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Welcome to Core IM, a virtual medical community! Core IM strives to empower its colleagues of all levels and backgrounds with clinically applicable information as well as inspire curiosity and critical thinking. Core IM promotes its mission through podcasts and other multimodal dialogues. ACP has teamed up with Core IM to offer continuing medical education, available exclusively to ACP members by completing the CME/MOC quiz.

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 “Lp(a)” is a subtype of LDL 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).  
• Lp(a) levels are genetically determined by the LPA gene. 
  • 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 it’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 isoforms 
    • Associated with higher circulating levels of Lp(a) and.
    • 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. 
  • The relationship between Lp(a) and ASCVD risk has been shown to be.
  • Lp(a) levels above the 90th percentile are associated with a, even in those
  • This relationship can be further reinforced in it’s absence
    • Individuals with a null allele at the LPA gene had lower risk of ASCVD events.
• The exact pathophysiology of Lp(a) leading to increased CVD is unknown, however: 
  • 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 it’s structural homology with plasminogen 
  • Recall that all of these mechanisms often occur in the setting of upstream endothelial damage/dysfunction caused by conditions such as hypertension and smoking. 
    • Endothelial damage and dysfunction is another key piece of atherogenesis and ASCVD events 

• 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

•  
  • 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 risk 

• This is to help restratify risk in these patients in the context of Lp(a)

• The EAS recommends the above categories in addition to
• and 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?
 

• • 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
    • associated with different levels across ethnicities, which may relate to it’s genetically determined nature 
• 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) 
  • 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 “discordant” 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. 
    • 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: 
    • 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, and 

• >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 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) = 

• ASCVD Risk x 1.11 ^ (Lp(a) nmol/L ÷ 50) 

• This can be used as a rough estimate in counseling patients by multiplying by their traditional PCE Risk. 
  • Ex. Lp(a) of 500 nmol/L with 7.5% ASCVD = 500/50 = 10 → 1.11¹⁰ * 7.5 = 2.83 * 7.5 = 21.22% (APPROXIMATE) 10-year ASCVD risk after incorporating Lp(a) 

Pearl 4 - Management: Management of Elevated Lp(a)

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)?

• There is (at the time of writing) NO FDA APPROVED pharmaceutical therapy for lowering Lp(a) 
• 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 “tie-breaker” 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 guidelines 
  • 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) 
  • by 10-20%
    • But statins are still and should not be discontinued for this reason!
• 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 development 
  • Most of these therapies target Lp(a) synthesis as Antisense oligonucleotides (ASO’s) or siRNA
  • - 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
  • Current data on Lp(a) and PCSK9 inhibitors are limited to retrospective reviews and benefits observed are hypothesis generating and may reflect elevated baseline risk in the high Lp(a) patients
  • PCSK-9 inhibitors have however been shown to lower Lp(a) levels, as was observed in a 
  •  
    • Observed lower NNT for composite death, MI, or revascularization
  • PCSK9 inhibitors can be used for patients with challenging to control LDL and elevated Lp(a)
• 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 it’s homology with plasminogen in addition to increased tissue factor expression and platelet activation/aggregation
  • Retrospective cohort data in,, and (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, stating aspirin may be considered on a case-case basis in patients with Lp(a) > 50mg/dL

Contributors
Shreya Trivedi, MD, ACP Member – Host, Editor, Producer
Ian Kelly, MD – Host, Editor, MOC questions
Steve Nissen, MD – Guest *
Greg Katz, MD - Guest
Ariane “CoCo” Fraiche, MD - Guest

Reviewers
Thomas Dayspring, MD, FACP *
Evan Harmon, MD

*Steven Nissen, MD – Amgen – Consultant; Astra Zeneca, Eli Lilly, New Amsterdam Pharmaceuticals, Novartis, Silence Pharmaceuticals – Grant/Contract; Eli Lilly – Travel.

*Thomas Dayspring, MD, FACP – Speaker - New Amsterdam Pharmaceuticals

Those named above, unless otherwise indicated, have no relevant financial relationships to disclose with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.  All relevant relationships have been mitigated.

Release Date:  April 9, 2025

Expiration Date: April 8, 2028

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