Cardiovascular events in individuals with small/medium LDL particle discordance

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Abstract Aims Despite similar LDL-C levels, size and composition of LDL particles (LDL-P) varies widely. Among the metabolically perturbed, or those with altered function of lipid regulatory proteins, LDL-C levels mask elevated atherogenic small-medium LDL-P (S/M LDL-P). We assessed the contribution of such discordance in S/M LDL-P on major adverse cardiovascular event risk (MACE). Methods and results UK Biobank participants with Nightingale NMR metabolomics (487,521 participants), were classified as high or low cardiometabolic burden. S/M LDL-P discordance was defined as the difference between LDL-C predicted S/M LDL-P and observed S/M LDL-P. Genetic variants encoding cholesterol ester transfer protein (CETP), which regulates cholesterol-triglyceride exchange and the production of small LDL particles, were identified via whole genome sequencing. Adjusted Cox proportional hazard regression was used to estimate MACE associations. S/M LDL-P discordance showed an LDL-C and Apo-B independent association with MACE (47,935 cases), which differed by cardiometabolic burden group: hazard ratio (HR) per standard deviation 1.09 (95%CI 1.05; 1.13) and HR 1.24 (95%CI 1.21; 1.27) for low/high burden, respectively. Loss of function (LoF) CETP variants were strongly associated with lower levels of both S/M LDL-P and S/M LDL-P discordance. For example, the S/M LDL-P discordance effect of CETP LoF carriership for low/high metabolic burden, respectively, was -4.62 nmol/L (95%CI -8.40; -0.83) compared to -11.10 nmol/L (95%CI -15.57; -6.63). Conclusion S/M LDL-P discordance (overabundance) is strongly associated with MACE risk, especially in people with high cardiometabolic burden. S/M LDL-P discordance is modified by CETP genetic variation, suggesting a role for CETP-mediated lipid remodelling beyond LDL-C changes. Translational perspective Conventional lipid parameters such as LDL-C and apolipoprotein B may underestimate the atherogenic burden conferred by an overabundance of small and medium LDL particles, particularly in patients with diabetes, obesity, or established atherosclerotic disease. We introduce a novel measure of small/medium LDL particle (S/M LDL-P) discordance, quantifying the excess of S/M LDL-P beyond what is predicted by LDL-C alone. S/M LDL-P discordance is independently associated with time to incident MACE, especially in people with increased cardiometabolic burden. Genetic loss of function in cholesteryl ester transfer protein ( CETP ), which regulates cholesterol-triglyceride exchange and the production of small LDL particles, reduced S/M LDL-P discordance, in particular among those with metabolically perturbed states where discordance was otherwise high. Taken together, these findings provide support for the potential role of CETP inhibition, as a therapeutic strategy that may lower cardiovascular risk in part through reduction of S/M LDL-P discordance. This hypothesis is currently being evaluated with obicetrapib in the PREVAIL trial.

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