The Need to Simplify Lipoprotein(a) Testing Guidelines: Test Everyone

Lipoprotein(a) (Lp[a]) has been proven to be a potent, common, independent risk for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic stenosis (CAS). Recent reviews summarize how its complex molecular structure is uniquely suited to initiate atherothrombotic disease and how the molecular genetics of an overactive LPA gene — coupled with its autosomal codominant inheritance pattern — assure its prevalence and persistence. ^1,2 Global epidemiologic studies project that fully 20% of the world’s population have high enough Lp(a) levels (>60 mg/dL) to double or triple their risk for coronary or cerebrovascular events, which often cluster in families and occur early in life. This stunning number places an excessive Lp(a) level toward the top of the hierarchy of ASCVD risk factors. 

Clarification of Lp(a) as a common, potent, genetically driven cause of ASCVD has significant implications for revising the calculation of individuals’ cardiovascular (CV) risk, the appropriate management of coexisting risk factors, and also identifying a target for potential gene-altering, preventative interventions. Yet somehow the response in the clinical world to what seems to be a landmark moment in the history of preventative cardiovascular disease is quite muted. The fact that the projected 63 million Americans with levels greater than 60 mg/dL (the top 20%), which includes 16 million with levels greater than 116 mg/dL (the top 5% with exceedingly high risk), are unaware, as are their physicians that they carry this substantial risk, is central to this issue. This is because, unlike other quantifiable risk factors that are tested for, often repeatedly, currently Lp(a) testing is rare.

Is It Time to Update Lp(a) Testing Guidelines?

Since the LPA gene is fully expressed at 1-2 years of age, a level of 60 mg/dL or greater is a unique, lifelong CV risk. This makes early identification and treatment of other coexisting vascular risk factors a compelling strategy, especially in the absence of available Lp(a) treatment. Certainly, an aggressive approach to LDL levels should be implemented in patients with high enough Lp(a) levels to be at increased risk for ASCVD or CAS, but given current guidelines for testing Lp(a) in the US, this happens infrequently and often only after advanced disease is evident.

These guidelines, summarized in a JACC review in 2019 ³ reflect the past limitations of our understanding of Lp(a)’s clinical significance and the fact that no lifestyle changes or available medications have sufficiently lowered Lp(a) levels enough to impact its CV consequences.  As such, ongoing compliance with these cumbersome, restrictive guidelines, only identifies a fraction of those at high risk from Lp(a) excess, a risk factor known to be more common than diabetes. Ideally, guidelines in this unique situation need to promote a more forward-looking posture to foster the development and validation of potential treatments and to whom and when they might be prescribed. Universal testing is fundamental to achieving these ends.

Research Developments in Universal Lp(a) Testing

The experience of the Cleveland Clinic serves as a model for the kind of critical data that universal testing provides. ⁴ For over 10 years, every patient enrolled in the cardiac prevention program had an Lp(a) test. Follow-up of this 25,000-plus patient base has confirmed the increased incidence of coronary and cerebrovascular events as well as an increased incidence of CAS and a striking acceleration to severe valvular obstruction in those with elevated Lp(a) levels. A substantial, unequivocal increase in mortality associated with this powerful risk factor was identified from this dataset. These findings support that early identification of individuals with high Lp(a) levels should not only prompt aggressive risk factor intervention, but also vigilance for early onset of peripheral, coronary, carotid, and aortic valvular disease.

The ability to generate this type of data on a national scale and to identify patients with a predictable risk of recurrent, expensive, vascular events has potential value in allocating preventative and treatment resources as well.  The recent endorsement of one-time Lp(a) testing in all citizens of Canada and Europe ⁵ speaks to this strategic investment, likely to have significant future returns, as effective pharmacogenetic treatments to prevent the CV effects of elevated Lp(a) are being developed. Importantly, apheresis, the only successful method proven to lower Lp(a) levels significantly has also been shown to improve CV outcomes.

Clinical Outcomes of Using Apheresis to Reduce Lp(a) Levels

This invasive, time- and resource-intensive, dialysis-like procedure performed biweekly has been utilized in Germany for 15 years in patients with high Lp(a) levels and recurrent vascular events.  Several observational studies have demonstrated a 70-80% decrease in CV events following apheresis.⁶ These numbers are comparable to the 70% reduction of Lp(a) levels. Should a more efficient, practical, accessible treatment with similar outcomes become available, the cost of an Lp(a) test — the only way to identify the highest risk patients with certainty — will be well worth it. A one-time $100 test would contribute to significant year-after-year savings as recurrent, costly vascular events decline in this previously underidentified cohort.

