Time Stamps

  • 02:17 Pearl 1: What makes Lp(a) unique? How does it raise ASCVD risk?
  • 10:32 Pearl 2: Who should be tested for Lp(a)? When and why?
  • 16:54 Pearl 3: Understanding and interpreting Lp(a) levels
  • 24:04 Pearl 4: How does an elevated Lp(a) affect management?
  • 37:05 Pearl 5: The role of aspirin and PCSK9 inhibitors in Lp(a)

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Show Notes

Pearl 1 – The Uniqueness of Lp(a): Lp(a) is an independent risk factor for atherosclerotic cardiovascular disease.

What is Lp(a), and how does it relate to cardiovascular disease risk? What makes it special relative to other lipoproteins?

  • Lipoprotein(a) or ā€œLp(a)ā€ is an LDL-like particle with a covalently attached apolipoprotein(a) moiety.
    • All LDL particles contain an apolipoprotein(B) or Apo(B)
      • Apo(B) levels tell you about the total # of LDL particles in circulation, but more specific assays are needed to identify the subtypes in circulation, including Lp(a).Ā Ā 
  • Lp(a) levels are genetically determined by the LPA gene.Ā 
    • Adult levels are usually reached by age 5 and change negligibly thereafter, with little to no influence from environmental factors identified at this time.
  • Individuals have different isoforms of apolipoprotein(a) and thus Lp(a) based on the number of kringle repeats (KIV-Type-2) present in the LPA gene.
    • Kringle repeats are a protein structural domain in apolipoprotein(a) which are also seen in plasminogen and lead to itā€™s structural homology with Lp(a) (and other particles involved in coagulation)
    • Differences in number of Kringle repeats can lead to discrepancy in measuring Lp(a) by mass.
    • Fewer Kringle IV-Type-2 repeats lead to smaller isoformsĀ 
      • Associated with higher circulating levels of Lp(a) and higher ASCVD risk.
      • This is thought to be due to faster rates of hepatic synthesis/assembly for these smaller isoforms
  • Lp(a) is an independent predictor of atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis.Ā 
  • The exact pathophysiology of Lp(a) leading to increased CVD is unknown, however several mechanisms of itā€™s atherogenicity have been proposed:Ā 
    • Lp(a) is a proinflammatory molecule
    • Lp(a) carries and leads to increased generation of oxidation phospholipids
    • Lp(a) may increase localized thrombogenicity
      • Apo(a) is hydrophilic and contains no lipid domains, helping it bind exposed lysine residues of exposed vascular endothelium – possibly reflecting itā€™s structural homology with plasminogenĀ 
    • Recall that all of these mechanisms often occur in the setting of upstream endothelial damage/dysfunction caused by conditions such as hypertension and smoking.Ā 
      • Endothelial damage and dysfunction is another key piece of atherogenesis and ASCVD eventsĀ 
  • Optimizing other modifiable risk factors is so critical in managing CVD risk in patients with elevated Lp(a).

Pearl 2 – Testing: Testing for Lp(a)

Who should receive testing for Lp(a)? Is there any utility to trending levels?

Explicit rules for testing for Lp(a) varies across society guidelines and expert opinions

  • The AHA recommends testing in the following clinical settings:Ā 
    • Family history of premature ASCVD (<55 in men, <65 in women)
    • Personal history of ASCVD unexplained by other risk factors or with progression/recurrent ASCVD despite optimal medical management
    • Patients with borderline-intermediate ASCVD riskĀ 
  • This is to help restratify risk in these patients in the context of Lp(a)
  • The EAS recommends the above categories in addition to once in a lifetime testing for all adults
  • The National Lipid Foundation and Canadian Cardiovascular Society is consistent with the above, endorses one time testing for all and emphasizes testing in patients with a family history of familial hypercholesterolemia
  • Indications for testing for Lp(a) at present can generally be sorted into three buckets
    • Patients who have had an MI or stroke that is not well explained by conventional ASCVD risk factors
    • Patients who have had progressive or recurrent ASCVD events despite optimal management of other risk factors (ie. BP, LDL, smoking cessation)
    • Patients with borderline-intermediate ASCVD risk based on traditional measures
  • Lp(a) is a negative acute phase reactant, and thus acute inflammatory states can falsely lower levels, though changes in levels can vary based on condition
    • Levels can be decreased in the setting of acute critical illness such as sepsis
    • Note that other acute insults such as MI have been associated with elevated Lp(a)
  • As of yet, there does not appear to be explicit identified benefit to trending levels given their genetic determination and steady state achieved around age 5 as mentioned above

Pearl 3 – Understanding Levels: Lp(a) measurement and interpretation of levels

How is Lp(a) measured? What constitutes an elevated level? How should levels be interpreted as a whole?

