In Which Biomarker Do We Trust?

Ravi Parekh
Mar 17
6 min read

Figure from: 8 Things to Know About Lipoprotein(a) — Figure from: **8 Things to Know About Lipoprotein(a)**

Written by Ivan Dejan and Edited by Ryan Le & Ravi Parekh

The Evolution of Cardiovascular Treatment: Beyond Statins

For the past century, statins have been the go-to treatment for patients battling high cholesterol and hypertension, with the goal of reducing the risk of arteriosclerosis and major cardiac events. Through statins mechanism of action, through the action of HMG-CoA reductase, statins effectively decrease cholesterol production in the liver. However, recent debates question whether statins significantly contribute to longevity, as some studies suggest no substantial difference in life expectancy between statin users and non-users. This has led researchers to explore alternative biomarkers for assessing cardiovascular risk.

Lipoprotein(a) vs. LDL: Structure, Similarities, and Key Differences

Lipoprotein(a) (Lp(a)) is a unique subclass of lipoproteins that shares structural similarities with low-density lipoprotein (LDL) but differs significantly in function and cardiovascular risk. Structurally, Lp(a) consists of an LDL-like core, containing a single apolipoprotein B-100 (ApoB-100) molecule, a phospholipid monolayer, and a cholesterol ester-rich core, similar to LDL. However, what sets Lp(a) apart is the covalent attachment of apolipoprotein(a) [Apo(a)] to ApoB-100 via a disulfide bond. Apo(a) is a highly glycosylated, kringle domain-containing glycoprotein with structural homology to plasminogen, giving Lp(a) unique pro-atherogenic and pro-thrombotic properties.

While both Lp(a) and LDL serve as cholesterol transporters, Lp(a) is not directly regulated by LDL receptors (LDLR), unlike LDL, which is cleared via hepatic LDLR-mediated uptake. Instead, Lp(a) levels are primarily determined by genetic factors, particularly variations in the LPA gene encoding Apo(a), with minimal influence from diet or lifestyle. Another key difference is that Lp(a) is more atherogenic than LDL, as it not only promotes foam cell formation and arterial plaque buildup like LDL but also impairs fibrinolysis due to structural mimicry of plasminogen, increasing thrombosis risk. In contrast, while LDL contributes to atherosclerosis by facilitating lipid accumulation in arterial walls, it lacks the thrombogenic properties of Lp(a).

Both Lp(a) and LDL contribute to cardiovascular disease (CVD), but Lp(a) is considered an independent risk factor for myocardial infarction, stroke, and calcific aortic valve disease, even in individuals with normal LDL levels. Due to its genetically determined levels, traditional lipid-lowering therapies like statins do not significantly reduce Lp(a), necessitating emerging treatments such as antisense oligonucleotides (ASOs) targeting Apo(a) synthesis. Understanding these structural and functional differences between Lp(a) and LDL is crucial for advancing targeted therapies and improving cardiovascular risk stratification.

The Biomarker Debate: LDL vs. Apolipoproteins

The medical community has long prioritized lowering LDL cholesterol as a primary strategy for reducing cardiovascular risk. However, emerging research suggests that apolipoproteins—specifically Lp(a) and ApoB—may be stronger indicators of major coronary events. Current findings highlight that:

Statin-induced LDL reduction correlates with a 22% decrease in major cardiac event risk.
A 100 nmol/L increase in Lp(a) is associated with a 24% increase in five-year cardiovascular event risk.
ApoB levels are linked to a 5% increased risk of cardiac events per 100 nmol/L increase.

With this knowledge, pharmaceutical companies are now racing to develop innovative drugs targeting these new risk markers, particularly Lp(a) and ApoB.

Emerging Research on Lp(a) as a Stronger Predictor than LDL

Unlike LDL, which is primarily affected by diet and statins, Lp(a) levels are largely genetically determined, making them much less modifiable by lifestyle changes. Some studies suggest that statins may slightly increase Lp(a) levels, which could be counterproductive for individuals with already elevated levels. Up to 20-30% of the population has high Lp(a) concentrations, putting them at greater risk for atherosclerotic cardiovascular disease (ASCVD).

Recent trials have underscored Lp(a)'s role in cardiovascular health:

Lp(a) increases the expression of vascular cell adhesion molecule-1 (VCAM-1) and E-selectin, promoting inflammation and plaque buildup.
Its oxidized phospholipids contribute to arterial damage, directly correlating with increased plaque deposits.
Unlike LDL, which can be controlled with statins, Lp(a) requires targeted therapies like Muvalaplin for effective reduction.

The Battle of Pharmaceutical Giants: Eli Lilly vs. Arrowhead Pharmaceuticals

Both Eli Lilly and Arrowhead Pharmaceuticals are pioneering novel therapies to combat hyperlipidemia, but their approaches differ:

Eli Lilly’s Muvalaplin is the first drug designed specifically to lower Lp(a) levels, targeting high-risk patients with elevated Lp(a).
Arrowhead’s Plozasiran is designed for familial chylomicronemia syndrome (FCS), an inherited metabolic disorder that prevents proper triglyceride metabolism. However, the drug also shows promise in treating mixed hyperlipidemia.

While these drugs initially target distinct patient populations, their broader impact on lipid management could lead to crossover FDA approvals, potentially reshaping the cardiovascular treatment landscape.

