OLPASIRAN significantly reduces oxidized phospholipids on apolipoprotein B in patients with atherosclerotic cardiovascular disease and elevated lipoprotein(a) levels, but has no effect on systemic inflammatory biomarkers, new research has shown.
Lipoprotein(a) [Lp(a)] is a well-established risk factor for atherosclerosis, partly due to its role in carrying oxidized phospholipids (OxPL), which are believed to promote inflammation and vascular disease. The OCEAN(a)-DOSE trial investigated the impact of olpasiran, a small interfering RNA that reduces Lp(a) levels by targeting apolipoprotein(a) mRNA, on OxPL and key inflammatory markers. Understanding these effects could help determine whether olpasiran offers additional cardiovascular benefits beyond Lp(a) lowering.
This phase 2, international, multicentre, placebo-controlled trial enrolled 281 patients with atherosclerotic cardiovascular disease and Lp(a) levels exceeding 150 nmol/L. Participants were randomised to receive one of four olpasiran dosing regimens or placebo. The primary endpoint was the placebo-adjusted change in OxPL on apolipoprotein B (OxPL-apoB) at week 36. Among 272 participants analysed, baseline Lp(a) and OxPL-apoB concentrations were 260.3 nmol/L and 26.5 nmol/L, respectively. Olpasiran led to a dose-dependent and significant reduction in OxPL-apoB, with placebo-adjusted mean percentage reductions ranging from 51.6% (10 mg every 12 weeks) to 93.7% (225 mg every 24 weeks) at week 36 (P < .001 for all). These effects were maintained at week 48. However, olpasiran did not significantly alter high-sensitivity C-reactive protein (hs-CRP) or interleukin-6 (hs-IL-6) compared with placebo.
These findings suggest that olpasiran effectively lowers OxPL-apoB in patients with high Lp(a), reinforcing its potential role in reducing atherosclerotic risk. However, the lack of effect on systemic inflammatory markers indicates that its cardiovascular benefits may be primarily mediated through Lp(a) and OxPL reduction rather than systemic inflammation modulation. Future studies should evaluate whether this translates into improved clinical outcomes and explore potential combination therapies targeting residual inflammation in high-risk patients. Integrating olpasiran into clinical practice will require further data on long-term efficacy and safety, as well as its impact on cardiovascular events.
Katrina Thornber, EMJ
Reference
Rosenson RS et al. Olpasiran, Oxidized Phospholipids, and Systemic Inflammatory Biomarkers: Results From the OCEAN(a)-DOSE Trial. JAMA Cardiol. 2025. DOI:10.1001/jamacardio.2024.5433.
