Decoding Lp(a): New Insights into a Complex Cardiovascular Risk Factor

The landscape of cardiovascular disease prevention is continuously evolving. New research, highlighted in a special JACC focus issue on lipids, is shedding more light on lipoprotein(a) (Lp[a]) – an independent genetic risk factor for cardiovascular disease and aortic stenosis. These findings are crucial for understanding who is most at risk and how future therapies might be deployed.

Lp(a) and Plaque Vulnerability: A Unique Role

A substudy of the PROSPECT II trial investigated the relationship between Lp(a) and various measures of coronary plaque in 865 patients. Researchers, led by David Erlinge, MD, PhD, FACC, found some intriguing distinctions:

• Traditional Cholesterol Markers: Elevated total cholesterol, LDL-C (low-density lipoprotein cholesterol), and non–HDL-C were strongly associated with overall atherosclerosis (pancoronary plaque volume) and lipid deposition within the arteries (pancoronary lipid core burden index).
• Lp(a)’s Specific Link: Interestingly, Lp(a) was not strongly associated with overall plaque burden or lipid deposition. However, elevated Lp(a) was strongly associated with the presence of focal vulnerable plaques. These are the unstable plaques that are more likely to rupture and cause a heart attack.

As Erlinge and colleagues explain, “These findings may explain the association between high Lp(a) levels and future myocardial infarction and suggest a unique role for Lp(a) in atherosclerosis progression and plaque vulnerability.”

This research underscores the need for dedicated imaging studies to see how Lp(a)-lowering agents affect plaque composition. Furthermore, the investigators suggest large-scale outcomes trials to explore the potential synergistic benefits of combination therapies that lower both LDL-C and Lp(a) in reducing major adverse cardiovascular events.

Global Variations in Lp(a) Levels: Implications for Treatment Access

A second significant study assessed Lp(a) levels in patients with coronary heart disease (CHD) across 13 countries and six geographical regions. The findings revealed substantial global variation, with potential implications for equitable access to emerging Lp(a)-lowering therapies:

• Overall Median: The overall median Lp(a) level was 32 nmol/L among the CHD patients studied.
• Regional Differences: Median levels were highest in Africa (62 nmol/L) and lowest in Western Pacific (22 nmol/L).
• Country-Specific Differences: Even within the same regions, wide variations were observed. For example, in Europe, Portugal had a median level of 59 nmol/L, while Poland’s was 19.5 nmol/L. In South America, Colombia’s median was 46 nmol/L compared to Argentina’s 32 nmol/L.

Eligibility for Lp(a)-lowering therapies (typically for levels >150 nmol/L):

• 13% of patients had Lp(a) >150 nmol/L.
• 9.3% had Lp(a) >175 nmol/L.
• 6.2% had Lp(a) >200 nmol/L.

Similar to median levels, these eligibility rates varied widely by country, with the highest rates in Portugal and the lowest in the Philippines.

Fotios Barkas, MD, PhD, and colleagues, the study authors, noted that “the vast majority” of patients had Lp(a) levels far below the “typical risk-enhancing threshold,” suggesting that “the attributable risk from Lp(a) is more complex than previously perceived.”

They also highlighted that most patients with elevated Lp(a) also had poorly controlled traditional risk factors. This means that “if emerging Lp(a)-lowering therapies are unavailable in some countries, traditional risk factor management needs to improve several-fold to offset the residual risk from high Lp(a).” The significant geographical variations, they caution, could “likely impact equitable access to emerging therapies should they demonstrate clinical benefit.”

In a related editorial, Ron Blankstein, MD, FACC, and colleagues, emphasized that this work “helps elucidate geographic and ethnic variability in Lp(a) levels, findings that have implications for both attributable risk as well as the role that future Lp(a)-directed therapies may play in the landscape of secondary prevention across the globe.” They stressed the importance of future research clarifying “not only who is at risk but also who stands to benefit most – ensuring that scientific progress translates into personalized cardiovascular care worldwide.”

The Dawn of a New Era in Plaque Management

These studies, along with a related editorial by Seong-Bong Wee, MD, and colleagues, signal the “dawn of a new era in assessment and management of vulnerable plaque.” However, important knowledge gaps remain in identifying, diagnosing, and optimally managing these high-risk plaques. Future efforts will focus on refining the definition of high-risk vulnerable plaques and improving their detection using advanced imaging and new biomarkers.

Key takeaways for your heart health:

• Lp(a) is an important and independent risk factor for cardiovascular disease and particularly for vulnerable plaques.
• While not directly tied to overall plaque burden in the same way as traditional cholesterol, Lp(a) plays a unique role in plaque vulnerability.
• Lp(a) levels vary significantly across different populations and geographical regions, which will be important for equitable access to emerging therapies.
• Controlling traditional risk factors remains paramount, especially for those with elevated Lp(a).

Stay tuned as research continues to unravel the complexities of Lp(a) and pave the way for more personalized and effective cardiovascular care.

References:

• Erlinge, D, Tsimikas, S, Maeng, M. et al. Lipoprotein(a), Cholesterol, Triglyceride Levels, and Vulnerable Coronary Plaques: A PROSPECT II Substudy. JACC. 2025 Jun, 85 (21) 2011–2024.

Barkas, F, Brandts, J, De Bacquer, D. et al. Global Variation in Lipoprotein(a) Levels Among Patients With Coronary Heart Disease: Insights From the INTERASPIRE Study and Implications for Emerging Lp(a)-Lowering Therapies. JACC. 2025 Jun, 85 (21) 2028–2042.