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Clinical and pathophysiological evidence supporting the safety of extremely low LDL levels­The zero-LDL hypothesis

low-ldl pcsk9 inhibitors cholesterol ezetimibe lipid-lowering therapy low-ldl safety ldl-c

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Posted 06 May 2018 - 02:55 PM




  • Many patients on proprotein convertase subtilisin/kexin type 9 inhibitors achieve extremely low low-density lipoprotein cholesterol (LDL-C) levels.
  • Extremely low LDL-C levels are associated with even less cardiovascular risk.
  • Extremely low LDL-C concentrations cause no clinically relevant side effects.
  • Low LDL-C levels due to higher clearance are a marker of adequate LDL–LDLreceptor function.




While the impact of very low concentrations of low–density lipoprotein cholesterol (LDL-C) on cardiovascular prevention is very reassuring, it is intriguing to know what effect these extremely low LDL-C concentrations have on lipid homoeostasis. The evidence supporting the safety of extremely low LDL levels comes from genetic studies and clinical drug trials. Individuals with lifelong low LDL levels due to mutations in genes associated with increased LDL-LDL receptor (LDLR) activity reveal no safety issues. Patients achieving extremely low LDL levels in the IMPROVE-IT and FOURIER, and the PROFICIO and ODYSSEY programs seem not to have an increased prevalence of adverse effects. The main concern regarding extremely low LDL-C plasma concentrations is the adequacy of the supply of cholesterol, and other molecules, to peripheral tissues. However, LDL proteomic and kinetic studies reaffirm that LDL is the final product of endogenous lipoprotein metabolism. Four of 5 LDL particles are cleared through the LDL-LDLR pathway in the liver. Given that mammalian cells have no enzymatic systems to degrade cholesterol, the LDL-LDLR pathway is the main mechanism for removal of cholesterol from the body. Our focus, therefore, is to review, from a physiological perspective, why such extremely low LDL-C concentrations do not appear to be detrimental. We suggest that extremely low LDL-C levels due to increased LDLR activity may be a surrogate of adequate LDL-LDLR pathway function.




Also tagged with one or more of these keywords: low-ldl, pcsk9 inhibitors, cholesterol, ezetimibe, lipid-lowering therapy, low-ldl safety, ldl-c

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