Plozasiran reduces triglyceride levels and acute pancreatitis incidence in persistent chylomicronemia

1. In this randomized controlled trial, among patients with persistent chylomicronemia, it was found that plozasiran more effectively reduced fasting triglyceride and apolipoprotein C-III levels, as well as acute pancreatitis incidence, compared with placebo.

2. Adverse events among patients who received plozasiran were generally similar to those in the placebo group, with severe adverse events being more common in the placebo group.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Persistent chylomicronemia is defined by fasting triglyceride levels >880 mg/dL and is classically caused by familial chylomicronemia syndrome (FCS). Persistent chylomicronemia significantly increases the risk of acute pancreatitis, with triglyceride-induced pancreatitis having a worse prognosis than pancreatitis from other causes, further highlighting the importance of effective treatment. Current triglyceride-lowering medications, including statins, fibrates, and fish oils, provide minimal benefit for these patients and have not been shown to lower the risk of acute pancreatitis. While strict dietary modifications can partially lower chylomicronemia and triglyceride levels, dietary adherence can be extremely challenging. Apolipoprotein C-III is a glycoprotein predominantly synthesized by the liver which increases triglyceride levels. Plozasiran is a hepatically targeted small interfering RNA that reduces the production and secretion of apolipoprotein C-III and has been shown in a phase one study to reduce apolipoprotein C-III levels in patients with persistent chylomicronemia. The present trial assessed the efficacy and safety of plozasiran compared with placebo among patients with FCS or symptomatic persistent chylomicronemia. Compared with placebo, plozasiran was more effective in reducing fasting triglyceride and apolipoprotein C-III levels, as well as the incidence of acute pancreatitis. Additionally, adverse events were similar between the two groups. Limitations of the study included its relatively small sample size as well as the limitation of follow-up to one year. Nevertheless, these findings are a valuable initial step in demonstrating the clinical value of plozasiran for the treatment of extreme hypertriglyceridemia to prevent acute pancreatitis in patients with persistent chylomicronemia, including FCS.

Click to read the study in NEJM

In-Depth [randomized controlled trial]: This phase three, double-blind, randomized trial assessed the efficacy and safety of plozasiran compared with placebo. Patients 18 years of age or older with a diagnosis of severe hypertriglyceridemia resistant to standard lipid-lowering therapy, a history of a fasting triglyceride level > 1000 mg/dL on at least three occasions, and at least one of the following criteria: genetic diagnosis of FCS, absent or low post-heparin lipoprotein lipase activity, history of acute pancreatitis not caused by alcohol or cholelithiasis, recurrent hospitalizations for severe abdominal pain without another identified cause, childhood pancreatitis, or a family history of hypertriglyceridemia-induced pancreatitis were included. The primary outcome was mean percent change in fasting triglyceride level from baseline at ten months. A total of 75 patients were included in the study, with 26 assigned to the 25-mg plozasiran group, 24 to the 50-mg plozasiran group, and 25 to the placebo group. At ten months, the median percent change in fasting triglyceride level compared with placebo was -59 percentage points in the 25-mg group (95% Confidence Interval [CI], -90 to -28; p<0.001) and -53 percentage points in the 50-mg group (95% CI, -83 to -22; p<0.001). Additionally, apolipoprotein C-III levels were significantly reduced with both the 25-mg and 50-mg dose of plozasiran, whereas levels were minimally changed with placebo. Of the patients who received plozasiran, 4% experienced acute pancreatitis compared with 20% of those who received (odds ratio, 0.17; 95% CI, 0.03 to 0.94; P=0.03). Finally, with regard to the safety of plozasiran, adverse events among patients who received plozasiran were generally similar to those in the placebo group, with severe adverse events being more common in the placebo group. In summary, among patients with persistent chylomicronemia, plozasiran was found to be safe and effective for reduction of fasting triglyceride and apolipoprotein C-III levels, as well as acute pancreatitis incidence.

Image: PD

©2025 2 Minute Medicine, Inc. All rights reserved. No works may be reproduced without expressed written consent from 2 Minute Medicine, Inc. Inquire about licensing here. No article should be construed as medical advice and is not intended as such by the authors or by 2 Minute Medicine, Inc.