High lipoprotein(a): Actionable strategies for risk assessment and mitigation

Abstract

High levels of lipoprotein(a) [Lp(a)] are causal for atherosclerotic cardiovascular disease (ASCVD). Lp(a) is the most prevalent inherited dyslipidemia and strongest genetic ASCVD risk factor. This risk persists in the presence of at target, guideline-recommended, LDL-C levels and adherence to lifestyle modifications. Epidemiological and genetic evidence supporting its causal role in ASCVD and calcific aortic stenosis continues to accumulate, although various facets regarding Lp(a) biology (genetics, pathophysiology, and expression across race/ethnic groups) are not yet fully understood. The evolving nature of clinical guidelines and consensus statements recommending universal measurements of Lp(a) and the scientific data supporting its role in multiple disease states reinforce the clinical merit to start population screening for Lp(a) now. There is a current gap in the implementation of recommendations for primary and secondary cardiovascular disease (CVD) prevention in those with high Lp(a), in part due to a lack of protocols for management strategies. Importantly, targeted apolipoprotein(a) [apo(a)]-lowering therapies that reduce Lp(a) levels in patients with high Lp(a) are in phase 3 clinical development. This review focuses on the identification and clinical management of patients with high Lp(a). Specifically, we highlight the clinical value of measuring Lp(a) and its use in determining Lp(a)-associated CVD risk by providing actionable guidance, based on scientific knowledge, that can be utilized now to mitigate risk caused by high Lp(a).

Keywords: Cardiovascular Disease (CVD); Lipoprotein(a) [Lp(a)]; Lp(a) testing; Risk mitigation.

Fig. 1

Overview of the structure, regulation, measurement considerations and level interpretation of Lp(a) and CVD-associated risk. A) Listing of non-genetic and genetic factors that modolute lipoprotein(a) [Lp(a)] levels. Lp(a) levels are primarily determined by variability in the LPA gene which codes for the apolipoprotein(a) [apo(a)] component of the particle. . The prevalence of High Lp(a) levels ranges from 10-30% and varies depending on ancestry . B) The Lp(a) particle comprises a single apolipoprotein B-100 (apoB-100) containing lipoprotein covalently associated with apo(a). Oxidized phospholipids (OxPLs) are covalently associated with apo(a), apoB-100 and the lipid core. Apo(a) consists of 10 kringle IV (KIV) domains, a single KV domain and an inactive, protease-like domain. Different apo(a) isoforms have different KIV₂ copy numbers . Recent guidance on important considerations when choosing Lp(a) assays, along with the risk thresholds for determining risk from an Lp(a) measurement are described [5,10]. C) Adjusted hazard ratios for select cardiovascular disease (CVD) outcomes comparing participants in the top percentile of Lp(a) distribution (>95th percentile for calcific aortic valve stenosis [CAVS], ischemic stroke and CV mortality; >99th percentile for myocardial infarction [MI] and heart failure[HF]) versus those with lower Lp(a) levels (<22nd percentile for CAVS; <34th percentile for MI and HF; <50th percentile for ischemic stroke and CV mortality) . Peripheral artery disease (PAD) risk is based on an adjusted odds ratio for Lp(a) >66th percentile compared to <33rd percentile . Atrial fibrillation risk is based on a Mendelian randomization analysis of the odds ratio per 50 nmol/L increase in Lp(a) .

Fig. 2

Clinical guidelines and consensus statements recommend screening for Lp(a): When, in whom, and why? Multiple global clinical guidelines and expert consensus statements recommend Lp(a) screening to manage dyslipidemia and mitigate Lp(a)-mediated CVD risk. Provided is a synopsis of key recommendations for measuring Lp(a) from the: American Heart Association/American College of Cardiology (AHA/ACC) , Canadian Cardiovascular Society , and European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) clinical guidelines ; and the ACC, American Association Clinical Endocrinology/American College of Endocrinology (AACE/ACE) , EAS , and National Lipid Association (NLA) [4,83] consensus statements.

Fig. 3

Lp(a) screening rates in the United States are sub-optimal and are currently concentrated within a small number of health care providers (HCPs) . Two dedicated ICD-10-CM codes, E78.41 and Z83.430, are available to enhance the diagnosis of high Lp(a) and allow familial risk to be assigned to patients with Lp(a)-mediated CVD risk. The available CPT® code (83695), reports an Lp(a) blood test, while direct-to-consumer Lp(a) assays that measure in nmol/L are available to order at a low cost.

Fig. 4

Mitigation of Lp(a)-associated risk in patients with ASCVD. Patients with high Lp(a) and ASCVD should be categorized as being a high risk for future CVD event(s). As per the Central Illustration, adoption of “Life's Essential 8″ should be advised with initial risk mitigation discussions. Further understanding of the pro-atherogenic, pro-inflammatory and pro-thrombotic burden of Lp(a)-associated ASCVD risk should prompt consideration of the armamentarium of therapies that can mitigate risk (including lipid-lowering therapies and/or lipoprotein apheresis, and anti-inflammatory, anti-platelet and/or anti-coagulant therapies) with consideration of a referral to a specialist (eg, lipidologist or preventive cardiologist). Therapies in bold indicate those where current evidence suggests a clinical benefit could be derived in patients with high Lp(a).

Central Illustration. Incorporation of an Lp(a) measurement into a primary prevention ASCVD risk assessment, with a risk-based prevention approach The upper panel describes how an Lp(a) measurement in nmol/L can be incorporated as a risk enhancer into a 10-year predicted ASCVD risk assessment. Lp(a) risk is derived from the standardized risk for ASCVD being 11 % higher per 50 nmol/L increment within a multiethnic population from the UK Biobank . Additional risk modifiers should also be factored in. The bottom panel describes risk mitigation approaches depending on assigned risk category; all of these should initially adopt the AHA's holistic approach to CV health, “Life's Essential 8″, including healthy diet, physical activity, avoiding nicotine, healthy sleep, healthy weight, and healthy levels of blood lipids, blood glucose and blood pressure . With increasing risk category (ie, moderate to high risk), pharmacotherapeutic intervention(s) should be considered to address overall ASCVD risk, with consideration for a specialist referral (eg, lipidologist or preventive cardiologist) to provide well-informed advice on Lp(a)-associated risk. ApoB = apolipoprotein B-100; LDL-C = low-density lipoprotein cholesterol.