  • It is estimated that 20-25% of the worldā€™s population has Lp(a) levels that are considered elevated
    • This varies across ethnicities with some notable observed differences
      • Some studies have noted higher Lp(a) levels associated with individuals identifying as Black and those identifying as Southeast Asian
      • There may be discrepancies in risk associated with different levels across ethnicities, which may relate to itā€™s genetically determined natureĀ 
  • In the context of the rest of the lipid panel, Lp(a) is another apo(B) carrying particle that is not specifically measured on a traditional lipid panel
    • Recall that all atherogenic cholesterol containing particles, including LDL, IDL, VLDL, and Lp(a) contain an apo(B)Ā 
    • LDL simply tells us how much cholesterol (mass) is being carried by LDL particles
    • Some individuals with high apo(B) levels and low LDL (so-called ā€œdiscordantā€ values) may have elevated Lp(a)
  • There are two main methods used to measure Lp(a) are reported in either mg/dL or nmol/L
    • These measures are not interconvertible due to differences in size of Lp(a) particles across individuals.Ā 
      • Ie. Some patients may have larger but fewer Lp(a) particles vs. smaller but a greater number of Lp(a) particles which could equate to the same mass on mg/dL but different nmol/L levels
      • Because of this, the nmol/L is preferred, though there is usually reasonable concordance between mass and particle number metrics for most individuals
  • Elevated levels are dependent on the assay and vary slightly across society guidelines
    • Values >50 mg/dL or 125 nmol/L are generally considered elevated and can be used for rapid reference
    • Specifically:Ā 
      • The AHA classifies levels >50 mg/dL or >125 nmol/L as elevated
      • The European Atherosclerosis Society considers three tiers of levels
  • <30 mg/dL (75 nmol/L) as being normal
  • 30-50 mg/dL (50-125 nmol/L) as being intermediate, andĀ 
  • >50 mg/dL or 125nmol/L as being elevated
  • The Canadian Cardiovascular Society and National Lipid Association notably uses >100 nmol/L as elevated in addition to the >50 mg/dL cutoff
  • The risk of ASCVD events attributable to Lp(a) elevation, like LDL, is more likely linear
    • This was shown in a retrospective analysis of the UK Biobank data but still needs further validation in other populations
    • The hazard ratio attributable to Lp(a) elevation can be quantified as 1.11n, where n = Lp(a) in nmol/L divided by 50
      • That hazard ratio is multiplied by the 10-year ASCVD risk %
      • So new ASCVD risk incorporating Lp(a) =Ā 
  • ASCVD Risk x 1.11 ^ (Lp(a) nmol/L Ć· 50)Ā 
  • This can be used as a rough estimate in counseling patients by multiplying by their traditional PCE Risk.Ā 
    • Ex. Lp(a) of 500 nmol/L with 7.5% ASCVD = 500/50 = 10 ā†’ 1.1110 * 7.5 = 2.83 * 7.5 = 21.22% (APPROXIMATE) 10-year ASCVD risk after incorporating Lp(a)Ā 

Pearl 4 – Management: Management of Elevated Lp(a)Ā 

How does Lp(a) affect primary prevention for patients with intermediate or borderline ASCVD risk as measured by conventional calculators? Are there any specific therapies that lower Lp(a)?Ā 

    • There is (at the time of writing) NO FDA APPROVED pharmaceutical therapy for lowering Lp(a)Ā 
    • Aggressive management of other modifiable risk factors in all patients with elevated Lp(a)
      • Tailor counseling to patient-specific risk factors: ie. smoking cessation, blood pressure control, BMI, LDL-C, management of diabetes
    • Lp(a) can be used as a ā€œtie-breakerā€ for initiation of statin therapy in patients for primary prevention
      • Initiation of statin therapy in patients with elevated Lp(a) and intermediate-borderline ASCVD 5-7.5% risk is favored per AHA guidelinesĀ 
      • There are no explicit LDL level goals specific to patients with elevated Lp(a), though it may be reasonable to target lower LDL goals (ie. <55mg/dL)Ā 
      • Statins may actually raise Lp(a) levels by 10-20%
    • Elevated Lp(a) in secondary prevention should support strict control of modifiable risk factors such as LDL goals, blood pressure control, and management of diabetes
      • There are as of yet no established differences in LDL goals, duration of DAPT, or blood pressure management in secondary prevention with elevated Lp(a)
  • Remember that because Lp(a) is genetically determined, levels are not modifiable through diet/lifestyle like LDL and thus risk reduction is focused on other factors
  • Though always happy to see patients, elevated Lp(a) does not automatically necessitate referral to Cardiology for further management.
  • There are a number of therapies for lowering Lp(a) in developmentĀ 
    • Most of these therapies target Lp(a) synthesis as Antisense oligonucleotides (ASOā€™s) or siRNA
    • The Horizon Trial – investigating pelacarsen, an ASO that inhibits Lp(a) production – is presently in phase 3 and is expected to publish results in 2025

Pearl 5 – Specific Therapies: The Role of Aspirin and PCSK-9i in managing elevated Lp(a)

Is there any role for aspirin for primary prevention in patients with elevated Lp(a)? When should PCSK-9 inhibitors be considered?

  • PCSK9 inhibitors ARE NOT approved for elevated Lp(a) alone
  • Aspirin may have a role in primary prevention for patients with elevated Lp(a), though prospective trials are needed
    • The anti-platelet activity of aspirin may help counteract the pro-coaguable risk-enhancing physiology of Lp(a) seen from itā€™s homology with plasminogen in addition to increased tissue factor expression and platelet activation/aggregation
    • Retrospective cohort data in MESA, WHS, and ASPREE (among others) has shown promise for the use of aspirin as primary prevention in patients with elevated Lp(a) or Lp(a) associated mutations, being associated with reduced risk of ASCVD events
    • This is reflected in a 2019 statement from the National Lipid Association, stating aspirin may be considered on a case-case basis in patients with Lp(a) > 50mg/dL

Transcript

Dr. Steven Nissen: Knowledge is power. Everybody needs to know what their lipoprotein A level is, including both of you. And if you don’t know what your lipoprotein A level is, find out – you might get a big surprise.Ā  And knowing that you have a risk factor is important.

Dr. Shreya Trivedi:Ā  Welcome to the Core IM 5 Pearls Podcast, bringing you high-yield, evidence-based pearls. Iā€™m Dr. Shreya Trivedi. And Iā€™m joined by…

Dr. Ian Kelly: I am Dr. Ian Kelly, a resident at BIDMC.

Dr. Shreya Trivedi:Ā  Today, weā€™re talking about Lp(a).Ā 

Ian: You know Shreya, when I first read about Lp(a), I never knew how it was pronounced. I cycled through a mumbled ā€œlipoprotein-level-aā€ or just ā€œlipoprotein aā€ under my breath until starting to interview for this episode and mercifully being informed by our first expert that it was in fact known as ā€œL-P little aā€

Dr. Shreya Trivedi:Ā  It is so humbling. It is not intuitive when you read it, so I definitely was thereĀ  with you. Alright, before we get started, let’s take a moment and challenge yourself with the following questions. Remember, the more you test yourself, the deeper your learning gains.

Dr. Ian Kelly: Pearl 1 – The uniqueness of Lp(a)

Dr. Shreya Trivedi:Ā  What makes Lp(a) different from other LDL particles and how does Lp(a) raise ASCVD risk?

