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

Abstract and Introduction


Low-density lipoprotein cholesterol (LDL-C) is a proven causative factor for developing atherosclerotic cardiovascular disease. Individuals with genetic conditions associated with lifelong very low LDL-C levels can be healthy. We now possess the pharmacological armamentarium (statins, ezetimibe, PCSK9 inhibitors) to reduce LDL-C to an unprecedented extent. Increasing numbers of patients are expected to achieve very low (<30 mg/dL) LDL-C. Cardiovascular event reduction increases log linearly in association with lowering LDL-C, without reaching any clear plateau even when very low LDL-C levels are achieved. It is still controversial whether lower LDL-C levels are associated with significant clinical adverse effects (e.g. new-onset diabetes mellitus or possibly haemorrhagic stroke) and long-term data are needed to address safety concerns. This review presents the familial conditions characterized by very low LDL-C, analyses trials with lipid-lowering agents where patients attained very low LDL-C, and summarizes the benefits and potential adverse effects associated with achieving very low LDL-C. Given the potential for cardiovascular benefit and short-term safe profile of very low LDL-C, it may be advantageous to attain such low levels in specific high-risk populations. Further studies are needed to compare the net clinical benefit of non-LDL-C-lowering interventions with very low LDL-C approaches, in addition to comparing the efficacy and safety of very low LDL-C levels vs. current recommended targets.

Graphical Abstract


Coronary artery disease (CAD) is the leading cause of morbidity/mortality in the western world.[1] Serum low-density lipoprotein cholesterol (LDL-C) is a proven causative factor for developing CAD and a log linear correlation has been found between LDL-C and CAD risk.[2] Randomized controlled trials (RCTs) unequivocally show that lowering serum LDL-C is associated with a significant reduction in major adverse cardiovascular events, which include a composite of cardiovascular death, myocardial infarction (MI), stroke, coronary revascularization, and unstable angina.[3–7]

Very low (<30 mg/dL) LDL-C can be found in patients with genetic conditions characterized by hypocholesterolaemia, in patients undergoing pharmacological treatment with lipid-lowering agents and transiently post LDL apheresis. Loss-of-function mutations in Proprotein Convertase Subtilisin/Kexin 9 gene (PCSK9), familial hypobetalipoproteinemia, abetalipoproteinemia, familial combined hypolipidaemia, chylomicron retention disease, and Smith–Lemli–Opitz syndrome are genetic conditions characterized by congenital, lifelong, very low LDL-C.[8,9] These conditions could be used as proxies for understanding the benefits and potential side effects of living with very low LDL-C levels in the long term. Finally, in patients undergoing LDL apheresis, very low LDL-C levels have been transiently observed post-apheresis, without any associated side effect.[10]

In recent years, potent LDL-C-lowering medications have emerged (high-intensity statins, statin/ezetimibe combination, PCSK9 inhibitors including evolocumab, and alirocumab). These agents reduce LDL-C to an unprecedented extent and have relatively minimal side effects at short to intermediate follow-up.[3–7,11–13] Cardiovascular benefit continues to increase with lowering LDL-C even when very low LDL-C is attained.[14–16] However, it is still unclear whether very low LDL-C per se is associated with significant clinical adverse effects. Existing literature has been controversial; few sub-studies of patients attaining very low LDL-C indicate a higher incidence of side effects,[17,18] whereas other sub-studies report no adverse effects.[15,16,19] As a growing number of patients taking potent lipid-lowering medications achieve very low (<30 mg/dL) LDL-C, it is of paramount importance to evaluate the safety of very low LDL-C levels in the long-term.

In light of recent data with favourable outcomes among patients attaining low LDL-C without proven concern for side effects, recent European and American Cholesterol Management guidelines have adopted a more aggressive lipid-lowering approach in high-risk patients. The 2016 European Society of Cardiology (ESC) CVD prevention guidelines recommended an LDL-C goal of <70 mg/dL or at least a 50% LDL-C reduction in high-risk patients with baseline levels 70–135 mg/dL.[20] Given evidence of cardiovascular benefit with even lower LDL-C, the 2019 ESC/EAS Cholesterol Guidelines recommended lowering LDL-C to <55 mg/dL in very high-risk patients for both primary and secondary prevention (Class I recommendation) and to <40 mg/dL in patients experiencing a second vascular event within 2 years (Class IIb).[21] The 2019 ESC/EAS guideline defines very high-risk patients as those with documented atherosclerotic cardiovascular disease (ASCVD) (clinical or on imaging), with diabetes (with associated target organ disease, at least three major risk factors, or early onset of T1DM >20 years), with advanced chronic kidney disease not on haemodialysis, or with familial hypercholesterolaemia plus a major risk factor.

In contrast, the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) Cholesterol Guidelines did not recommend a specific minimum LDL-C target. Instead, guidelines recommended that preferred statin intensity and percent LDL-C reduction goal should be based upon patient's cardiovascular risk.[22] The 2018 AHA/ACC/Multi-society guidelines, which incorporated data from three new RCTs (IMPROVE-IT, FOURIER, ODYSSEY OUTCOMES) addressed the need for a more aggressive approach of LDL-C lowering in very high-risk ASCVD patients, recommending achieving at least a 50% reduction in LDL-C and a 70 mg/dL LDL-C threshold to consider further LDL-C lowering with ezetimibe, and if needed by a PCSK9 inhibitor.[23]

This review presents the familial conditions characterized by very low LDL-C, analyses lipid-lowering trials where patients attained very low LDL-C, and summarizes the benefits and potential adverse effects associated with achieving very low LDL-C. Several reviews analysing the mechanisms and safety of achieving very low LDL-C levels have been published in the past few years.[24,25] However, given management of hypercholesterolaemia continues to drastically evolve, an up-to-date comprehensive review is needed. Of note, there is not a universal definition of very low LDL-C and there are different methods to determine the LDL-C value. For the purpose of this review, we define very low serum LDL-C as below 30 mg/dL.