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

Research output: Contribution to journalReview articlepeer-review

30 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)2154-2169
Number of pages16
JournalEuropean Heart Journal
Issue number22
Publication statusPublished - 7 Jun 2021
Externally publishedYes


  • Cholesterol guidelines
  • Ezetimibe
  • PCSK9 inhibitors
  • Statins
  • Very low LDL-C levels


Dive into the research topics of 'How low is safe? The frontier of very low (<30 mg/dL) LDL cholesterol'. Together they form a unique fingerprint.

Cite this