Lipoprotein(a): Small Particle, Big Risk?

The cardiovascular (CV) risk series to date has primarily focused on 3 types of risks: so-called residual risk (that is, risk remaining after LDL is lowered to target); LDL-cholesterol itself (and its treatment targets in different clinical situations, such as CKD); and contributions from inflammation implicated by surrogate markers (for example, C-reactive protein in HIV/AIDS). It is time delve more deeply into the complicated molecules that carry and package cholesterol.

We begin with lipoprotein(a) (Lp[a]). 
 
Lp(a) is an LDL-like particle that exists in plasma in the VLDL range (in fact it is cleared by the VLDL receptor).¹ It possesses a density intermediate between that of LDL and HDL.¹ Lp(a) increases CV risk. What we know will not hurt us, but what we do not know is perplexing. The physiologic role of Lp(a) has not been completely clarified. There are not many ways by which to lower Lp(a),¹ as will be reviewed. And, as of yet, we do not know whether lowering Lp(a) will, in fact, decrease CV risk.¹   
 
To start, let’s look at what is known about Lp(a)’s role in CV risk. Lp(a) has been identified in plaques in levels correlating with plasma levels (ie, high in plaques when high in plasma and vice versa).² In fact, it accumulates in plaques to a greater degree than LDL.¹ Apropos of CV risk as a consequence of inflammation, Lp(a) also attracts macrophages and  stimulates interleukin-6 and adhesion molecule activity. With these myriad negative reactions attributed to Lp(a), it should not be surprising that this particle is characterized as an independent risk factor for CV events.³ Reflecting on disease states already studied in this series that are high CV-risk equivalents, Lp(a) is elevated in people with CKD.⁴

So, if Lp(a) is a prominent culprit in CV risk, why not just lower it like we do LDL?

It’s not quite that easy. Statins lower Lp(a) only inconsistently and diet does not affect it either.¹ Fibrates also are inconsistent.¹ Niacin can lower Lp(a) by 20% to 25%, but the therapy is fraught with side effects. That said, perhaps a niacin trial in select patients is worth it, since it is, to date, the best drug we have to lower Lp(a).⁵ The title of the first paper referenced below brings us back to reality: “Lipoprotein(a): where are we now”?¹  

Until the discovery of other pharmaceutical agents that specifically lower Lp(a) and affect its proposed risks, the molecule has been relegated to a role in CV risk prediction. A recent paper⁶ demonstrated that persons with Lp(a) levels at or greater than the 80th percentile could be correctly reclassified with higher CV risks.⁶ More aggressive Lp(a)-lowering therapies, including apheresis, have been proposed as well for those in the highest Lp(a) percentiles.⁷

Lp(a) is a problematic risk factor. It is not completely understood and therapeutic options are limited when it is elevated. The good news is that Lp(a) is under intensive study. New data may locate important pieces that fit the residual CV risk puzzle. Until then, use Lp(a) as a risk predictor and consider niacin as a proven option for treatment.  


1. Tziomalos K, Athyros VG, Wierzbicki AS, et al. Lipoprotein a: where are we now? Curr Opin Cardiol. 2009;24:351-357.
2. Dangas G, Mehran R, Harpel PC, et al. Lipoprotein(a) and inflammation in human coronary atheroma: association with the severity of clinical presentation. J Am Coll Cardiol. 1998;32:2035-2042.
3. Nguyen TT, Ellefson RD, Hodge DO, et al. Predictive value of electro-phoretically detected lipoprotein (a) for coronary heart disease and cerebro-vascular disease in a community-based cohort of 9936 men and women. Circulation. 1997;96:1390-1397.
4. Munter P, Hamm LL, Kusek JW, et al. The prevalence of non-traditional risk factors for coronary heart disease in patients with chronic kidney disease. Ann Intern Med. 2004;140:9-17.
5. Athyros VG, Tziomalos K, Mikhailidis DP, et al. Do we need a statin-nicotinic acid-aspirin mini-polypill to treat combined hyperlipidemia? Expert Opin Pharmacother. 2007;8:2267-2277.
6. Kamstrup PR, Tybjaerg-Hansen A, Nordestgaard BG. Extreme lipoprotein(a)
levels and improved cardiovascular risk prediction. JACC. 2013;61:1146-1156. doi:10.1016/j.jacc.2012.12.023.         
7. Malaguarnera M, Vacante M, Russo C, et al. Lipoprotein(a) in cardiovascular diseases. Biomed Res Int. 2013 Dec 30; [Epub ahead of print].