Understanding Mixed Hyperlipidemia and Familial Chylomicronemia Syndrome

Mixed Hyperlipidemia involves elevated levels of LDL, HDL, and triglycerides, increasing the risk of atherosclerosis.
Familial Chylomicronemia Syndrome (FCS) is a rare genetic disorder characterized by the inability to break down triglycerides due to mutations in the lipoprotein lipase enzyme. This leads to triglyceride accumulation, causing symptoms such as acute pancreatitis, eruptive xanthomas, and hepatosplenomegaly.

Clinical Trial Data and Efficacy Comparisons

While statins remain a cornerstone therapy, the latest clinical trials highlight the effectiveness of these new lipid-lowering drugs:

Muvalaplin trial results have demonstrated a substantial reduction in Lp(a) levels over a defined period. Compared to statins’ ability to reduce LDL by 30-50%, Muvalaplin specifically targets Lp(a), addressing a known independent cardiovascular risk factor.
Plozasiran’s impact on triglyceride levels is remarkable, with studies showing over 80% reductions in triglyceride levels in patients with FCS or mixed hyperlipidemia—offering a potential breakthrough for those unresponsive to statins or dietary changes.

Mechanistic Differences Between Statins, Muvalaplin, and Plozasiran

Understanding how these drugs work reveals their unique contributions:

Statins block cholesterol synthesis in the liver, primarily reducing LDL production.
Muvalaplin prevents Lp(a) formation by blocking the interaction between Apo(a) and ApoB100, reducing plaque buildup and inflammatory responses.
Plozasiran inhibits APOC3 gene expression, preventing it from interfering with lipoprotein lipase activity, allowing for better clearance of triglyceride-rich lipoproteins (TRLs).

Future Market and Potential Combination Therapies

The cardiovascular drug market is evolving toward personalized lipid management, where patients might receive a combination of:

Statins for LDL reduction,
Muvalaplin for Lp(a) control, and
Plozasiran for ApoB/ApoC3 inhibition.

This multi-targeted approach could redefine treatment strategies for high-risk cardiovascular patients, particularly those who do not respond adequately to statins alone.

Regulatory and Commercial Challenges

Despite their promise, Muvalaplin and Plozasiran face hurdles before widespread adoption:

Long-term safety and cost-effectiveness must be demonstrated in large-scale trials.
Insurance coverage will be a key factor—will these high-cost drugs be reimbursed, or will patients face significant financial barriers?
Competitive landscape: Other pharmaceutical companies may enter the space, increasing competition for Lp(a)- and ApoC3-targeting drugs.

The Future of Cardiovascular Treatment: Statins, Muvalaplin, or Plozasiran?

With the rise of these novel therapies, the question remains: which treatment is best?

Statins remain a mainstay for lowering LDL, but their impact on overall longevity remains debated.
Muvalaplin offers a groundbreaking approach for high Lp(a) patients, addressing an independent risk factor for atherosclerosis.
Plozasiran shows promise in treating hypertriglyceridemia by targeting APOC3, potentially improving outcomes for patients with mixed hyperlipidemia and FCS.

As research advances, it is possible that a combination approach—incorporating statins, Lp(a)-targeting drugs, and ApoB/ApoC3 inhibitors—will redefine cardiovascular disease management. The future of lipid-lowering therapies is here, and the competition among pharmaceutical innovators will determine which biomarker we ultimately trust to guide treatment strategies.

References:

Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, et al. Lipoprotein(a) Reduction in Persons with Cardiovascular Disease. N Engl J Med. 2023;389(10):901-911. doi:10.1056/NEJMoa2305493.
Reyes-Soffer G, Ginsberg HN, Ramakrishnan R, et al. Effects of PCSK9 Inhibition on Lipoprotein(a) Kinetics in Healthy Subjects. J Clin Endocrinol Metab. 2019;104(8):3451-3460. doi:10.1210/jc.2018-02646.
Nordestgaard BG, Chapman MJ, Ray K, et al. Lipoprotein(a) as a cardiovascular risk factor: Current status. Eur Heart J. 2010;31(23):2844-2853. doi:10.1093/eurheartj/ehq386.
National Heart, Lung, and Blood Institute. Lipoprotein(a): What to know about elevated levels. Published 2024. Accessed March 8, 2025. https://www.nhlbi.nih.gov/news/2024/lipoproteina-what-know-about-elevated-levels#:~:text=Lp(a)%20is%20a%20type,can%20show%20up%20in%20plaque.
Muvalaplin shows promise in lowering Lp(a) levels in clinical trial. News Medical Life Sciences. Published November 19, 2024. Accessed March 8, 2025. https://www.news-medical.net/news/20241119/Muvalaplin-shows-promise-in-lowering-Lp(a)-levels-in-clinical-trial.aspx.
Grundy SM. Statin Therapy in the Prevention of Atherosclerotic Cardiovascular Disease. StatPearls. Published August 10, 2023. Accessed March 8, 2025. https://www.ncbi.nlm.nih.gov/books/NBK343489/.

Disclaimer: The information provided in this article is for educational and informational purposes only. It is not intended as medical advice, diagnosis, or treatment. Always consult a qualified healthcare provider for any questions regarding a medical condition. The author and publisher of this article do not endorse or recommend any specific medical products or treatments mentioned in the text. The reader should rely on their healthcare provider's judgment and expertise in making healthcare decisions. The author and publisher shall not be responsible or liable for any errors or omissions in this article or for any actions taken based on the information provided.