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.