Dr. Ian Kelly: Pearl 2 – Testing

Dr. Shreya Trivedi:Ā  Which patients should receive Lp(a) testing? And, is there any utility in trending levels over time?

Dr. Ian Kelly: Pearl 3 – Understanding Levels

Dr. Shreya Trivedi:Ā  How do you interpret the Lp(a) level?Ā 

Dr. Ian Kelly: Pearl 4 – ManagementĀ 

Dr. Shreya Trivedi:Ā  How does an elevated Lp(a) change your management, and when should you consider starting statins?

Dr. Ian Kelly: Pearl 5- Potential roles for aspirin and PCSK9 inhibitors

Dr. Shreya Trivedi:Ā Is there a role for aspirin in primary prevention for an elevated Lp(a)? What about PCSK9 inhibitors?

PEARL 1: Lp(a) Basics -What is Lp(a)?

Dr. Ian Kelly: So first things first, we sat down with Dr. Coco Fraiche, a cardiologist at BIDMC to figure out exactly is what Lp(a) is.

Dr. Ariane Coco Fraiche:Ā It’s a subtype of LDL. So, LDL is low density lipoprotein cholesterol C, that’s actually distinct from LDL because on its surface it carries a single molecule of apolipoprotein A, and is genetically determined primarily. But this subtype of LDL has an independent role in increasing atherosclerotic cardiovascular risk

Dr. Ian Kelly: So, Lp(a) is basically an LDL particle with this special apolipoprotein(a) attached.

Dr. Shreya Trivedi:Ā  That’s crazy that just a small structural difference compared to other LDL particles gives such significant cardiovascular risk.

Dr. Steven Nissen: Now, it is important to understand that it is unlike LDL or any other lipid particle because it’s almost exclusively determined by genetics, and both alleles from each parent contribute. And so we see that there’s a high concordance rate for the disorder amongst first degree relatives of people who have a high lipoprotein a about half of first degree relatives will also have a very high lipoprotein(a). And it’s associated with a very high risk of coronary artery disease and other atherosclerotic vascular disease events

Dr. Ian Kelly: That was Dr. Steve Nissen, a cardiologist at the Cleveland Clinic. And it turns out, fascinatingly, this information has been out there for decades. A study from 1981 looked at 76 male post-MI patients and compared Lp(a) levels to age-matched controls and what they found was patients with Lp(a) levels > 50 mg/dL had 2.3 fold higher risk of a heart attack.

Dr. Shreya Trivedi:Ā You know Ian, this makes me wonder: whatā€™s special about Lp(a) that makes it lead to more CV badness?Ā 

Dr. Greg Katz: If I’m not sure to be completely completely honest with you, if we fully understand why that doesn’t mean that we don’t have a lot of ideas about what makes that particle more likely to cause atherosclerosis.Ā  It’s an atherogenic particle. It increases the rate of oxidation, it carries oxidized phospholipids. And so it’s pro oxidative.Ā  In order for LDL to cause inflammation when they’re inside the artery wall, they need to become oxidized. And Lp (a)LP little A increases the rate of oxidation.

Dr. Ian Kelly: Thatā€™s Dr. Greg Katz, a cardiologist at NYU. So, it sounds like Lp(a) will increase oxidation of phospholipids at a much higher rate and therefore worsen the inflammatory milieu inside the plaque.

Dr. Shreya Trivedi:Ā But this seems to be common across LDL particles at least to an extent. There must be something else?

IDr. Ian Kelly: Yeah I was surprised to learn that Lp(a) actually increases local thrombosis. One of the leading thoughts is that Lp(a) has structural similarities to plasminogen and may compete for binding sites at the endothelium, making things more coagulable.

Dr. Shreya Trivedi:Ā  Nice. We will get more into why Lp(a) is prothrombogenic and why that matters clinically in pearl 5.

Dr. Ian Kelly: Either way, I think the main takeaway for me is that Lp(a) has 3 main mechanisms proposed for increasing ASCVD risk: it increases oxidation of phospholipids, itā€™s pro-inflammatory, and itā€™s maybe or probably thrombogenic.Ā 

Dr. Shreya Trivedi:Ā Yeah, i think i knew the headline read that Lp(a) carries this independent risk for CV badness and its genetically determined. You know I used to get tripped on Lp(a) until I understood how Lp(a) tells us vs. what the conventional lipid panel tells us. And how is that different from what the conventional lipid panel tells us that I figured things out more?

Dr. Ian Kelly: Same, I had an ah-ha moment after I finally understood how Lp(a) is different from what an LDL-C on a lipid panel or ApoB is telling us!

Dr. Greg Katz: A lipid panel tells you the amount of cholesterol that is carried by LDL particles or LDLC, and that’s different than the number of particles in circulation. I think the simplest way to think about this is we want to think about a traffic problem and we want to know how many cars are on the road. All of these cars or all of these vehicles, like LDL is one type of vehicle. Lp (a) the sedans, or LDL, are the majority of the problem, but there’s also other all vehicles that lead to traffic right?, Just like many of these particles can lead to atherosclerosis.? And counting vehicles directly should be better than estimating based on how many people are in them. Ā So, I guess the question is, how do we find how many vehicles are actually on the road? All of those vehicles are marked as vehicles because they have a license plate. A and that license plate is apolipoprotein B. And so every single particle that is floating through your bloodstream that has the ability to cause atherosclerotic cardiovascular disease, aka heart disease, every single one of those particles has one apolipoprotein B on it. And because they all have one ApoB that means that ApoB is a really good metric for the total number of particles that can cause heart disease that are floating through your bloodstream. When you check an ApoBĀ it doesn’t tell you how many of those particles are LDL or how many of those particles are LPLA or VLDL. It tells you the total number of vehicles on the road.

Dr. Shreya Trivedi:Ā Wow that license plate analogy really hit home. So Apo(B) is our way to see how many potentially atherosclerotic particles are in circulation in total. But, what if we want to go looking for 18 wheelers? What about those particles like Lp(a) which may contribute to atherosclerosis (more of a traffic jam than others vs. worse crashes) more than others?

