is an ongoing multicentre, double-blind, RCT with 15 000 patients, investigating the effect of inclisiran on reducing cardiovascular events.[116] Bempedoic acid, an inhibitor of ATP citrate lyase, is an oral anti-lipidemic agent that significantly reduces LDL-C when added to maximally tolerated statin therapy without observed muscle-related adverse effects but with associated higher hyperuricemia and gout risk.[117] CLEAR Outcomes is a randomized, double-blind, RCT with 14 000 participants to assess the effects of bempedoic acid on the occurrence of major cardiovascular events in patients who are statin intolerant.[118] An anti-ANGPTL3 antibody (evinacumab) and an antisense oligonucleotide targeting ANGPTL3-mRNA are currently undergoing clinical trials for the management of dyslipidaemias.[119,120] An MTP inhibitor (lomitapide) and an ApoB-100 mRNA inhibitor (mipomersen) significantly reduced LDL-C in patients with Homozygous Familial Hypocholesterolemia (HoFH) in phase III trials, but given MTP and ApoB-100 mRNA inhibitors have been shown to cause hepatotoxicity and hepatic steatosis, these drugs have been FDA approved only for managing patients with HoFH.[121–125] The recent development of several novel medications addressing hypercholesterolaemia based upon research related to populations with hypocholesterolaemia is a triumph of translational medicine.

An increasing number of patients will likely achieve LDL-C levels below 30 mg/dL, given the availability of efficient and safe lipid-lowering agents as well as the more aggressive primary and secondary prevention recommendations per updated guidelines. Evidence supports that cardiovascular clinical benefit increases monotonically in association with lowering LDL-C, without reaching any plateau even for LDL-C as low as 10 mg/dL. However, there is concern with the limited data regarding long-term safety of exposure to LDL-C < 15 mg/dL in RCTs (Table 1). Thus far, it remains unclear if the incremental benefit of reducing LDL-C below 30 mg/dL is significantly advantageous to warrant the potential for increased complications and/or expenses. Moreover, cost-effectiveness, relative cardiovascular benefit and concomitant comorbidities (e.g. hypertriglyceridaemia) will need to be assessed before further reducing LDL-C to very low levels (<30 mg/dL) with an additional lipid-lowering agent vs. using a non-LDL-C-lowering intervention in patients at highest risk. The recent RCT results showing a significant reduction in ischaemic events in patients taking icosapent ethyl, especially in the subgroup of patients with ASCVD, triglycerides >135 mg/dL and LDL-C < 100 mg/dL, raises the question that lowering LDL-C to very low levels may not be the only option for all high-risk patients.[126] Given the potential for cardiovascular benefit and short-term safety profile of very low (≤30 mg/dL) LDL-C levels, it may be advantageous to attain such low levels in specific high-risk subsets of patients. Further studies are needed to compare the net clinical benefit of non-LDL-C-lowering interventions with aggressive LDL-C lowering, as well as to compare the efficacy and safety of attaining very low LDL-C levels vs. current recommended targets.