Effect of Targeting ApoC-III with Plozasiran on Lipoprotein Particle Size and Number in Hypertriglyceridemia (JACC May 2025-1)-Article: Effect of Targeting ApoC-III with Plozasiran on Lipoprotein Particle Size and Number in Hypertriglyceridemia

Article: Effect of Targeting ApoC-III with Plozasiran on Lipoprotein Particle Size and Number in Hypertriglyceridemia

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The study investigates the effects of plozasiran, a novel siRNA therapy targeting apolipoprotein C-III (apoC-III), on lipoprotein particle size and number in patients with hypertriglyceridemia and mixed hyperlipidemia. ApoC-III is a peptide that regulates triglyceride-rich lipoproteins (TRLs), and its inhibition is hypothesized to reduce triglyceride levels and potentially decrease cardiovascular risk.<br /><br />In two Phase 2 studies, SHASTA-2 and MUIR, involving 403 participants, plozasiran was administered in varying doses or as a placebo. The effects were assessed via nuclear magnetic resonance (NMR) spectroscopy. Results showed a significant reduction in TRL-particle concentrations, averaging about 50% compared with placebo. While plozasiran did not increase total low-density lipoprotein particles (LDL-P), it shifted LDL to larger, potentially less atherogenic particles. Additionally, high-density lipoprotein particle (HDL-P) concentrations increased, notably larger HDL-P. This shift in lipoprotein profiles suggests a possible reduction in atherosclerotic cardiovascular disease (ASCVD) risk.<br /><br />The study authors note that unlike some high-potency TRL-lowering therapies that increase LDL cholesterol levels, plozasiran did not elevate LDL-P numbers. Instead, it demonstrated potentially beneficial qualitative changes in LDL size distribution. The findings support further exploration of plozasiran in larger, long-term outcome trials to confirm its cardiovascular risk reduction potential. The study acknowledges some limitations, including the short follow-up duration and predominantly Caucasian sample, which may affect generalizability.<br /><br />The promising changes in lipoprotein numbers and sizes induced by plozasiran, without an increase in LDL-P or apoB, suggest its potential as a treatment to decrease ASCVD risk, warranting further investigation in prospective trials. The results indicate that plozasiran could offer a novel approach to managing hypertriglyceridemia and reducing cardiovascular risk.

Keywords

plozasiran

siRNA therapy

apolipoprotein C-III

hypertriglyceridemia

lipoprotein particle size

cardiovascular risk

Phase 2 studies

nuclear magnetic resonance spectroscopy

atherosclerotic cardiovascular disease

LDL size distribution