Efficacy and safety of olezarsen in patients with vs without baseline fibrate use

BACKGROUND Hypertriglyceridemia is associated with increased atherosclerotic cardiovascular disease and pancreatitis risk, yet durable triglyceride reduction remains challenging. Olezarsen, an antisense oligonucleotide targeting APOC3, substantially reduced triglycerides in phase 3 trials. Fibrates lower triglycerides through complementary lipoprotein lipase and apolipoprotein C-III (APOC3) pathways. Whether fibrate therapy modifies olezarsen's effects is unknown. OBJECTIVE To evaluate the effects of olezarsen on triglycerides and other lipid parameters according to baseline fibrate use. METHODS This prespecified secondary analysis included 3 phase 3, randomized, double-blind, placebo-controlled trials. Adults with severe hypertriglyceridemia (triglycerides ≥500 mg/dL; CORE-TIMI 72a/CORE2-TIMI 72b, pooled) or moderate hypertriglyceridemia with elevated cardiovascular risk (triglycerides 150-499 mg/dL; Essence-TIMI 73b) were randomized to monthly olezarsen (50 or 80 mg) or placebo. Placebo-adjusted triglyceride changes at 6 and 12 months were estimated using adjusted analysis-of-covariance models with treatment-by-fibrate interaction terms. Secondary endpoints included levels of APOC3 and lipid parameters, with subgroup analyses by diabetes. RESULTS Among 1061 patients with severe and 1349 patients with moderate hypertriglyceridemia, 64% and 23% used fibrates at baseline. Olezarsen reduced triglycerides across all groups, with greater effects in fibrate users. In severe hypertriglyceridemia, placebo-adjusted triglyceride changes for fibrate users vs nonusers were -68.0% (95% CI: -75.2, -60.8) vs -53.2% (-62.9, -43.5) at 6 months (interaction P [Pint] = .02) and -66.3% (-73.4, -59.1) vs -48.4% (-58.2, -38.7) at 12 months (Pint = .004). In moderate hypertriglyceridemia, changes were -71.1% (-84.1, -58.1) vs -57.4% (-64.9, -49.9) at 6 months (Pint = .07) and -76.0% (-95.8, -56.2) vs -49.5% (-61.3, -37.8) at 12 months (Pint = .02). Similar patterns were observed for APOC3 and select atherogenic lipoproteins. Interactions were more consistently observed among patients with diabetes. Safety was similar across groups. CONCLUSION Olezarsen reduced triglycerides across the hypertriglyceridemia spectrum, with greater effects in patients on background fibrates, particularly with diabetes. Findings support potential complementary mechanisms and further investigation of concomitant triglyceride-reducing therapy.