What does an elevated Lipoprotein(a) (Lp(a)) level mean and how is it managed?

Understanding and Explaining Elevated Lipoprotein(a)

What Elevated Lp(a) Means

Elevated Lipoprotein(a) is a genetically determined, lifelong cardiovascular risk factor that acts independently of your cholesterol levels and cannot be modified by diet or exercise. 1, 2

The Basic Science

• Lp(a) is an LDL-like particle with an attached plasminogen-like protein called apolipoprotein(a) that accumulates in blood vessel walls and heart valve tissue, contributing to both atherosclerosis (plaque buildup) and blood clot formation 2
• Your Lp(a) level is approximately 70-90% determined by your genetics—specifically variants in the LPA gene—meaning it remains relatively constant throughout your life regardless of lifestyle changes 3, 4
• This is fundamentally different from LDL cholesterol, which responds to diet, exercise, and medications like statins 1

Risk Thresholds and What They Mean

• Elevated Lp(a) is defined as >30 mg/dL (or >75 nmol/L), which represents the 75th percentile in white populations and the point where cardiovascular risk begins to increase 1, 2
• Significant risk occurs at >50 mg/dL (approximately 100-125 nmol/L) according to European guidelines 1, 2
• Very high risk occurs at >100 mg/dL, where cardiovascular event rates are substantially elevated 1
• Risk increases continuously with higher levels—there is no safe threshold below which risk disappears 5

Clinical Impact

• Elevated Lp(a) affects approximately 20-30% of the global population, representing over one billion people worldwide 6
• Even when your LDL cholesterol is well-controlled with statins, elevated Lp(a) contributes to "residual cardiovascular risk"—meaning you still have increased risk of heart attack, stroke, peripheral arterial disease, heart failure, and aortic valve stenosis 2, 6
• In patients with familial hypercholesterolemia, elevated Lp(a) further increases cardiovascular risk and predisposes to aortic valve calcification 1

Management Strategy

Primary Approach: Aggressive LDL Cholesterol Reduction

The cornerstone of management is achieving lower LDL cholesterol targets than would otherwise be recommended, because patients with elevated Lp(a) have higher cardiovascular event rates at any given LDL-C level. 1

• Randomized trial evidence demonstrates that aggressive LDL-C reduction reduces cardiovascular events in patients with elevated Lp(a), with some analyses suggesting benefit beyond LDL-C lowering alone 1
• This is critical because standard "LDL-C" laboratory measurements actually include the cholesterol content from Lp(a) particles, potentially making it harder to achieve true LDL-C targets 1, 2

Important Caveat About Statins

• Statins and ezetimibe may actually increase Lp(a) mass and Lp(a)-cholesterol levels, though they remain essential for LDL-C reduction 1, 2
• This paradoxical effect does not negate their cardiovascular benefit, but it explains why additional Lp(a)-specific strategies may be needed 1

Specific Lp(a)-Lowering Therapies

For patients with Lp(a) >100 mg/dL or additional cardiovascular risk factors:

• PCSK9 inhibitors (evolocumab or alirocumab) reduce Lp(a) by approximately 25-30% while providing an additional 50-60% LDL-C reduction 1, 3
• Niacin (immediate- or extended-release) up to 2000 mg/day reduces Lp(a) by 30-35% and is currently the most recommended conventional medication specifically for Lp(a) reduction 1, 5
• Niacin should be used optimally in conjunction with glycemic control and LDL control 1

For patients with Lp(a) >60 mg/dL who develop cardiovascular events or disease progression despite optimal medical therapy:

• Lipoprotein apheresis reduces Lp(a) by up to 80% and has been shown to reduce cardiovascular events by approximately 80% in this high-risk population 1
• Apheresis also improves coronary blood flow and reduces frequency of angina in patients with refractory angina and elevated Lp(a) 1

Special Population Considerations

• Children with elevated Lp(a) have a fourfold increased risk of acute ischemic stroke, with risk of recurrent strokes increased by more than 10-fold when Lp(a) is >90th percentile 1, 2
• Patients with chronic kidney disease or end-stage renal disease have substantially increased Lp(a) levels, and Lp(a) is an independent predictor of coronary heart disease events and mortality in this population 1, 2

Common Pitfalls to Avoid

• Failing to measure Lp(a) in high-risk patients—particularly those with premature cardiovascular disease, familial hypercholesterolemia, family history of premature CVD, or recurrent cardiovascular events despite optimal therapy—is a critical missed opportunity 2, 6
• Relying solely on LDL-C targets without considering Lp(a)-mediated risk may not adequately address total cardiovascular risk 2
• Overlooking that measured "LDL-C" includes Lp(a)-cholesterol may lead to misinterpretation of lipid profiles and inadequate risk assessment 1, 2
• Not recognizing that lifestyle modifications and standard statins do not lower Lp(a) may lead to false reassurance that risk is being adequately addressed 7

Emerging Therapies

• Antisense oligonucleotides (ASO) targeting Lp(a) show strong efficacy with up to 90% reductions in Lp(a) levels with good safety profiles 3, 7
• The ongoing Lp(a)HORIZON cardiovascular outcomes trial will provide definitive evidence on whether selective Lp(a) lowering with ASO reduces major cardiovascular events 3