Integrating Lipoprotein(a) Into Cardiovascular Risk Assessment

Lipoprotein(a), or Lp(a), has emerged as a genetically determined and causal risk factor for both atherosclerotic cardiovascular disease and calcific aortic valve disease. Unlike traditional lipids, its levels are largely fixed by genetics, stable across a lifetime, and minimally influenced by lifestyle. Roughly one in five people worldwide have elevated Lp(a), which can substantially raise cardiovascular risk.

What makes Lp(a) unique is its structure: an LDL-like particle bound to apolipoprotein(a), which carries oxidized phospholipids and interferes with fibrinolysis. Together, these features make it highly atherogenic, proinflammatory, and prothrombotic. Epidemiological and genetic studies have repeatedly confirmed that elevated Lp(a) is not just a marker but a causal driver of disease.

How should Lp(a) be measured?

One of the challenges with Lp(a) testing is that the protein portion of the particle—apolipoprotein(a)—comes in many different sizes. Older laboratory tests were affected by this variability, which made results hard to compare across patients and centers. To address this, newer “isoform-insensitive” assays have been developed. These are calibrated against international reference standards and give results that are more accurate and consistent, regardless of apolipoprotein(a) size.

Experts now recommend that results be reported in nanomoles per liter (nmol/L), which reflects the actual number of Lp(a) particles in the blood. This is considered more meaningful than reporting mass concentration (mg/dL), which can be distorted by differences in particle size. However, in practice, both units are still used, and conversion between them is not straightforward. This lack of harmonization remains a barrier for clinicians who want to apply results consistently in risk assessment.

Because levels are stable, a once-in-a-lifetime measurement is often sufficient for most patients. This single test can provide lifelong insight into inherited risk, with targeted repeat testing considered only in select scenarios, such as those receiving investigational Lp(a)-lowering therapies.

Who Should Be Tested?

Guidelines are increasingly converging on broader testing. The European Society of Cardiology and the European Atherosclerosis Society already recommend one-time testing for all adults, while U.S. guidelines highlight testing in individuals at increased risk. Overall, there are several priority groups, including patients who have:

• Premature cardiovascular disease
• A strong family history of early heart disease
• Recurrent events despite LDL cholesterol control
• Familial hypercholesterolemia
• African or South Asian ancestry
• Calcific aortic valve disease at a young age

In these groups, identifying elevated Lp(a) can refine risk assessment and guide management.

Implications for Care

At present, there is no widely available pharmacotherapy specifically targeting Lp(a). Therefore, management centers on optimizing overall cardiovascular risk with aggressive LDL cholesterol reduction, blood pressure control, glucose management, and lifestyle measures.

Post hoc analyses suggest that PCSK9 inhibitors may offer incremental benefit in patients with high Lp(a), lowering both LDL cholesterol and Lp(a) itself. Low-dose aspirin has also shown promise in reducing events among those with genetically elevated levels.

Targeted therapies, however, are rapidly advancing. Antisense oligonucleotides such as pelacarsen and small interfering RNA agents like olpasiran and lepodisiran have reduced Lp(a) by more than eighty percent in early trials, and several large cardiovascular outcomes studies are underway. These agents could, for the first time, provide a direct way to lower Lp(a)-associated risk.

Despite progress, important gaps remain. Much of the evidence is derived from white European populations, leaving uncertainty about thresholds in diverse groups. Assay variability also complicates risk classification. Most critically, while therapies can dramatically lower Lp(a), whether this translates into improved survival is not yet proven. Ongoing outcomes trials will be pivotal in answering this question.

The evidence to date makes a compelling case: Lp(a) is not just another number on the lipid panel but a major inherited risk factor that has been underrecognized. One-time testing, especially in high-risk patients, can identify individuals who might otherwise be missed by traditional risk scores.

While clinicians currently have to manage risk indirectly, emerging therapies may soon transform how Lp(a)-driven cardiovascular risk is approached.

Reference
Razavi AC, Koschinsky ML, Hegele RA, et al. Why, how and in whom should we measure levels of lipoprotein(a)? A review of the evidence and recommendations for clinical practice. Diabetes Obes Metab. 2025;27(3):469-486. doi:10.1111/dom.16125