Key Moments
210 - Lp(a) and its impact on heart disease | Benoît Arsenault, Ph.D.& Peter Attia, M.D.
Peter Attia MDKey Moments
Lp(a) is a genetically determined heart disease risk factor, impacting 20% of the population, and new therapies are on the horizon.
Key Insights
Lp(a) is a significant genetically inherited risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis.
Measuring Lp(a) is crucial for risk assessment, with about 20% of the global population having elevated levels, particularly those of African ancestry.
Historically, difficulties in assay measurement led to conflicting study results; however, modern assays providing results in nanomoles per liter offer more accurate risk assessment.
While statins do not significantly lower Lp(a) levels, they remain beneficial, especially in patients with high Lp(a).
PCSK9 inhibitors can modestly reduce Lp(a) levels (around 30%), but the full impact on cardiovascular events is still under investigation.
Emerging therapies like antisense oligonucleotides and siRNA are showing significant Lp(a) reduction (up to 80%) and hold promise for future treatment.
THE SCIENTIFIC JOURNEY OF LP(A) DISCOVERY
The discussion delves into the history of Lp(a) research, beginning with Benoît Arsenault's early work during his post-doc years (2006-2009). Initially, Lp(a) was not widely discussed due to negative studies linking it to cardiovascular disease. However, genetic association studies published between 2009-2011 resurrected the field, revealing Lp(a) as a potent predictor of residual cardiovascular risk, even stronger than other emerging biomarkers in trials like TNT.
EPIDEMIOLOGY AND THE CHALLENGE OF MEASUREMENT
Elevated Lp(a) levels affect approximately 20% of the world's population, with higher prevalence in individuals of African ancestry. Discovered in 1963, its association with cardiovascular events was noted early on, but inconsistent results in the 1990s and early 2000s stemmed from problematic assays. These assays struggled with Lp(a)'s complex structure, particularly the copy number variation in its gene, leading to inaccurate estimations, especially for smaller, more atherogenic isoforms.
GENETICS OVER ASSAYS: THE POWER OF GWAS
Genome-wide association studies (GWAS) provided a breakthrough by focusing on genetic variants associated with Lp(a) levels, bypassing assay limitations. Published in 2009, three major studies convincingly linked genetic variants predisposing to higher Lp(a) with increased cardiovascular events. This approach allowed for a more robust understanding of the causal relationship between Lp(a) and ASCVD, serving as a bridge between observational epidemiology and clinical trials.
LP(A) BIOLOGY AND ITS ATHEROGENIC MECHANISMS
Lp(a) is essentially an LDL particle with an attached apolipoprotein(a) (Apoa). This unique structure contributes to its atherogenicity. Apoa shares homology with plasminogen, potentially influencing thrombosis and fibrinolysis. Crucially, Lp(a) transports a higher concentration of oxidized phospholipids (OxPLs) compared to LDL. OxPLs trigger inflammatory and pro-calcifying signals in endothelial cells, smooth muscle cells, macrophages, and aortic valve cells, driving atherosclerosis and calcification.
LP(A) AND AORTIC VALVE STENOSIS: A STRONG CONNECTION
Lp(a) is strongly associated with aortic valve stenosis (AS), acting as a potential initiator and accelerator of the disease. Studies have shown Lp(a) co-localizes with OxPLs in the aortic valve, driving inflammatory and bone-like processes in valvular interstitial cells. Elevated Lp(a) levels correlate with increased AS risk, and imaging studies detect metabolic changes indicative of early AS processes even before calcification is apparent. The risk is particularly pronounced in individuals with very high Lp(a) levels.
THERAPEUTIC STRATEGIES: PAST, PRESENT, AND FUTURE
While niacin can reduce Lp(a) levels, large outcome trials have not demonstrated cardiovascular benefit, leading to its decline in use for this purpose. Statins, though not lowering Lp(a), are still beneficial by managing LDL. PCSK9 inhibitors offer a modest reduction in Lp(a) (around 30%) and significantly lower LDL, contributing to cardiovascular risk reduction. The most promising developments are antisense oligonucleotides and siRNA therapies, which have shown substantial Lp(a) reductions (up to 80%) in clinical trials and are poised to become a major advancement in treating ASCVD.