Exploring Lp(a)-Targeted Therapy to Decrease Cardiovascular Events

The LPA gene is responsible for Lp(a) synthesis, and levels remain relatively constant throughout life. This makes it an ideal target for genomic interventions, and several mRNA-mediated approaches are being investigated. To date, an antisense oligonucleotide (ASO), developed by Ionis Pharmaceuticals, has been shown to reliably and safely inhibit Lp(a) synthesis in 2 published phase 2 trials. ⁷ This hepatocyte-directed, single-strand DNA sequence disrupts the translation of the LPA gene’s blueprint for apolipoprotein-A synthesis at the mRNA level. This essentially turns off Lp(a) synthesis and is accomplished with a self-administered, once-a-month, subcutaneous injection that lowers Lp(a) levels 70-80% — essentially identical to apheresis. Its clinical efficacy in reducing CV events is the focus of the Lp(a) Horizon trial (ClinicalTrials.gov Identifier: NCT04023552).

For this study, researchers are enrolling 7,680 patients with a history of previous vascular events or documented peripheral artery disease. Participants with Lp(a) levels over 70 mg/dL are randomly assigned to receive placebo or active treatment with an agent formerly identified as TQJ230, now labeled Pelacarsen. Primary endpoints over a 4-year period include CV death, nonfatal myocardial infarction, nonfatal stroke, or urgent coronary revascularization requiring hospitalization. 

Unfortunately, as with all clinical trials initiated in the COVID-19 era, enrollment and execution have encountered unavoidable delays. This worldwide effort involves over 1000 academic centers, and it is hard not to think that US enrollment would have been significantly facilitated were universal testing already in place.  Nevertheless, this is unquestionably a pivotal trial, similar to the 4S Trial in scope, design, and potential impact.     

The Potential Future With Universal Lp(a) Testing

Universal Lp(a) testing would help spotlight advances that have clarified its previously underestimated role in ASCVD and CAS. It would expand the pool for future clinical trials to evaluate appropriate treatments and inform guidelines for management of individuals at high risk. It would help to correct the current significant underestimation of the risk for ASCVD in 20% of the population, hence improving comprehensive risk factor management. It would identify and inform those who have puzzled over their family’s multigenerational legacy of strokes and heart attacks.

Once elevated Lp(a) gets its rightful attention as a genetic issue affecting 1 in 5 people and which contributes significantly to the most lethal disease on the planet, patients will certainly be asking “Does this mean me?” There is only one way to provide that answer.

References

1. Miksenas H, Januzzi Jr JL, Natarajan P. Lipoprotein(a) and cardiovascular diseases. JAMA. Published online July 8, 2021. doi:10.1001/JAMA.2021.3632
2. Tsimikas S. A test in context: Lipoprotein(a) : diagnosis, prognosis, controversies, and emerging therapies. J Am Coll Cardiol. Published online February 6, 2017. doi: 10.1016/j.jacc.2016.11.042
3. Grundy SM, Stone NJ, Baily AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. J Am Coll Cardiol. 2019; 73 (24:3168-3209)
4. Nissen S. Role of Lipoprotein (a) in Coronary Disease: What CV Risks Can You Expect? How to Manage the Condition? VuMedi Keck School of Medicine and USC Video Conference January 5, 2021.
5. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidemias: lipid modification to reduce cardiovascular risk: the task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur Heart J. Published online August 31, 2019. doi: 10.1093/eurheartj/ehz455
6. Roeseler E, Julius U, Heigl F, et al. Lipoprotein apheresis for lipoprotein (a)-associated cardiovascular disease; prospective 5 years of follow-up and Apolipoprotein(a) characterization. Arterioscler Thromb Vasc Biol. Published online July 14, 2016. doi: 10.1161/ATVBAHA.116.307983
7. Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, et al. Lipoprotein(a) reduction in persons with cardiovascular disease. N Engl J Med. Published online January 16, 2020. doi:10.1056/NEJMoa1905239.