Lipoprotein (a): An Under-appreciated, Under-diagnosed and Under-treated yet significant Risk Factor for ASCVD

Last Updated: October 14, 2021

Disclosure: None
Pub Date: Thursday, Oct 14, 2021
Author: Shobha Ghosh, PhD, FAHA
Affiliation: Department of Internal Medicine, Virginia Commonwealth University Medical Center

It is now well-established that increased levels of Lipoprotein(a) or Lp(a) confer an increased risk for cardiovascular disease (CVD), even in the setting of effective reduction of plasma low-density lipoprotein cholesterol (LDL-C). Although the causal role of Lp(a) in the development of CVD is amply supported by epidemiological, genome-wide association and Mendelian randomization data, multiple factors contribute to the lack of a standard management approach regarding Lp(a) in the clinical setting. These include variations in the definition of high Lp(a) level that diverge based on the assays used and units of measurement, the population ancestry and the clinical characteristics of the study population. Moreover, lack of approved therapies for specifically lowering Lp(a) and evaluation of the downstream effects on CVD risk reduction further contributes to the absence of clinical guidelines pertaining to the use of Lp(a) as a novel therapeutic target. in their AHA Scientific Statement: “Lipoprotein (a): A Genetically Determined, Causal, and Prevalent Risk Factor for Atherosclerotic Cardiovascular Disease” summarize the emerging biology, pathophysiology and clinical epidemiology of Lp(a) with an ultimate goal of utilizing the detailed understanding of the role of Lp(a) in CVD to provide clinical direction for screening and risk reduction. This workgroup consisting of diverse basic scientists and clinicians very concisely layout the historic perspectives, basic biology and metabolism of Lp(a), the current understanding of the genetics, the challenges of quantification of Lp(a) in human plasma and how to appropriately use the information obtained in modifying therapy options. The authors do a wonderful job in identifying priorities to address the current gaps in knowledge as well as clinical implementation of Lp(a) levels in the risk assessment for the primary prevention of CVD.

The challenges of defining the normal range for Lp(a)

Ill-defined normal (or high) levels of plasma Lp(a) pose a significant problem in the clinical utility of this important parameter. In the absence of any other clinical conditions, Lp(a) levels do not substantially change over the lifetime (1) but significant intra-individual variability, often as high as 20%, exist in serial measurements. In large cohorts, especially of European descent show as high as 100-fold variation (2). Interestingly, population Lp(a) levels are reported as median values since these are not normally distributed. In addition, race and ethnicity, significantly affect Lp(a) levels; individuals with African descent and South Asian populations have higher median Lp(a) levels compared to White or East Asians (1). Defining the role of genes contributing to the overall plasma Lp(a) levels and mechanism(s) involved in Lp(a) clearance from the plasma represent some of the priorities towards addressing the gaps in the knowledge. In addition, inconsistency associated with the currently used assay procedures (3, 4) and lack of uniform calibration (3) further adds to the observed variability in reported plasma Lp(a) levels and currently limit its clinical decision-making potential as a risk factor. The authors outline these underlying issues and provide guidelines for the clinicians to facilitate the future standardization of plasma Lp(a) measurement and the use of that data for therapeutic purposes.

Clues from genetics

Plasma levels of Lp(a) are greatly influenced by genetics making it an excellent candidate for Mendelian randomization studies and several recent studies have provided evidence for a causal relationship between high Lp(a) levels and CVD (2). LPA risk genotypes as well as causative LPA SNPs have been identified (5, 6). LPA also remains the only monogenic factor identified for aortic stenosis (7). Despite these significant advances, randomized CVD outcome trial data is needed to provide the final proof of causality. In addition, the mechanism(s) underlying the effects of these genetic variants on plasma Lp(a) levels, the functional characteristics of SNPs and targeted ancestry studies to determine the role on the magnitude of risk associated with high Lp(a) levels continue to be defined to fill the gaps in knowledge and advance the utility of understanding Lp(a) genetics in ascertaining CVD risk.

Hurdles in the development of Lp(a)-lowering therapies

The pathophysiology of Lp(a) is far from being fully defined with data supporting the pro-inflammatory and pro-calcific effects of Lp(a) (8), increased adhesion to the endothelial layer and retention within the intimal space (9), and directly inhibiting fibrinolysis (10) thereby promoting thrombosis to increase the risk for atherothrombotic diseases. Furthermore, currently there is no definitive proof that specific pharmacological lowering of Lp(a) reduces cardiovascular outcomes. Collectively, these two important factors represent the major challenge in the development, and possible use, of targeted Lp(a) lowering therapies. However, the genetic and epidemiological evidence is strong and lowering Lp(a) in addition to LDL-C is increasing being recognized as a clinical goal especially in patients experiencing recurrent CVD events despite aggressive LDL-C lowering. Lipoprotein apheresis is the most effective clinical intervention currently available and experimental therapies in development include use of antisense oligonucleotide (11) and small interfering ribonucleic acid (siRNA) molecules targeting apo(a). The outcome studies using these new strategies are in progress and are likely to advance the development of Lp(a) as a novel therapeutic target to reduce CVD risk.


