Residual Cardiovascular Risk at Low LDL: Remnants, Lipoprotein(a), and Inflammation

Abstract

Background: Current guidelines target low-density lipoprotein cholesterol (LDL-C) concentrations to reduce atherosclerotic cardiovascular disease (ASCVD) risk, and yet clinical trials demonstrate persistent residual ASCVD risk despite aggressive LDL-C lowering.

Content: Non-LDL-C lipid parameters, most notably triglycerides, triglyceride-rich lipoproteins (TGRLs), and lipoprotein(a), and C-reactive protein as a measure of inflammation are increasingly recognized as associated with residual risk after LDL-C lowering. Eicosapentaenoic acid in statin-treated patients with high triglycerides reduced both triglycerides and ASCVD events. Reducing TGRLs is believed to have beneficial effects on inflammation and atherosclerosis. High lipoprotein(a) concentrations increase ASCVD risk even in individuals with LDL-C < 70 mg/dL. Although statins do not generally lower lipoprotein(a), proprotein convertase subtilisin/kexin type 9 inhibitors reduce lipoprotein(a) and cardiovascular outcomes, and newer approaches are in development. Persistent increases in C-reactive protein after intensive lipid therapy have been consistently associated with increased risk for ASCVD events.

Summary: We review the evidence that biochemical assays to measure TGRLs, lipoprotein(a), and C-reactive protein are associated with residual risk in patients treated to low concentrations of LDL-C. Growing evidence supports a causal role for TGRLs, lipoprotein(a), and inflammation in ASCVD; novel therapies that target TGRLs, lipoprotein(a), and inflammation are in development to reduce residual ASCVD risk.

Fig. 1.

Remnant lipoprotein metabolism. Chylomicrons secreted from the intestine and very-low-density lipoprotein (VLDL) secreted from the liver are lipolyzed by lipoprotein lipase (LPL), leading to triglyceride-rich lipoprotein (TGRL) remnants. Chylomicron secretion is largely regulated by food intake, whereas VLDL secretion is controlled by insulin. Remnant particles undergo remodeling via the enzymatic action of cholesteryl ester transfer protein (CETP) with high-density lipoprotein (HDL), hepatic lipase (HL), and the exchange of soluble apolipoproteins such as E, C-I, C-II, and C-III. TGRL remnants are cleared from the circulation via receptor-mediated uptake involving the low-density lipoprotein (LDL) receptor (LDLR), LDL receptor–like protein (LRP), and heparan sulfate proteoglycans (HSPG). Chylomicron remnants and VLDL remnants compete for the same lipolytic pathway, a process mediated by apoE. While chylomicron remnant clearance may be mediated by LDLR, LRP, or HSPG, VLDL remnants are believed to be cleared predominantly via LDLR. Individuals with apoE2 isoforms have reduced remnant clearance and are postulated to have compensatory upregulation of cellular LDLR expression that may lead to decreased LDL-TG and LDL-C concentrations. The purported role of HL in the lipolytic conversion of IDL to LDL may at least partly explain why individuals with decreased HL activity due to genetic variation in the LIPC gene (e.g., rs 2070895) have high LDL-TG concentrations. Reproduced with permission from Saeed et al. (7).