The Olpasiran Paradox: Lowering Lp(a) Without Reducing Inflammation

 In the ever-evolving field of cardiology, lipoprotein(a) [Lp(a)] has emerged as a crucial risk factor for atherosclerotic cardiovascular disease (ASCVD). Many believed that lowering Lp(a) would also reduce inflammation, given its suspected role in triggering inflammatory pathways. However, recent findings from the OCEAN(a)-DOSE trial challenge this widely held assumption.

Breaking the Link: Lp(a) and Inflammation

The trial investigated the effects of olpasiran, a novel small interfering RNA (siRNA) therapy. The results confirmed that olpasiran significantly lowers Lp(a) levels, with reductions ranging from 51.6% to 92.3% at 36 weeks. Furthermore, oxidized phospholipids (OxPL), which are thought to contribute to ASCVD, also decreased in parallel with Lp(a). Despite these promising findings, a surprising revelation emerged: there was no corresponding drop in key inflammatory markers such as high-sensitivity interleukin-6 (hs-IL-6) and C-reactive protein (hs-CRP).

One investigator summarized the unexpected nature of these results: “There was a concept that has been promulgated that this pathway was linear: high Lp(a), high oxidized phospholipids, high levels of inflammation, and more cardiovascular events. If you read the literature, everybody’s convinced that this is the pathway, and we’re demonstrating that this is not the pathway.”

What Does This Mean for Cardiovascular Risk?

For years, the prevailing hypothesis suggested that reducing Lp(a) would automatically mitigate inflammation, thereby reducing cardiovascular risk. This study suggests otherwise, raising important questions:

• If Lp(a) isn’t directly driving inflammation, what mechanism makes it so dangerous?

• Are circulating inflammatory markers like hs-IL-6 and hs-CRP inadequate for assessing vascular inflammation?

• Could other, yet-to-be-identified inflammatory proteins be responsible for Lp(a)-related cardiovascular events?

One expert calls these findings “head-scratching,” but emphasizes that they do not change the well-established role of Lp(a) in increasing cardiovascular risk. “In the end, all that matters is outcomes. We just need the clinical trials.”

The Road Ahead: OCEAN(a) Cardiovascular Outcomes Trial

The ongoing OCEAN(a) cardiovascular outcomes trial aims to provide definitive answers. It will assess whether lowering Lp(a) with olpasiran translates into fewer cardiovascular events, irrespective of inflammatory marker changes. If successful, olpasiran could become a key therapeutic option for patients with high Lp(a), a population historically lacking targeted treatments.

As cardiologists, we must remain open to new paradigms in cardiovascular disease. The OCEAN(a)-DOSE trial reminds us that even well-established concepts can be challenged, and understanding the true nature of Lp(a) in cardiovascular risk remains a complex puzzle yet to be fully solved.

Stay tuned as we await the results of the OCEAN(a) outcomes trial—because in medicine, outcomes always matter more than theories.