Dr. Greg Katz: It does not tell you about the relative contributions of all of those particles. And so if you have a high ApoB, it could all be LDL and that’s what it is for most people. But it could also be you have a pretty normal LDL and you have a lot of LP(a) floating through your bloodstream, and if that’s the case, then your risk is probably a little bit higher. So there’s a subset of people who have an apolipoprotein B that looks high and an LDL that looks low. And the term that we use for those patients is they have discordant ApoB and LDL. And when you have a discordant ApoB and LDL, the ApoB is a better predictor of your heart disease risk. And for some patients that’s because they have a lot of LP(a).

Dr. Shreya Trivedi:Ā  All right Ā so getting an Lp(a) in these patients can help us identify those high risk vehicles that might be contributing more to traffic jams that might not be seen as well or captured in a traditional lipid panel.

Dr. Ian Kelly: I think that’s a great point to remember. What i’m taking away is that Lp(a) is one of several atherogenic particles that contributesĀ  to ASCVD and Lp(a) is different because it is genetically determined and an independent risk factor for someone’s cardiovascular risk. Lp(a) is pro-inflammatory, carries oxidized phospholipids and increases their rate of oxidation, and on top of that is pro-coagulable.Ā 

PEARL 2: Who & When to test

Dr. Shreya Trivedi:Ā All right, so now that we know Lp(a) is a type of LDL that has structural properties making it more atherogenic, let’s get into who we should be testing Lp(a) levels in and when to test?

Dr. Ian Kelly: So, looking into who to test and different guidelines was really fun to dive into. Turns out different guidelines and groups have different recommendations and .. so did our discussants! Ā 

Dr. Shreya Trivedi: Yeah so first up Dr. Fraicheā€™s approach. Itā€™s in line with American Heart Association guidelines.. at least what it is currently. And i really appreciated how she broke down who to send testing on into 3 memorable buckets which really stuck with me:

Dr. Ariane Coco Fraiche:Ā I’m thinking about patients who have had an event, an MI or a stroke that may be not explained by major well-known risk factors or suspected familial hypercholesterolemia. And patients who have recurrent or progressive ASCVD despite just being really optimally managed.

Dr. Shreya Trivedi: Yeah so the 1st bucket of people to send off Lp(a) ins those secondary prevention, are those people who had an MI or stroke but don’t have the traditional risk factors or worrisome family history.Ā  OR it is those who continue to have ASCVD events despite being optimally managed of an LDL goal, blood pressure, smoking status.. All the good things!Ā 

Dr. Ian Kelly: And one of our reviewers made sure to highlight that testing in those patients that have had an early MI or stroke is super important because elevated Lp (a) is actually the leading cause of heart disease in these patients.

Dr. Shreya Trivedi: But those are patients who have already hadhave an event, what about those that havenā€™t?

Dr. Ariane Coco Fraiche: The second bucket is primary prevention. So those are predominantly the patients who fall into this borderline or intermediate category risk kind of based on some of our traditional tools such as the pooled cohort equations.Ā And so when we’re looking for a way to better risk stratify our patients who we think are not super, super low risk, then they’re in this borderline or intermediate risk and you’re trying to have conversations about risk reduction or understanding risk. Lp (a) can be helpful in that context.Ā 

Dr. Ian Kelly: So 2nd bucket is primary prevention for those who fall into this intermediate or borderline risk category, so maybe around 5-7% on the traditional ASCVD pooled cohort equations or those of similar risk.

Dr. Shreya Trivedi: And last but not least, who falls into the 3rd bucket for getting a Lp(a) done?Ā 

Dr. Ariane Coco Fraiche: Patients fall into this category if maybe they haven’t had a personal history of A-S-C-V-D, but perhaps they have a strong family history of premature ASCVD or they’ve had a family member who’s had very high Ā Lp (a) testing.Ā 

Dr. Shreya Trivedi: Just so we are on the same page when we talk about premature ASCVD risk. Itā€™s going to be a family hx of a <55 years old in person assigned Male at birth and <65 in those assigned female.Ā 

Dr. Ian Kelly: Alright so now we have those 3 buckets in mind, it was really interesting to hear about different practice patterns on who to test and different society recommendations from our other discussants.

Dr. Steven Nissen: Some organizations like the National Lipid Association recommend that every person, every adult, have it tested at least once, preferably early in life, like in their twenties. If you’re 25 years old and you find out your lipoprotein A is 315 nanomoles per liter, are you going to do anything differently? Am I going to counsel you to do anything differently during the course of the next few decades of your life? You bet I am.

Dr. Ian Kelly: Testing everybody really makes sense when you think about the prevalence of elevated Lp(a).

Dr. Shreya Trivedi: Really? How bad are some of the prevalence numbers?

Dr. Ian Kelly: Most epidemiologic studies report 20-25% of people worldwide have elevated Lp(a)!

Dr. Shreya Trivedi: Oh thatā€™s a ton of people! I’m guessing also it probably varies based on ethnicity, especially as genetics are in place, I bet there’s like clusters in different places in the world.

Dr. Ian Kelly: When i was writing the show notes, I did see that some studies breakdown Lp(a) by different groups, and showed individuals with a higher percentage African ancestry and individuals of South Asian descent may have higher levels of Lp(a)

Dr. Shreya Trivedi: So to recap, you know, there are some practitioners who fall in the camp of testing everybody. And there’s some who are more judicious in testing patients who have more early events, have a significant family history or recurrent events despite optimal therapy. I think one last thing before we close out the when to test section is thinking about is there any other influences on the LPLA level? I think I’m always mindful of how we interpret the number and is there something that could make me make it more variable?

Dr. Greg Katz: It’s a negative acute phase reactant. I think just from my experience, the difference between the value that you get inpatient is not all that different from the value that you get outpatient because they tend to be pretty similar within 10 or 20%. And so the stuff that you read about it being something that’s an unreliable test when somebody is acutely inflamed or acutely sick, that doesn’t match what my clinical experience is, which is that it’s actually pretty similar. It’s more so that it’s not influencing anything about your inpatient management.

