AHA 2026 Series | Lp(a): Lowering Lp(a) Isn't Always Enough

A major cardiovascular trial presented at AHA 2026 delivered a disappointing result.

Pelacarsen, a drug designed to lower lipoprotein(a), reduced Lp(a) levels by nearly 78%. Yet this did not translate into fewer heart attacks, strokes, or other major cardiovascular events.

The HORIZON trial included 8,350 patients with established cardiovascular disease and elevated Lp(a).

Key findings:

• Lp(a) dropped nearly 78%.

• Major cardiovascular events were not reduced (HR 1.02).

• Treatment discontinuation was higher with pelacarsen (35.1% vs 18.3%).

Why does this matter?

Lp(a) is largely inherited and is an important cardiovascular risk factor. However, substantial Lp(a) reduction did not translate into clinical benefit in this trial.

My take: Does lowering Lp(a) stabilize existing plaques?

Lp(a) carries oxidized phospholipids that contribute to vascular inflammation and atherosclerosis. Whether lowering Lp(a) changes plaque composition or stabilizes vulnerable plaques remains unproven.

HORIZON was an outcomes trial, not a coronary imaging study. We still need imaging evidence to understand whether Lp(a) reduction changes plaque biology.

Does this mean Lp(a) doesn't matter? Absolutely not.

We still need to understand whether earlier intervention, greater Lp(a) reduction, or newer therapies can translate into meaningful cardiovascular benefits.

Full article: https://nejm.org/doi/full/10.1056/NEJMoa2610159