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Overview Guidelines and Lp(a)
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What's New in the Scientific World regarding Lipoprotein(a)?

 

As a result, in part, due to advocacy efforts by the Lipoprotein(a) Foundation over the last six years, in 2018 and 2019, the American Heart Association (AHA) and the American College of Cardiology (ACC), the National Lipid Association (NLA), and the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) released updated cholesterol guidelines. The best and most recent available evidence from clinical trials of cholesterol-lowering therapies and other historic scientific sources of evidence were used to create these recommendations. 

 

 

What do the AHA/ACC guidelines say about lipoprotein(a)? See Guidelines here

  

One of the key themes in this current update is an emphasis on involving the patient as an active partner in creating a treatment plan. They recommend a clinician/patient discussion include consideration of factors called "risk enhancers." These risk enhancers could be a deciding factor in some patients, as to whether cholesterol medications should be used to reduce the risk of heart disease. High levels of lipoprotein(a), diabetes, and a family history of premature heart disease are a few of the factors included in the list of risk enhancers. 

 

What do these guidelines consider a high level of lipoprotein (a)?

 

An Lp(a) ≥ 50 mg/dL or ≥125 nmol/L meets the criteria for a risk enhancing factor. 

 

In whom should a lipoprotein(a) level be measured?

 

The guidelines also recommend that a relative indication for the measurement of lipoprotein(a), is a family history of premature cardiovascular disease (CVD). Premature disease means less than 55 years old for men and 65 for women. 

 

Has anything new been published in 2019?

 

In June 2019, the National Lipid Association published "Use of Lipoprotein(a) in Clinical Practice: A Biomarker Whose Time Has Come. A Scientific Statement from the National Lipid Association (NLA)." See Statement here

 

What are the major takeaways from the NLA document?

 

  • Research has shown a causal connection between high Lp(a) and cardiovascular disease (CVD), including heart attack, stroke, coronary artery disease, valvular aortic stenosis, peripheral vascular disease, and heart failure. A high Lp(a) level increases CVD risk independent of the standard lipid profile (total cholesterol, LDL-cholesterol, and HDL-cholesterol). Importantly, this means that a person can have a normal standard lipid/cholesterol profile, and still have a lipid abnormality-high Lp(a)- that increases CVD risk.

 

  • Testing Lp(a) in the lab: Lab measurement of Lp(a) is currently not well standardized, and the Lipoprotein(a) Foundation has been advocating for six years for a harmonized Lp(a) measurement. Many characteristics of the Lp(a) particle, including the size/molecular weight of the apolipoprotein(a) component, in each individual (their isoform size), complicates accurate measurement. And in addition, concentration cut points vary by race and additional risk factors i.e., diabetes. For example, an Lp(a) level >50 mg/dL (>125 nmol/L) may be a "risk-enhancing factor," favoring the initiation of drug treatment with statin therapy. This level equates to the 80th percentile population cut point in white populations, whereas the 80th population percentile in African Americans is approximately 150 nmol/L. So, different races and ethnicities may require a different risk threshold or cut point. The risk associated with high Lp(a) may be different in various populations, and a high level of Lp(a) seems particularly dangerous in South Asians, Blacks, and Latinos.

 

Guidance on adults who should have their Lp(a) tested

 

  • Lp(a) testing recommended if you have premature CVD or have a first-degree relative with premature CVD. (The first-degree relative is a parent, sibling, or offspring)
  • Very high levels of LDL-C (LDL-C of 190 mg/dL) or suspected inherited high LDL-C levels (familial hypercholesterolemia)
  • To use as a risk enhancer in the clinician-patient discussion about whether to prescribe a statin in patients aged 40-75 years with a borderline CVD risk level
  • To evaluate a cause for a less-than-expected LDL-C lowering with drug therapy
  • To assess the cause of aortic valve stenosis (narrowing) 

  

Also, in September 2019, the European Society of Cardiology and the European Atherosclerosis Society, leading cardiovascular prevention physician societies in Europe published "2019 ESC/EAS Guidelines for the management of dyslipidemias: lipid modification to reduce cardiovascular risk (European Heart Journal 2019 -doi: 10.1093/eurheartj/ehz455)" See Guidelines here

 

 

What are the major takeaways from the ESC/EAS document?

 

  • The guidelines support a one-time lipoprotein(a) screening for all adults over the age of 40 (class IIa, level of evidence C) to identify people who have inherited an extremely elevated level of Lp(a) ≥ 180 mg/dL (≥ 430 nmol/L) and therefore have a very high lifetime risk of ASCVD that is approximately equivalent to the risk associated with heterozygous familial hypercholesterolemia. Also, this strategy can identify people with less-extreme Lp(a) elevations who may be at a higher risk of ASCVD, which is not reflected by the SCORE system (an ESC risk assessment method), or by other lipid or lipoprotein measurements.
  • Even though there are no treatments currently approved by the FDA for Lp(a)-lowering, identifying those with "very high" levels is still crucial because other cardiovascular risk factors may require treatment. Novel Lp(a)-lowering drugs are under investigation in the hopes they will reduce cardiovascular events
  • Racial differences make it hard to determine an optimal cut-off level of Lp(a), and so the Europeans do not see Lp(a) as a primary screen for prevention for people under the age of 40."

 

Guidance on adults who should have their Lp(a) tested

  •  Lp(a) measurement should be considered at least once in each adult person's lifetime to identify those with very high inherited Lp(a) levels >180 mg/dL (>430 nmol/L) who may have a lifetime risk of ASCVD equivalent to the risk associated with heterozygous familial hypercholesterolemia.
  • Specific individuals declare themselves to be at high or very-high CVD risk without needing risk scoring and require immediate attention to all risk factors. For example, patients with documented CVD, diabetes, familial hypercholesterolemia, chronic kidney disease, carotid or femoral plaques, coronary artery calcium (CAC) score >100, or extreme Lp(a) elevation.

 

  

So, what does this all mean and what's next?

 

These three recent statements by leaders in the field based on sound scientific evidence demonstrates that our knowledge about the role of lipoprotein (a) in the development and progression of atherosclerotic and aortic valvular CVD continues to evolve. These statements will help generate awareness to a broader audience, which should lead to increased testing and identification. Unanswered questions about lab test standardization and race/addition risk markers and associated cut points are currently under review. The foundation is advocating for standardization/harmonization of existing assays or a disruptive technology to replace them. Recognition of elevated Lp(a) concentrations should lead to more aggressive CVD risk reduction efforts.

The major unanswered question remains: Will lowering lipoprotein(a) with therapy (selective modification) lower CVD risk-prevent heart attack, stroke, and other CV events?

 

The research (Phase III clinical trial) designed to answer this question in patients with very high Lp(a) is pending regulatory (FDA) approval. Hopefully, the trial will start in early 2020, and it will test a compound AKCEA-APO(a)-LRx, which lowers Lp(a) by as much as 80%. 

 

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