The Residual Risk Odyssey: From LDL to Lp(a)

Robert S. Rosenson, MD; Sascha N. Goonewardena, MD

Disclosures

J Am Coll Cardiol. 2021;78(5):434-436. 

Lowering low-density lipoprotein (LDL) with lifestyle and statin therapy is the dominant means of attenuating atherosclerotic cardiovascular disease (ASCVD) risk. When LDL cholesterol (LDL-C) levels remain ≥70 mg/dL on maximum tolerated statin treatment, nonstatin agents are recommended to achieve minimal acceptable risk-based targets regardless of the mechanism of action of the 2 evidence-based second-line therapies.[1] Cost considerations have influenced guideline committee recommendations that favor blocking absorption of dietary and biliary cholesterol and plant sterols with a Niemann-Pick C1-like transporter inhibitor (ezetimibe) in preference to enhanced LDL receptor–mediated clearance of LDL and other atherogenic lipoproteins with a human monoclonal antibody inhibitor of proprotein convertase subtilisin/kexin type 9 (alirocumab, evolocumab). Evidence supporting second-line cholesterol-lowering therapy is limited by a paucity of clinical trial data comparing different approaches, creating an urgent need to identify quantifiable biomarkers that further inform our understanding of residual risk in patients with ASCVD.

LDL-C measurements encompass the cholesterol component of lipoprotein(a) (Lp[a]). In some patients, a substantial fraction of LDL-C may be transported by Lp(a) particles rather than the archetypical LDL particle. On the basis of prospective observational studies and Mendelian randomization studies, excess Lp(a) is considered an independent risk factor for ASCVD events. A meta-analysis of 29,029 statin-treated patients with high baseline ASCVD risk showed that patients with elevated Lp(a) mass levels of 15 to <30, 30 to <50, and ≥50 mg/dL compared with patients with Lp(a) levels <15 mg/dL had hazard ratios (HRs) for cardiovascular events of 0.95 (95% confidence interval [CI]: 0.82–1.11), 1.08 (95% CI: 0.95–1.23), and 1.42 (95% CI: 1.16–1.74), respectively.[2] Additionally, among statin-treated patients with ASCVD enrolled in the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) study, which compared evolocumab with placebo, patients with baseline Lp(a) in the highest quartile (>165 nmol/L) had a higher risk for coronary heart disease death, myocardial infarction, or urgent revascularization compared with those in the lowest quartile (HR: 1.22; 95% CI: 1.01–1.48).[3] In post–acute coronary syndrome patients enrolled in ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab), a 1 mg/dL reduction in Lp(a) mass was associated with an HR of 0.994 (95% CI: 0.990–0.999) for ASCVD events.[4] In a post hoc analysis of ODYSSEY Outcomes in this issue of the Journal, Schwartz et al.[5] expand our knowledge of ASCVD risk and raise provocative questions about the pathobiology of ASCVD and the drivers of residual risk in patients with ASCVD. The investigators found that a higher (>13.7 mg/dL) versus lower (≤13.7 mg/dL) Lp(a) level in patients with recent acute coronary syndromes was associated with a higher cardiovascular event rate regardless of whether LDL-C levels were <70 or >70 mg/dL.[5] Additionally, the investigators found a reduction in cardiovascular events with proprotein convertase subtilisin/kexin type 9 inhibitors in the subgroup with LDL-C <70 mg/dL among patients with higher Lp(a) levels (>13.7 mg/dL).

This study has several strengths, including the focus on a high-risk ASCVD population near guideline-recommended levels of LDL-C and further illumination of Lp(a) as a quantifiable target variable that could capture residual risk in patients with LDL-C <70 mg/dL. As the investigators state, this post hoc analysis is primarily hypothesis generating and requires validation in other cohorts with greater inclusion of minorities and more precise characterization of Lp(a) phenotypes using molar concentrations and isoform analysis. This latter consideration is especially important in that Lp(a) is a complex lipoprotein composed of a single copy of apolipoprotein A with substantial variation in molecular weight. The oversimplification of Lp(a) heterogeneity complicates the use of Lp(a) measurements to individualize patient therapies and hinders our ability to understand the myriad pathological mechanisms mediated by Lp(a). Nonetheless, this analysis from the ODYSSEY Outcomes investigators will serve as an impetus for further investigations that enhance our understanding of the relationship between Lp(a) and ASCVD and the mechanisms through which Lp(a) mediates residual risk beyond LDL-C.

Over the past decade, the search for the mechanisms through which plasma Lp(a) drives ASCVD has accelerated. Lp(a) is known to be proatherogenic in part through the response-to-retention effects of apolipoprotein B–containing particles. However, the surprisingly large impact of Lp(a) compared with LDL-C on ASCVD risk suggests that Lp(a) possesses other pathogenic properties.[6] Evidence from experimental models and clinical studies has demonstrated that Lp(a) is the primary lipoprotein carrier of oxidized phospholipids (OxPLs).[7] OxPL is a danger-associated molecular pattern that can be recognized by pattern recognition receptors on innate immune cells, triggering inflammation, thrombosis, and plaque destabilization (Figure 1). In observational studies, the level of OxPL on apolipoprotein B–containing lipoproteins (primarily Lp[a]) was found to be highly predictive of future ASCVD risk.[8] An important secondary analysis of the ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High Risk for Vascular Outcomes) trial demonstrated that Lp(a) levels are most predictive on ASCVD events in patients with inflammation (high-sensitivity C-reactive protein >2 mg/mL), reinforcing the mechanistic link between Lp(a) and immune dysregulation.[9] Integrating our mechanistic understanding of how Lp(a) orchestrates thrombosis, inflammation, and atherogenesis with clinical variables and phenotypes will allow more nuanced, causally linked assessments of ASCVD residual risk. As more potent and selective Lp(a)-lowering therapeutics become available for clinical use, understanding which patients are most likely to benefit from Lp(a) lowering and how Lp(a) levels can be used to precisely define and contextualize residual risk in patients with ASCVD is critical.

Figure 1.

Lipoprotein(a) and Atherosclerotic Cardiovascular Disease
Lipoprotein(a) drives atherosclerotic cardiovascular disease through myriad mechanisms, including activation of innate immune cells (A), endothelial cells (B), platelets (C), and drives early atherogenesis (D), and plaque destabilization (E). ROS = reactive oxygen species.

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