CLINICAL IMPLICATIONS AND THE CALL FOR ACTION
Given its prevalence and potent risk, measuring Lp(a) at least once in a lifetime is recommended by many guidelines, particularly for individuals with a family history of premature ASCVD or existing cardiovascular issues. While identifying high Lp(a) poses a challenge due to the lack of specific Lp(a)-lowering therapies, aggressively managing other modifiable risk factors like LDL, blood pressure, and lifestyle remains critical and can significantly mitigate risk. The development of targeted therapies offers hope for addressing this significant, genetically driven risk factor.
Mentioned in This Episode
●Software & Apps
●Companies
●Organizations
●Books
●Studies Cited
●Concepts
●People Referenced
Common Questions
Lp(a), or lipoprotein (a), is a little lipoprotein linked to cardiovascular disease. Interest in it has been resurrected due to genetic association studies, revealing its impact on a significant portion of the population and its role in residual cardiovascular risk even after LDL lowering.
Topics
Mentioned in this video
Apolipoprotein B, a protein component of lipoproteins like LDL, important in understanding cardiovascular risk.
A set of seven cardiovascular health factors (smoking, healthy diet, physical activity, low body weight, good LDL, no diabetes, controlled blood pressure) used to assess overall risk.
Studies increasingly used to identify genetic variants associated with specific diseases and pharmacogenetic studies, which resurrected the field of Lp(a) research.
A gene that might be associated with Lp(a) but also regulates HDL and triglycerides, so not used in Mendelian randomization for Lp(a).
Proprotein convertase subtilisin kexin type 9, discovered in 2003, acts as a regulator of the LDL receptor, preventing its recycling and leading to higher LDL levels.
Genetic variants that act within the window of the gene expressing their protein, often used in Mendelian randomization studies for Lp(a).
A gene with parallels to Lp(a), affecting Alzheimer's and cardiovascular disease risk, with different isoforms.
A gene on another chromosome that codes for beta-2 glycoproteins, potentially influencing the presence of oxidized phospholipids on ApoA.
A researcher who became involved in Lp(a) research during his postdoc years at Laval University, focusing on lipids and cardiovascular outcomes.
A collaborator of Benoît Arsenault in Amsterdam, worked on the TNT trial and sub-analyses related to cardiovascular biomarkers.
A researcher who collaborated with George Thanassoulis on GWAS studies of Lp(a) levels.
A researcher at Mount Sinai in New York who ran the Initial trial, looking at arterial wall inflammation using fluorodeoxyglucose.
A researcher from the UK whose group published one of the first studies identifying SNPs in Lp(a) regions associated with heart disease using the Procardis consortium.
A researcher at UT Southwestern whose group showed in 2006 that common variants in PCSK9 were associated with lower LDL levels and protection against cardiovascular diseases.
A researcher who developed an assay to measure oxidized phospholipids on ApoB-containing lipoproteins and Lp(a), finding it to be a good predictor of disease.
A Swedish scientist who discovered Lp(a) in 1963 and showed its association with cardiovascular events.
A researcher in Perth, Australia, who showed the complex interaction of PCSK9 inhibitors and statins on Lp(a) catabolism.
A researcher at the University of Chicago whose group cloned the Lp(a) gene in the 1980s.
A colleague at the Robarts Research Institute in London, Ontario, who assisted in isolating Lp(a) from blood samples for research.
A CETP inhibitor by Merck that showed a small, though not spectacular, cardiovascular benefit in the REVEAL trial, but drug accumulation in adipose tissue stopped further development.
A PCSK9 inhibitor drug approved by the FDA based on its LDL-lowering effects.
Antibodies developed by the pharmaceutical industry to inhibit PCSK9, leading to significant LDL reduction and cardiovascular event reduction.