Dr. Ian Kelly: Yeah unfortunately, thereā€™s not a ton of studies looking into correlation between inpatient and outpatient Lp (a) levels, though one thing thatā€™s clear is that our discussants and our reviewers echoed that levels change pretty minimally even with acute illness.

Dr. Shreya Trivedi: I think that’s a good high level takeaway if youā€™re worried about a patient being lost to follow up or tough with lab draw,s it can be reasonable to get an Lp(a) inpatient but being mindful that the value can vary a little bit, but if it does come back high, it does give you a heads up that Lp(a) this is at play.

PEARL 3: Interpreting Levels

Dr. Shreya Trivedi: All right, and now onto the fun part. Now how do we actually interpret them?Ā 

Dr. Steven Nissen: First, of all, it’s important to understand that unfortunately about half the world uses one unit system and the other half uses another nanomoles per liter is preferred. It’s a concentration measure, but in the United States, most institutions use mass units of milligrams per deciliter.Ā 

Dr. Shreya Trivedi: And one mistake Iā€™ve made when interpreting results and trying convert someones lab in nanomoles per liter to mg per deciliter.

Dr. Ariane Coco Fraiche: So we really should not be interchanging measurements between milligrams per deciliter or nmol per liter. There’s really no interchangeable way to do that because these assays are different. And so we have different cutoffs for the different assays. And so why is that the case and what do we prefer? We prefer the particle assay, which is the NAN animals per liter because that measures the total Ā Lp(a). versus the mass assays, which also include LDL like particles. And the limitation to this is that Ā Lp (a) particles vary in size.

Dr. Ian Kelly: So basically, not all Lp(a) particles are created equal! Some people have larger particles, some might be smaller, but the key for the most part is the number of these particles in circulation.Ā 

Dr. Shreya Trivedi: so then, what’s normal vs. abnormal?

Dr. Greg Katz: So there’s different scales depending on what lab and the cutoffs are going to be different depending on what your units are. In general, I think that most labs are using 75 milligrams per deciliter as the cutoff between this is really high and this is actually fine.

Dr. Ian Kelly: And of course, different societies use different levels and measurements, but the big takeaway for me was that levels >50mg/dL orĀ  >125nmol/L are considered elevated by most of these groups.

Dr. Greg Katz: But you should think of this, it’s a continuous variable and it’s not ā€œit’s positive or negative.ā€ This risk relates to the degree of elevation.Ā 

Dr. Steven Nissen: If you look at the UK Biobank data, the relative risk is essentially a straight line, almost down to zero. And so it’s like LDL. The higher your LDL, the higher your risk, the higher your LP(a), the higher your risk.Ā Ā Ā 

Dr. Ian Kelly: So as Dr. Nissen mentioned, this UK biobank study looked at about half a million patients over a mean follow up of 11 years

Dr. Shreya Trivedi: Nice, half a million, 11 years. So not too bad, not shabby in terms of trying to see a robust relationship. The caveat here I think is this is just from one population, the Europeans.

Dr. Ian Kelly: One point made by one of our reviewers is that patients at high extreme levels, like >100mg/dl or >200nmol/L, may have even greater risk than these linear estimates

Dr. Shreya Trivedi: So, this it just makes me wonder,how can we leverage these known risk factors, we already have these like pooled cohort equations and things, and leverage that with someone’s LP (a) number. So how do we reconcile the traditional ASCVD risk calculators and then the genetic piece with an Lp (a) in estimating someone’s risk and getting it to be a bit more precise?

Dr. Ian Kelly: Well youā€™re in luckā€¦ if youā€™re someone who likes numbers. Basically you can take your patientā€™s traditional ASCVD risk score and use a multiplier based on fold increase by the Lp(a) to get someoneā€™s new estimate of their 10 year ASCVD risk

Dr. Shreya Trivedi: Letā€™s take an example, say we have a 65 year old woman nonsmoking nondiabetic patient with a total cholesterol of 170, HDL of 50, SBP 110 on an antihypertensive which gives you about a ~5-6% risk by conventional pooled ASCVD risk calculator. Now, just for dramatic effect and also making it easier for the calculations, let’s say she has a really high Lp(a)Ā  likeĀ  500 nmol/L.Ā  How do we get more accurate estimate of their ASCVD risk

Dr. Ian Kelly: So the teaching point is that for every 50 nmol/L increase in Lp(a) there is is 1.1 fold increase in the hazard ratio for ASCVD event. And then this math is really cool and so informative to recalculate. And don’t worry this goes over your head (tho for me, it got a lot more clear when working through an example and trying to work it out by myself), we will lay out the equation in the show graphic so that you can review that after going through the example.Ā 

Dr. Ariane Fraiche:Ā So using that hazard ratio of 1.11 and their pooled cohort risk we’ll just say it’s five and a half for math sake. What we can do is say, okay, so the Ā Lp (a) is 500, we would divide 500 by 50.Ā  So we said, remember for those increments of the nanomole increments of increased linear risk for ASCVD. 500 divided by 50, easy 10. So if we did 1.1 that hazard ratio to the 10th power, we would get something like 2.8. If you then multiplied that by their pooled cohort risk of 5.5, so 2.8 times 5.5, you would get something like 15.4 doing the math. The way you can think about that and help guide your discussions about risk modification is that that patient who originally had a pooled cohort equation risk of five and a half percent, you’re now talking to them as related to a risk of 15%.

Dr. Shreya Trivedi: Boy, I cannot wait until someone puts this in MDcalc!

Dr. Ian Kelly: Oh, that would be so great,maybe the reason why we don’tdont have an easy website calculator for this yet is Ā we still need further validation and exploration of this relationship between Lp(a) and ASCVD and this equation should really be used for a rough estimate at this point and might even break down at extreme levels. So use with caution.

