Cardiovascular Disease

Lipoprotein(a)’s Outsized Per-Particle Risks

A pair of JACC studies laid what might be a new scientific foundation for all that research showing that people with high lipoprotein(a) have elevated cardiovascular risks.

The first study analyzed 502k UK Biobank participants, identifying two clusters of genetic variants that either raise apoB by increasing Lp(a) or LDL, showing that the Lp(a) cluster faced far greater cardiovascular risks:

  • Each 50 nmol/L higher Lp(a)-apoB brought a 28% greater risk for coronary heart disease, versus 4% with LDL-apoB.
  • Based on polygenic scores, subjects in the Lp(a) cluster had a 47% higher risk of  coronary heart disease per 50 nmol/L apoB, versus 4% again in the LDL cluster.
  • With that, the researchers estimated that Lp(a)’s per-particle atherogenicity is 6.6-times greater than LDL.

A second study analyzed data from 356k UK Biobank participants, finding that apoB-containing Lp(a) particles have far greater cardiovascular event risks:

  • Lp(a) particles carry 5-times greater risks than non-Lp(a) apoB particles (e.g LDL-C apoB particles).
  • Each 100 nmol/L increase in Lp(a) brought a 24% greater risk, while 100 nmol/L increases in non-Lp(a) apoB came with just a 5% higher risk.

These results underscore the need to develop effective LP(a)-lowering therapies, and there appears to be some promising options on the horizon:

  • Amgen’s injectable siRNA olpasiran slashed Lp(a) by as much as 100% in its Phase II trial, and has moved on to Phase III.
  • Lilly’s injectable siRNA lepodisiran’s Phase II is underway, its other injectable siRNA LY3819469 is in Phase II trials, and its oral small molecule inhibitor muvalaplin performed well in its Phase I trial.
  • Silence Therapeutics’ injectable siRNA zerlasiran cut Lp(a) levels by 90% in a Phase 1 trial, and has progressed to Phase II.

More candidates are surely on the way, noting that Lilly has entered into a Lp(a)-targeted gene editing alliance with Verve Therapeutics, and Novartis and Ionis Pharmaceuticals recently expanded their antisense-based Lp(a) therapy alliance.

The Takeaway

Years of studies have shown that people with high Lp(a) have worse cardiovascular outcomes, and this new research adds solid particle-level evidence showing why this is the case, while further supporting the need for Lp(a)-lowering therapies. In fact, these studies suggest that it might be more beneficial to target Lp(a) reduction rather than prescribing a second or third LDL therapy, even if cutting LDL remains the primary focus.

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