An siRNA compound developed by Amgen targeting Lp(a), with data released in Nature Medicine.
A very exciting new class of drugs currently in development, designed to specifically lower Lp(a) levels by targeting the Lp(a) gene.
A class of drugs that raise HDL cholesterol, but trials (like Reveal) showed no or even negative outcomes, suggesting HDL cholesterol quantity is not the key metric.
The scientific journal in which the paper on the discovery of PCSK9 (then called NARC1) was published in 2003.
The scientific journal in which data on Olpasiran (an siRNA against Lp(a)) was released.
A journal where a study by Gerald Watts was published, complex to fully appreciate, showing that if you treat patients with a PCSK9 inhibitor and a statin, you see an increment in the fractional catabolic rate of Lp(a).
A pharmaceutical company that produces PCSK9 inhibitors and is developing an siRNA compound (Olpasiran) against Lp(a).
A San Diego-based company, formerly called ISIS, that developed a second-generation antisense oligonucleotide against the Lp(a) gene.
A pharmaceutical company partnering with Ionis for the Horizon trial.
Pharmaceutical company that developed Anacetrapib.
An siRNA company that has an Lp(a) inhibitor in development, but has not yet released its phase one study.
The institution in Quebec City where Benoît Arsenault trained during his postdoc years, conducting research in the field of lipids.
A search engine for life science and biomedical articles, used to track the rise and fall of interest in Lp(a) research.
A cohort from Iceland that unequivocally showed Lp(a) isoform size was not associated with heart attack or stroke risk once Lp(a) levels were considered.
An organization whose guidelines are more up-to-date and advise measuring Lp(a) in everyone at least once in their lifetime.
A research institute in London, Ontario, where Marlies Kashiwada practices, who collaborated on Lp(a) research.
A consortium in which a genome-wide association study on aortic valve calcification identified Lp(a) as the most important variant.
A large genetic consortium that found Lp(a) to be the most important genetic risk factor explaining statin response.
A consortium from the UK used in a study that identified genetic variants in the Lp(a) region linked to heart disease.
An organization whose guidelines advise measuring Lp(a) in everyone to identify patients with very high Lp(a) levels due to its link with familial hypercholesterolemia.
The institution where Helen Hobbs's group conducted research on PCSK9 variants and their association with cardiovascular disease protection.
An organization whose guidelines for Lp(a) measurement are less favorable, typically recommending it only in patients with existing cardiovascular disease or strong family history.
A university in Montreal where George Thanassoulis's group conducted genome-wide association studies on Lp(a).
The institution where Zahi Fayad conducted research on arterial wall inflammation.
One of the first trials that demonstrated incremental benefits in cardiovascular outcomes by reducing LDL levels through increased statin dose.
A cardiovascular outcomes trial that tested PCSK9 inhibitors, showing a reduction in cardiovascular events.
A large cardiovascular outcomes trial that showed no cardiovascular benefits from niacin therapy.
The Heart Protection Study 2 to THRVIVE trial, a large cardiovascular outcomes trial that showed no cardiovascular benefits from niacin therapy.
A large clinical trial testing Anacetrapib, which showed a modest reduction in events but prompted discontinuation due to drug accumulation in adipose tissue.
A European prospective investigation into cancer and nutrition, used to study the effect of Lp(a) on cardiovascular events in relation to 'Life Simple 7' risk factors.
A trial that tested the effect of a PCSK9 inhibitor on patients with Lp(a), showing a small reduction of approximately 15% in Lp(a) levels.
A type of genetic analysis that links genotype to phenotype, used to bridge observational epidemiology and clinical trials to infer causal relationships.
A cardiovascular outcomes trial that tested PCSK9 inhibitors in patients already on statins, showing a 15% reduction in relative risk of cardiovascular events over 2.2 years.
A cardiovascular outcomes trial launched by Ionis/Novartis to study the effect of their antisense oligonucleotide on preventing major atherosclerotic cardiovascular events in patients with stable cardiovascular diseases.
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