Effect of lipid-lowering therapies on lipoprotein(a) levels

Most conventional lipid-lowering therapies have little or no effect on lipoprotein(a) [Lp(a]), while a few agents (PCSK9 inhibitors, niacin, some CETP inhibitors, and nucleic acid–based therapies) produce modest to very large reductions, with the largest effects seen with investigational RNA-targeted drugs.​

Overview of Lp(a) and available therapies

Lp(a) is an inherited, largely fixed lipoprotein that is an independent causal risk factor for atherosclerotic cardiovascular disease and aortic valve stenosis. Most standard lipid-lowering drugs were developed to target LDL-C or triglycerides and therefore do not specifically target Lp(a).​

Therapies with minimal or no Lp(a) effect

• Statins tend to slightly increase or leave Lp(a) unchanged, so they are not used to lower Lp(a) despite their clear benefit on LDL-C and outcomes.​

• Ezetimibe, bile-acid sequestrants, and fibrates generally have little or inconsistent effect on Lp(a) concentrations.​

Therapies that lower Lp(a) modestly

• PCSK9 monoclonal antibodies (evolocumab, alirocumab) reduce Lp(a) by roughly 15–30%, with a recent meta-analysis reporting around 29% reduction in trials and real‑world data showing median reductions near 17–20%.​

• Inclisiran (siRNA to PCSK9) produces similar LDL-C effects and appears to lower Lp(a) by about 20% on average in randomized data.​

Therapies with larger Lp(a) reductions

• Niacin (nicotinic acid), especially extended‑release formulations at typical lipid doses, lowers Lp(a) by about 20–25% on average, with meta‑analyses showing roughly a 23% reduction, though outcome trials have not shown cardiovascular benefit when added to modern therapy and tolerability is a concern.​

• CETP inhibitors can substantially lower Lp(a); pooled randomized data suggest average reductions around 40–45%, although individual CETP inhibitors differ in efficacy and clinical outcome profiles.​

Emerging nucleic acid–based Lp(a) drugs

• Antisense and siRNA agents directed specifically at LPA mRNA (for example, olpasiran and similar compounds) produce very large Lp(a) reductions, often 70–100% in phase 2 studies, with dose‑dependent effects and sustained lowering between injections.​

• These agents are not yet widely approved for clinical use; ongoing phase 3 trials are testing whether such deep Lp(a) lowering translates into fewer cardiovascular events.​

Practical clinical implications

• At present, no widely available therapy is approved solely for Lp(a) lowering, so management focuses on aggressive control of other risk factors (LDL-C, blood pressure, diabetes, lifestyle) and considering PCSK9 inhibition in high‑risk patients with markedly elevated Lp(a).​

• Future practice may change substantially if ongoing outcome trials confirm that RNA-based Lp(a)-targeting therapies reduce cardiovascular events proportional to their large Lp(a) reductions.​

• Ocular disease associations with high Lp(a)

  High Lp(a) has been associated with an increased risk of retinal vein occlusion in several observational studies and meta-analyses, suggesting a prothrombotic and pro‑inflammatory role in the retinal circulation. Elevated Lp(a) has also been reported as a risk factor or marker for diabetic retinopathy and vision‑threatening diabetic retinopathy in patients with type 2 diabetes.

Author

Paddy Kalish OD, JD and B.Arch Author and Blogger