Clinical relevance of per-particle atherogenicity of triglyceride-rich lipoproteins, Lp(a) and LDL for cardiovascular risk

Circulating apoB-containing lipoproteins fall into three principal categories- low-density lipoproteins (LDLs), triglyceride-rich lipoproteins (TRLs) and lipoprotein(a) Lp(a). These three different lipoproteins are all causally related to atherosclerotic cardiovascular disease (ASCVD) and together account for the full spectrum of apoB-related atherogenic risk. They vary substantially in metabolic and kinetic properties, size and lipid composition and may affect the atherosclerotic pathogenic process differently. Indeed, genetic evidence indicates that TRLs and Lp(a) are several-fold more atherogenic per particle than LDL in terms of ASCVD risk. On the other hand, Lp(a) and TRLs are typically much less abundant than LDL. How should these countervailing factors be balanced to understand their net contribution to risk? In this review, we summarize the evidence relating to the atherogenicity of LDLs, TRLs and Lp(a) and explore the implications for risk stratification and therapeutic strategies. We argue that LDL lowering will remain the cornerstone of apoB-related risk reduction, but eradication of residual risk necessitates combination therapies targeting TRLs and/or Lp(a) in addition to LDL.