Dr. Shreya Trivedi: So big takeaway if we need to think of Lp(a) as a continuous variable, the higher it is, the worse the CV risk. As a rule of thumb,Ā  levels >50mg/dL or >125nm/LĀ  are considered elevated by most societies. And yes, there is an equation that weā€™ll link to in the graphics that can help us re-estimate someone’s ASCVD risk.

Section 4 – Counseling/Management of elevated Lp(a)

Dr. Shreya Trivedi: All right, now on to what I Ā think isĀ  the most imp pearl: how do we counsel and manage these patients? Both at the time point before we get an Lp(a) level and certainly when it does come back high.Ā 

Dr. Greg Katz: I cannot tell you how many MyChart messages or how many messages from patients I’ve gotten on Epic when we do their initial cardiovascular prevention labs and I check Lp (a) in everybody, but somebody gets a value back and it is 150 and they start Googling. And it sends people down not just a rabbit hole of doing research, but it sends them down this incredibly stressful pathway about am I a ticking time bomb and am I about to die and am I about to have a heart attack?

Dr. Shreya Trivedi: Yeah, I’ve definitely had a bunch of friends who’ve unfortunately had heart attacks in their 40s despite being fitness enthusiasts and they have alsoĀ  asked me just the sameĀ  gut-wrenching questions;

Dr. Greg Katz: I am very much a believer that the first conversation someone has with a doctor about a condition is that it frames for the rest of their life the way they think about that condition. AndĀ so yes, high LP little A is a risk factor for heart disease, but it is not the only thing that determines whether or not you’re going to have a heart attack. Now that we know about this, if we are really proactive in testing, screening, and treating you for all of the other things that cause heart disease, I fully believe that we’re going to totally change the trajectory of your lifelong risk.Ā 

Dr. Ian Kelly: So in some ways, checking Lp(a) can be can anxiety trap for patients unless we counsel them ahead of time, but on the other hand, for some patients, knowing this level, it can liberatingĀ 

Dr. Greg Katz: There’s a lot of people who come in with uncertainty about why their family history looks the way it does. And the interaction betweenĀ  Lp (a) and family history is so profound because for a lot of people it’s an aha moment and it’s an explanation that nobody in their family has high cholesterol, nobody in their family has diabetes, nobody in their family smokes, but everybody has heart attacks. Itā€™sĀ  almost like the peace of mind that people get of, oh, I didn’t cause this wasn’t my faultĀ 

Dr. Shreya Trivedi: I appreciate all that framing for the patient. I’m just going to steal some of those words before sending off an alpha-mullet level next. But I’m also curious, you know, say when we see an alpha-mullet level in our patients that’s high, how does that change how we frame things for us as clinicians?

Dr. Ariane Coco Fraiche: I like this prevention 1.5. It’s not exactly primary prevention. It’s almost that we treat them more akin to secondary prevention because of such high risk though they haven’t had their event.Ā 

Dr. Shreya Trivedi: I love that. Prevention 1.5.Ā 

Dr. Steven Nissen: When I see these patients, I take time with them because many of them they need to understand and they also need to understand that because although we have investigational treatments that are quite promising, there’s no treatmentĀ 

Dr. Ian Kelly: No treatment YET. Dr. Nissen and a bunch of other really smart, really dedicated people are working hard on some promising therapeutics. And fortunately, theyā€™re not alone. There are multiple treatments at various stages in the pipeline which Dr. Nissen was happy to teach us about.

Dr. Steven Nissen: I have a very simple and encouraging message. Help is on the way. Trials like the LPA HORIZON trial with Pelican are going to be completed within the next couple of years. We have a high confidence level that they will be successful, although I obviously don’t know and won’t know until I’m unblinded and we are going to then, if the trials are successful, we will do everything we can to get this in front of the FDA for an accelerated approval, for an rapid approval.

Dr. Ian Kelly: Iā€™ll admit I totally went down the rabbit hole nerding out about these treatments and their mechanisms, which Iā€™ll spare you from. But weā€™ll plan to release a short supplementary video on youtube based on our discussions with our experts for those interested.Ā 

Dr. Shreya Trivedi: All right. Thank you for sparing us, Ian. Itā€™s great these treatments are on the way, But I think more practically speaking, you know, at least for right now, How doĀ  we manage these patients? You know, how do we approach counseling and coach them through this?

Dr. Steven Nissen: So let me tell you, the most important message that I give to these patients is I say, we can’t lower your lipoprotein A, but we can take all your other risk factors off the table. We get your LDL down. Typically, I try to get down below 55 milligrams per deciliter. We get your blood pressure under good control. We make sure you’re not overweight. We make sure you exercise and we try to either prevent or treat diabetes. So all of the conventional risk factors, and what we find is if you really treat the other risk factors well, you can often keep people safe, at least in the short term, and those that have had an event, we can help prevent a recurrent event.

Dr. Shreya Trivedi: And to hammer this home (because honestly before this episode i pretty much like looked at Lp(a) level and CV risk something you really had no control) but to hammer home the point on taking other risk factors off the table, we should think about one of the main drivers of CV events in the first place. And yes, the pathophys of cardiovascular events is complicated, but one of the main events is endothelial dysfunction and damage, right? And this brings us back to thinking about what actually causes that endothelial damage.

Dr. Greg Katz: The damaged endothelium is not something that the lipoprotein is doing, and that’s going to be caused by hypertension, by tobacco or other particulate matter by age-related changes. But the endothelial damage increases the permeability to those proteins with cholesterol in them that are going to increase the risk of cardiovascular disease.