Although our understanding of the role of Lp(a) as an independent CVD risk factor has significantly advanced in recent years, number of unanswered questions still remain. Reyes-Soffer and her expert colleagues have performed a great service by clearly summarizing the current status of Lp(a) research. In addition, their identification of challenges and hurdles, gaps in mechanistic understanding and status of the development of targeted therapies provide an excellent summary useful in defining the future perspectives.


Reyes-Soffer G, Ginsberg HN, Berglund L, Duell PB, Heffron SP, Kamstrup PR, Lloyd-Jones DM, Marcovina SM, Yeang C, Koschinsky ML; on behalf of the American Heart Association Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular Radiology and Intervention; and Council on Peripheral Vascular Disease. Lipoprotein (a): a genetically determined, causal, and prevalent risk factor for atherosclerotic cardiovascular disease: a scientific statement from the American Heart Association [published online ahead of print October 14, 2021]. Arterioscler Thromb Vasc Biol. doi: 10.1161/ATV.0000000000000147


  1. Enkhmaa B, Anuurad E and Berglund L. Lipoprotein (a): impact by ethnicity and environmental and medical conditions. J Lipid Res. 2016; 57:1111-1125.
  2. Kamstrup PR. Lipoprotein(a) and Cardiovascular Disease. Clin Chem. 2021; 67:154-166.
  3. Marcovina SM and Albers JJ. Lipoprotein (a) measurements for clinical application. J Lipid Res. 2016; 57:526-537.
  4. Marcovina SM, Albers JJ, Gabel B, Koschinsky ML and Gaur VP. Effect of the number of apolipoprotein(a) kringle 4 domains on immunochemical measurements of lipoprotein(a). Clin Chem. 1995; 41:246-255.
  5. Clarke R, Peden JF, Hopewell JC, Kyriakou T, Goel A, Heath SC, Parish S, Barlera S, Franzosi MG, Rust S, Bennett D, Silveira A, Malarstig A, Green FR, Lathrop M, Gigante B, Leander K, de Faire U, Seedorf U, Hamsten A, Collins R, Watkins H and Farrall M. Procardis Consortium. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med. 2009; 361:2518-228.
  6. Kamstrup PR, Tybjaerg-Hansen A, Steffensen R and Nordestgaard BG. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA. 2009; 301:2331-2339.
  7. Capoulade R, Chan KL, Yeang C, Mathieu P, Bosse Y, Dumesnil JG, Tam JW, Teo KK, Mahmut A, Yang X, Witztum JL, Arsenault BJ, Despres JP, Pibarot P and Tsimikas S. Oxidized Phospholipids, Lipoprotein(a), and Progression of Calcific Aortic Valve Stenosis. J Am Coll Cardiol. 2015; 66:1236-1246.
  8. van der Valk FM, Bekkering S, Kroon J, Yeang C, Van den Bossche J, van Buul JD, Ravandi A, Nederveen AJ, Verberne HJ, Scipione C, Nieuwdorp M, Joosten LA, Netea MG, Koschinsky ML, Witztum JL, Tsimikas S, Riksen NP and Stroes ES. Oxidized Phospholipids on Lipoprotein(a) Elicit Arterial Wall Inflammation and an Inflammatory Monocyte Response in Humans. Circulation. 2016; 134:611-624.
  9. Nielsen LB. Atherogenecity of lipoprotein(a) and oxidized low density lipoprotein: insight from in vivo studies of arterial wall influx, degradation and efflux. Atherosclerosis. 1999; 143:229-243.
  10. Boffa MB and Koschinsky ML. Lipoprotein (a): truly a direct prothrombotic factor in cardiovascular disease? J Lipid Res. 2016; 57:745-757.
  11. Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, Tardif JC, Baum SJ, Steinhagen-Thiessen E, Shapiro MD, Stroes ES, Moriarty PM, Nordestgaard BG, Xia S, Guerriero J, Viney NJ, O'Dea L and Witztum JL. AKCEA-APO-LRx Study Investigators. Lipoprotein(a) Reduction in Persons with Cardiovascular Disease. N Engl J Med. 2020; 382:244-255.

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