In a patient on statin therapy with elevated lipoprotein(a), is ezetimibe recommended to lower lipoprotein(a)?

Ezetimibe Is Not Recommended for Lowering Elevated Lipoprotein(a)

Ezetimibe does not lower lipoprotein(a) levels and is not indicated for this purpose; in fact, statins and ezetimibe may modestly increase Lp(a) mass and Lp(a)-C levels. 1

Why Ezetimibe Does Not Address Elevated Lp(a)

• Ezetimibe blocks intestinal cholesterol absorption via the NPC1L1 protein and effectively lowers LDL-C by approximately 15–20%, but it has no mechanism of action that targets Lp(a) metabolism. 1, 2

• Both statins and ezetimibe tend to increase Lp(a) mass and Lp(a)-C levels, making them counterproductive for patients whose primary concern is elevated Lp(a). 1

• The Lp(a)-C content is included in the laboratory measurement of "LDL-C", which means that patients with elevated Lp(a) are less likely to achieve target LDL-C despite aggressive statin and ezetimibe therapy—but this does not mean ezetimibe is treating the Lp(a) elevation. 1

What Ezetimibe Does Accomplish in Statin-Treated Patients

• When added to statin therapy, ezetimibe provides an additional 15–25% LDL-C reduction and has proven cardiovascular benefit in the IMPROVE-IT trial (6.4% relative risk reduction in major adverse cardiovascular events over 6 years). 1, 2

• The ACC and ESC assign a Class I recommendation for ezetimibe as second-line therapy in patients who do not achieve LDL-C targets on maximally tolerated statin therapy, based on long-term safety and established cardiovascular outcomes data. 1

• Ezetimibe is most effective when added to high-potency statins, as patients on high-dose statins have the lowest cholesterol synthesis markers and the highest cholesterol absorption markers at baseline, making them ideal candidates for an absorption inhibitor. 3, 4

Therapies That Do Lower Lipoprotein(a)

• PCSK9 inhibitors (alirocumab, evolocumab, inclisiran) reduce Lp(a) levels in addition to lowering LDL-C by approximately 50–60%; this is the only currently approved class with demonstrated Lp(a)-lowering effects. 1

• Niacin can lower Lp(a) by up to 30%, but it has not shown cardiovascular benefit when added to maximal statin therapy in randomized trials (AIM-HIGH, HPS2-THRIVE), and it increases adverse effects such as worsened glycemic control. 1

• Some CETP inhibitors (anacetrapib) have shown Lp(a) reduction, but most agents in this class (dalcetrapib, evacetrapib) failed to demonstrate cardiovascular benefit in outcomes trials. 1

Clinical Algorithm for a Patient on Statin with Elevated Lp(a)

1. Measure Lp(a) level if the patient has a family history of premature ASCVD, personal history of ASCVD not explained by major risk factors, or difficulty achieving LDL-C targets despite statin therapy. 1

2. Optimize LDL-C lowering first, as LDL-C remains the primary therapeutic target:

   • Ensure the patient is on maximally tolerated high-intensity statin therapy (atorvastatin 40–80 mg or rosuvastatin 20–40 mg). 1
   • Add ezetimibe 10 mg daily if LDL-C remains ≥70 mg/dL (very high-risk patients) or ≥100 mg/dL (high-risk patients). 1

3. If Lp(a) is elevated (>50 mg/dL or >100 nmol/L) and the patient has very high cardiovascular risk, consider adding a PCSK9 inhibitor:

   • PCSK9 inhibitors lower both LDL-C (by ~50–60%) and Lp(a) (by ~20–30%). 1
   • The ACC provides a Class IIa recommendation for PCSK9 inhibitors in very high-risk patients with LDL-C ≥70 mg/dL on maximally tolerated statin ± ezetimibe. 1

4. Do not add ezetimibe specifically to lower Lp(a)—it will not accomplish this goal and may modestly increase Lp(a) levels. 1

Key Pitfalls to Avoid

• Do not assume that achieving very low LDL-C with ezetimibe will address elevated Lp(a); the two lipid fractions are distinct, and Lp(a) requires targeted therapy (PCSK9 inhibitors) if it is to be lowered. 1

• Do not delay PCSK9 inhibitor therapy in patients with markedly elevated Lp(a) (>100 mg/dL) and recurrent cardiovascular events, as these patients represent an extremely high-risk subgroup who may derive the greatest benefit from Lp(a) lowering. 1

• Recognize that patients with elevated Lp(a) are less likely to achieve very low LDL-C targets (e.g., <20 mg/dL) because the Lp(a)-C component is included in the LDL-C measurement; this does not indicate treatment failure but rather the need for Lp(a)-specific therapy. 1