Dr. Shreya Trivedi: So yes! Knowledge is power and if Lp(a) is playing a factor for your patient which apparently it is for maybe up to 20% of our patients depending on where we are in terms of prevalence, then yes, lets aggressively try our best to minimize all the things that cause endothelial damage

Dr. Greg Katz: A high Lp (a)might make me escalate the dose of statin or add on ezetimibe to get the LDL closer to 55. It might make me more likely to treat a blood pressure that’s consistently 133 systolic instead of letting it ride. It may make me spend five extra minutes talking to the patient about smoking cessation and their common triggers and what they like about smoking. It does influence the 55-year-old who’s had an LDL of one 30 for 10 years, and it’s starting to creep up and it makes me push the lipid lowering discussion a little bit more aggressively.Ā It makes my recommendation go from, I think this is a reasonable thing to do to this is what I would do if I were sitting where you are. And so it changes the tone of my recommendations and it changes the confidence with which I deliver them. And so I’m using Lp (a)as a tiebreaker more than I’m using it as an arbiter of do we do this or do we not do this?

Dr. Shreya Trivedi: this got me thinking just to ask explicitly, how should we think about lipid goals for these patients with Lp(a) level or a malignant family history? Do they have different LDL goals?

Dr. Ian Kelly: Well, it turns out, this is a bit of a gray zone, and management is really going to be tailored to the patient in front of you and people really have different practice patterns, which we learned from our discussants.

Dr. Steven Nissen: If theirĀ  Lp (a) is greater than about 70 milligrams per deciliter or maybe 125 to 150 nmol per liter at those levels, I think very aggressive treatment of their LDL and other risk factors is warranted. If you’re in that borderline area, if you’ve got a lipoprotein A of 40 milligrams per deciliter or 80 nmol per liter, well, it all depends on other factors.Ā I tend to put almost all of them on a statin unless their LDL is 40 or something like that. If you look at the PCSK9 inhibitor trials, we treated people to LDLs as low as 30 milligrams per deciliter median, and we got benefits. So I treat these people almost uniformly with a statin because I think it’s the right thing to do, and I think the guidelines just need to catch up.

Dr. Shreya Trivedi: Okay maybe the takeaway is to get these patients LDLĀ  as low as possible unless they’re already coming in with an LDLas low as 40 or something.Ā But say we chart review pt, they already had an Lp(a) done a few yrs ago, and this was really motivational for them to change a lot of things in terms of their lifestyle. Ā Iā€™m curious because you know, Iā€™m a sucker for trending things and also people want to know if their lifestyle changes are effective. Do we test again? Should we get to another level after it’s been a few years?Ā 

Dr. Steven Nissen: Once you’ve obtained a level, there is no reason to repeat it in the absence of some therapy because it doesn’t change. Remember that it’s not affected by lifestyle or anything else. If you’re at 180 nmol per liter when you’re 25, that’s what you’re going to be when you’re 45 or 65.

Dr. Ian Kelly: Yeah this really reinforces that Lp(a) levels are not significantly affected by anything aside from genetics and to add to that, I was reading that levels stay static after about age 5.

Dr. Steven Nissen: And so one of the most important questions I ask patients when I see them with a high lipoprotein A is do you have any children? Do you have any siblings? Are your parents still alive? And I recommend that all of those people be tested and you would be surprised how often it comes back that the family, many people in the family have the disorder and many of them have had atherosclerotic vascular disease events.

Dr. Shreya Trivedi: Okay so that being said when do these patients automatically warrant a referral to cardiology?Ā 

Dr. Greg Katz: Not necessarily,, it’s not like a cardiologist is not doing anything magical for a patient like this. I’m always happy to see those patients, Ā but I do not think that there is something magic about LP little A that only a cardiologist is able to treat and take care of.Ā 

Dr. Shreya Trivedi: Okay appreciate that empowerment! One thing I had heard about Lp(a) in making this episode is that statins may actually raise Lp(a)? Is that true? I can imagine a patient freaking out that their Lp(a) levels went up after a statin, god forbid they were toĀ  get a check again.

Dr. Greg Katz: There is a lot of data that statins will raise your levels of LP little A by somewhere along the lines of 10 to 20%. Just because statins raise LP little A does not mean that they are bad for patients who have high LP little A statins are risk reducing medications, and the benefit that you get is really kind of like irrespective of whether or not your LP little A is elevated. And so a high LP little A or a rise in LP little A after starting statin therapy is not a reason to stop a statin. Statins are still at risk of reducing medications for those patients.Ā 

Dr. Ian Kelly: Phew. Itā€™s definitely good to know that for patients with elevated Lp(a) and high LDL with already high ASCVD risk that rise in Lp(a) should not factor into decision making for starting these medications and is really offset by the cardioprotective effects that statins provide.

Dr. Shreya Trivedi: And then last thing, say your patient already hadĀ  a cardiovascular event, howĀ  do we then manage an LLP and Lp (a) level?

Dr. Greg Katz: If somebody is coming in for secondary prevention, meaning they have had a heart attack or they have had a stroke, then I am going to try to optimize every single risk factor that I have the ability to optimize. And so, if somebody has high LP little A and they have an acute mi, Iā€™m going to try to get their LDL down to 40. If somebody has lowĀ  Lp (a) and they have an acute mi, Iā€™m probably still going to try to get their LDL down to 40. And it goes the same for blood pressure.

Dr. Steven Nissen: These are the people that, yes, itā€™s shared decision making, but when I talk with them, I say, you really do need to deal with these risk factors. If you have a high lipoprotein A and you have poorly treated diabetes or you have hypertension, not well controlled, youā€™re just asking for trouble.

Dr. Shreya Trivedi: Ā So to summarize, weā€™ve established that Lp(a) can be something that tips the scales for more aggressive lifestyle and LDL lowering therapies in all patients ā€“ Then this is especially true in our patients for primary prevention in that more intermediate risk group. And then it pushes us to be even more aggressive in patients who have already had an event when managing patients for secondary prevention

PEARL 5: Specific Medication Uses in Lp(a) – Aspirin & PCSK9i in Elevated Lp(a)

Dr. Shreya Trivedi: You know, I was thinking back to earlier in the episode where we were talking about Lp(a) and some of the ways itā€™s unique and that itā€™sĀ  prothrombotic.Ā  So I’m curious, how does that hyper-cracklability piece play a role in terms of our management.

