Plasma reduction of apolipoprotein C-III with olezarsen leads to significant reductions in postprandial triglyceride levels: Results from a randomized trial

Abstract Background Hypertriglyceridemia is an established risk factor for cardiovascular disease and acute pancreatitis with postprandial elevations as an important contributor. Olezarsen, an investigational antisense oligonucleotide targeting plasma apolipoprotein C-III (apoC-III), markedly reduces fasting triglyceride levels, though its effect on postprandial triglyceride levels remains to be established. Design In a double-blind, placebo-controlled trial, 28 patients with fasting triglycerides ≥4 mmol/L received either 2 doses 80mg olezarsen (19 patients) or placebo (9 patients) every 4 weeks. Triglyceride levels were measured in the fasting state and postprandially both at baseline and 7 weeks into treatment. Postprandial triglyceride levels were assessed by calculating the area under the curve (AUC). Results The mean (±SD) age was 58.6±9.4 years, 82.1% (23) were male and the median IQR baseline fasting triglyceride levels were 5.9 4.5, 9.2 mmol/L. At 7 weeks of olezarsen treatment led to a placebo adjusted triglyceride reduction of 59.3% (-77.3 to -41.2%, p0.0001). The mean (95% CI) postprandial placebo-adjusted triglyceride AUC was reduced by 50.1% (-68.3 to -31.8%, p0.0001). Mean (95% CI) incremental AUC (iAUC) was reduced by 30.3% (-56.2 to -4.3%, p=0.026) in the olezarsen versus baseline group; the placebo-adjusted iAUC remained unchanged. The proportion of patients reaching any triglyceride levels ≥10 mmol/L, indicative of increased risk estimation of acute pancreatitis, decreased from 47% to 5% after olezarsen treatment, a 96.6% (p0.0001) reduction. Conclusion Olezarsen significantly reduces both fasting and postprandial triglyceride levels, these findings highlight olezarsen as a promising intervention to managing hypertriglyceridemia and reducing the risk of hypertriglyceridemia induced acute pancreatitis.