RNA Inhibitor Reduces “Bad Cholesterol” in Patients With Cardiovascular Disease

The RNA inhibitor olpasiran significantly reduces a type of “bad cholesterol” that’s associated with a high risk of cardiovascular events, according to results from an analysis by a Mount Sinai researcher of a phase 2 trial. The study reported that higher doses of olpasiran lowered the type of cholesterol called lipoprotein(a) [Lp(a)] by more than 95 percent in participants with atherosclerotic cardiovascular disease. Findings were published February 12, 2025, in JAMA Cardiology.

“Our study is the first clinical trial to investigate the association between oxidized phospholipids on lipoprotein(a) and inflammatory mediators,” says Robert Rosenson, MD, Professor of Medicine (Cardiology) at the Icahn School of Medicine at Mount Sinai and lead author of the analyses. “We found that in addition to its beneficial effects on lowering lipoprotein(a), olpasiran reduced levels of oxidized phospholipids, which are presumed to promote atherosclerosis.”

Lipoprotein(a) is believed to be a major carrier of oxidized phospholipids, considered a potent driver of inflammation and atherosclerosis. Olpasiran (manufactured by Amgen), a small interfering RNA, blocks Lp(a) production by inducing degradation of apolipoprotein(a) messenger RNA (mRNA). Apolipoprotein(a) is a major protein component of lipoprotein(a), along with apolipoprotein B (apoB).

OCEAN(a)-DOSE, the randomized phase 2 clinical trial, enrolled 282 patients with cardiovascular disease and Lp(a) levels greater than 150 nmol/L (60 mg/dL)—levels that are believed to promote clotting and inflammation, significantly increasing the risk of heart attack, stroke, aortic stenosis, and peripheral artery disease. The reason for that danger is that Lp(a) can accumulate in the walls of blood vessels, forming plaques that are similar to low-density lipoprotein (LDL), a known risk factor for cardiovascular events. In fact, Lp(a) is believed to carry a cardiovascular risk five to six times that of LDL cholesterol.

Specifically, the research team reported that patients who received 75 mg or higher of olpasiran every 12 weeks had a 95 percent or greater reduction in Lp(a) compared to the placebo group at 36 weeks. Moreover, at week 36, Lp(a) increased by an average of 3.6 percent in the placebo group, while there were substantial reductions of Lp(a) levels in all of the olpasiran groups. The rates of adverse events were similar in the olpasiran and placebo cohorts.

“Results of our trial revealed that olpasiran led to a significant and sustained reduction in oxidized phospholipids on apolipoprotein B,” notes Dr. Rosenson, who also is Director of the Metabolism and Lipids Program for Mount Sinai Fuster Heart Hospital, which enrolled the largest number of participants in the study of any site worldwide. “We observed no significant effects of olpasiran, however, on the secretion of the proinflammatory cytokine interleukin-6 or C-reactive protein compared to the placebo group.”

Dr. Rosenson credits his analyses with exploring, even challenging, the leading hypothesis of Lp(a)-associated risk for cardiovascular disease. “Further work is needed in this area,” he emphasizes, “but OCEAN will enable us to more accurately select patients for future trials who are likely to show an anti-inflammatory response from selective RNA inhibitors of lipoprotein(a).”

Reference: Rosenson RS, López JAG, Gaudet D, 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

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