Dr. Greg Katz: The thing that I personally find most interesting about Lp (a)is the prothrombotic or hypercoagulable aspect of it.. And one of the sort of teleological or evolutionary explanations of why we have Lp (a) at all is that it might’ve been protective against trauma because of its prothrombotic nature. And so evolution may have selected for actually high Lp (a) because it doesn’t cause problems until we’re way past reproductive age. And it may have a survival advantage early on in the prothrombotic nature of how that particle works.And that has to do with the structural homology of something called these Kringle repeats to plasmin.

Dr. Shreya Trivedi: So if lPa is structurally similar to plasmin and competes with plasminogen. Then, there is less plasminogen being converted to local plasmin and that means there is less fibrinolysis.

Dr. Ian Kelly: Yeah, so,Ā  overall less local fibrinolysis means more clotting in regions where Lp(a) is binding to exposed or damaged endothelium, which means potentially higher risk of MI or stroke.

Dr. Shreya Trivedi: So this got me thinking, if it’s prothrombogenic, I know aspirin for primary prevention is like a loaded topic, but I’m curious if it is prothrombogenic, is there any role for aspirin here? Ā 

Dr. Steven Nissen: We don’t have very good data. We have some data from some of the aspirin trials that does suggest a benefit of aspirin in primary prevention in people with a high lipoprotein A. It’s not very good data. It wasn’t primarily what they were investigating.Ā 

Dr. Shreya Trivedi: So data right now comes from retrospective analysis of large studies where aspirin for primary prevention in these patients with elevated Lp(a) was NOT the original hypothesis right , and we have all learned that that means it’s definitely under the umbrella of hypothesis generating.Ā 

Dr. Ian Kelly: One of our reviewers took this even further to point out that in some of these studies, this benefit only applied to a subgroup of patients with a specific Lp(a) mutation instead of measuring Lp(a) levels directly.

Dr. Steven Nissen: That being said, because lipoprotein A is both pro atherogenic and prothrombotic, I treat many of these people with low dose aspirin and I treat almost nobody else in primary prevention with low dose aspirin. But these people, I make an exception for.

Dr. Greg Katz: The question of aspirin for primary prevention and LP little A is so important and we just don’t know.Ā I think that for my patients who have high LP little A, and when I say high LP little A, I’m generally thinking of a value over 75 with any family history of heart attack or stroke. I’m generally saying aspirin is pretty reasonable

Dr. Shreya Trivedi: Okay now switching gears. Last thing, I think we would be remiss if we did not talk about the cool kid on the block for lipid lowering. PCSK-9 inhibitors. Where do PCSK-9fall into treatment of Lp(a)?

Dr. Ian Kelly: Yeah I read into the FOURIER trial and some of the other analyses off of that. And in thatwe saw evolucumab lowered Lp(a) levels, which was shocking to me just given this just doesn’t seem to be talked about!

Shreya: Yeah, wait hold on, I thought you just told meĀ  there isn’t treatment for Lp(a)? Should we start everyone with a high Lp(a) on PCSK-9i ASAP?!

Dr. Steven Nissen: I don’t, and I’m going to tell you why. If you look at some of the data,, the people that got the biggest reduction in lipoprotein A were people that had mid range low to mid range lipoprotein A levels. Those in the top quartile got a 16 milligram per deciliter reduction in lipoprotein A, it’s not very much, and you’ve got a therapy that’s expensive, requires self-injection every couple of weeks, has no substantial data suggesting a benefit, so I don’t do it. Now, there are other practitioners who do, and I don’t fault them for it. I just look at the data and say, it’s not good enough.Ā 

Dr. Ian Kelly:Ā Oof, sounds like I should pump the brakes a little bit on excitement for PCSK9 inhibitors .Ā 

Dr. Shreya Trivedi: And of course of the unexpected themes of this episode is that everyone has a littleĀ  different practice patterns, and I think this is especially true when we find ourselves with patients who maybe havenā€™t tolerated statin as well or a xenamide as well.

Dr. Greg Katz: I do not make a decision to use a PCSK nine inhibitor because it lowersĀ  Lp (a). I use a PCSK nine inhibitor because it lowers my total atherogenic particle number. It lowers my LDL, it lowers my ApoB, and so I’m using it as a risk reducing medication and using that as my metric of success, not what happens to the LP little A.

Dr. Ian Kelly: So to recap the last two pearls, Aspirin has theoretical use for primary prevention for elevated Lp(a) based on physiology and retrospective reviews, but we need more data in the form of prospective trials going forward before we can definitively say if itā€™s protective or not in these patients.

Dr. Shreya Trivedi: And for PCSK9 inhibitors, PCSK9 does lower Lp (a) level,but not enough to get them down to clinically significant lower risk bracket. But you can certainly use to to lower the total atherogenic particles if thereā€™s trouble getting them in LDL goals you want. That is all for today, thank you so much for listening. If you found this episode helpful, please share with your team and colleagues and give it a rating on Apple podcasts or whatever podcast app you use! It really does help people find us!Ā 

Dr. Ian Kelly:Ā  Thanks to our reviewers for this podcast. Thank you to Jerome Reyes for the audio editing and Dr. Jesse Powell for the accompanying graphics. This episode was made as a part of the Digital Education Track at BIDMC.

Dr. Shreya Trivedi: Opinions expressed are our own and do not represent the opinions of any affiliated institutions. Thank you, take care!

Behind the Scenes Interviews

Key Points:

  • Elevated Lp (a) is common and strongly associated with atherosclerotic vascular disease and aortic stenosis.
  • Lp (a) levels are largely genetically determined.
  • Lp (a) elevation in one family member may indicate that others should be tested.
  • People with highly elevated Lp (a) benefit from intensified measures to reduce CV risk (i.e. lifestyle modification, statin, and aspirin therapy).

Key Points:

  • New strategies to durably reduce Lp(a) have great promise for loweing risk of MACE.
  • Small interfering DNA or RNA particles are being designed to block lipoprotein a particle formation in hepatocytes.
  • CRISPR technology may also be capable of knocking out the Lp (a) gene.
  • These therapies have the potential to decrease Lp (a) and reduct CV risk over the longterm.

References