February 17th, 2014

Another Satellite of JUPITER: Lipoprotein(a)

CardioExchange’s Harlan M. Krumholz interviews Amit V. Khera, lead author of an analysis of lipoprotein(a) concentrations and residual vascular risk among participants in the placebo-controlled JUPITER trial of rosuvastatin. The study is published in Circulation.

Krumholz: How did you get interested in lipoprotein(a)?

Khera: Relatively few circulating biomarkers, when measured in patients on moderate- to high-intensity statin therapy, retain their ability to predict future events. My interest in lipoprotein(a) assessment relates to:

  1. A large body of epidemiologic studies from general populations linking elevated Lp(a) levels with future risk for cardiovascular events
  2. Multiple putative mechanisms by which Lp(a) may be linked to events, including a prothrombotic role, carrier of oxidized phospholipids, and increasing expression of endothelial adhesion molecules.
  3. Lp(a) levels are highly stable over time, with more than 50% of variation genetically determined. Furthermore, people born with genetic polymorphisms that correlate with higher Lp(a) levels are at increased risk for disease, thus supporting a causal role for the molecule in atherothrombosis.

Data regarding Lp(a) in the context of potent statin therapy and low-achieved LDL-cholesterol levels is both limited and conflicting, serving as the primary motivation for this analysis.

Krumholz: What should clinicians remember about Lp(a), beyond its being an LDL-like particle with apolipoprotein B covalently linked to apolipoprotein(a)?

Khera: Lipoprotein(a) is linked to both atherosclerotic events and valvular calcification in a relationship that is likely causal in nature. It retains its predictive value beyond standard risk factors, although incremental value is modest. Lp(a) was discovered more than 50 years ago, but we still have a lot to learn about which mechanism of its link to disease is most important and whether we can manipulate its metabolism in risk reduction.

Krumholz: How did the “little a” nomenclature evolve?

Khera: Apo(a), discovered in the 1960s, is a protein byproduct of the LPA gene in humans. The genetic locus is among the most highly polymorphic across the entire human genome, specifically with regard to the number of kringle IV repeats. This apo(a) protein is then covalently linked to apolipoprotein B, thus known as “little a.”

Krumholz: No guideline recommends measurement of this lipid. Do you routinely measure it in your patients? If so, when and why?

Khera: The role of lipoprotein(a) assessment in clinical practice is currently uncertain. In a 2010 consensus statement, the European Atherosclerosis Society suggested measurement of Lp(a) in high-risk patients. A 2011 expert panel convened by the National Lipid Association suggests that measurement is reasonable in selected intermediate- to high-risk patients, such as those with a family history of premature cardiovascular disease.

In my own practice, I have measured Lp(a) using validated assays in a small subgroup of patients with cardiovascular or valvular disease burden otherwise unexplained by conventional risk factors. If Lp(a) is elevated, current evidence would support aggressive risk-factor modification with statins and antiplatelet therapy to achieve global cardiovascular risk reduction. Niacin is known to decrease Lp(a), but its use in patients with elevated values for risk reduction does not have a strong evidence base at this time. I counsel patients that knowledge of their values may become increasingly relevant in the coming years, as we have multiple novel agents that decrease Lp(a) values in development, and I ultimately hope for targeted therapy of Lp(a) metabolism. Patients with extreme values may benefit from lipoprotein apheresis.

Krumholz: What is the main message from your findings?

Khera: In JUPITER, a primary-prevention trial involving patients with low-to-normal LDL-cholesterol but elevated C-reactive protein, lipoprotein(a) values were measured at both baseline and while participants were on potent rosuvastatin therapy. Lp(a) values were highly stable over time and largely independent of other risk factors. Statin therapy had minimal effect on Lp(a) concentrations despite a marked reduction in LDL-cholesterol. Black participants had a more than twofold higher Lp(a) concentration than whites. Both baseline and on-statin values of Lp(a) were linked to increased risk for cardiovascular events. Notably, this finding is in contrast to those from a limited number of smaller studies indicating that Lp(a) may not predict future events once low LDL-cholesterol levels are achieved. Our study, which showed that Lp(a) remains a significant risk factor despite a median on-treatment LDL-cholesterol level of 54 mg/dL, supports ongoing efforts to target Lp(a) metabolism in risk reduction.


Share your thoughts on Dr. Khera’s analysis of the lipoprotein(a) findings from JUPITER.

2 Responses to “Another Satellite of JUPITER: Lipoprotein(a)”

  1. Brett Forge, MB BS FRACP says:

    My interest in lipo a is in a genetic disorder. I have 7 or 8 families with individuals with levels of lipo a around 5 x the upper limit of normal. It appears to be transmitted as an autosomal dominant gene and in these families is strongly associated with premature IHD. I routinely check for it in pts with IHD who have very low risk on standard risk assessment. It is a very important diagnosis as it can be easily screened in family members and statin therapy appears to be effective in reducing risk although this would need to be confirmed in larger studies.

  2. Seth Martin, MD says:

    Congratulations on the great work, Amit! This is a very informative Q&A. I am very hopeful about the novel agents in the pipelines. Here is a really cool JACC paper that just came out showing a reduction in Lp(a) through PCSK9 inhibition with evolocumab:


    Can’t wait for the results of the outcomes trials for PCSK9 inhibitors.

    Brett Forge – thanks for sharing…very interesting observations. Hopefully we will have more treatment options in the not too distant future.