Lipoprotein (a): Little but Mighty?
Written by Joseph Kummer, MD, FACC
Lipoprotein(a), Lp(a), is directly atherogenic and associated with a higher risk of atherosclerotic cardiac and cerebrovascular events. However, its clinical utility has been very limited since it is largely genetically based and therefore considered unmodifiable. The question arises whether checking it adds important additional information to a patient’s cardiac risk assessment, or does it simply reinforce the management plan that we would already recommend based upon other lipid levels and risk factors?
Lp(a) levels are mildly lowered by some treatments, such a nicotinic acid or apheresis. However, nicotinic acid therapy is not effective at lowering ASCVD events and apheresis is of course not practical. More recently, there has been some excitement as we have learned that PCSK9 Inhibitors can lower Lp(a) by about 20%. However, it is not known whether reduction in cardiac events with these agents is due to an effect on Lp(a) vs several other potential mechanisms.
So when is it helpful to check this level? Since Lp(a) levels are about 90% genetically programmed, assessment only once in a lifetime is considered adequate whereas repeat testing is generally not helpful. European guidelines recommend testing all individuals once in a lifetime to see if they have a very high level (about 180 mg/dL). US guidelines do not currently recommend screening.
Similar to a coronary calcium score, patients with known or high risk for ASCVD may not benefit from assessing Lp(a) as it is unlikely to change management. However, those with intermediate risk or a family history of premature coronary disease certainly may benefit from the additional risk stratification. We generally recommend statin therapy for those with a ten-year ASCVD Risk of 7.5% or more. It has been postulated to check Lp(a) levels in those perhaps with a 5.0-7.5% risk.
There has been a great deal of buzz in this area recently. A retrospective cohort analysis in JACC in March of this year showed that Lp(a) levels were independently associated with about a 26% increase in major adverse cardiac events in patients with known CAD. But of course, these patients should already be on aggressive treatment for their known disease. Importantly, in those without known CAD, the highest decile of Lp(a) was associated with an almost double risk for cardiac events.
To keep the excitement going, there have been two recent studies showing that we now have medications with the ability to markedly lower Lp(a) levels. One is with an antisense oligonucleotide called pelacarsen and the other is a small interfering RNA molecule called olpasiran. Clinical outcomes from these studies are pending, but safety and efficacy have been documented. Expectations are very high for these agents. If it is shown that these agents provide improved clinical outcomes above and beyond standard current therapies for lipid management, then Lp(a) levels may become an independent, and now modifiable, target for prevention of future adverse cardiac events. Bryan Heart is currently participating in the clinical trial investigating olpasiran, and are eagerly awaiting to see the early results, once long-term follow-up has been completed.
To summarize, Lp(a) is a genetically determined lipid that is strongly associated with adverse cardiac events. Screening can be done once in a lifetime and while indicated in Europe, it is not indicated in the US. While there is currently not an approved therapy to lower the level of this lipid, there are new encouraging trials with two medications to lower Lp(a) levels. If these prove beneficial, Lp(a) may become a common and meaningful target of therapy in the near future.
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