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REDUCTIONS IN VLDL AND REMNANT CHOLESTEROL THROUGH INHIBITION OF ANGPTL3 PROTEIN SYNTHESIS: AN ANALYSIS FROM TRANSLATE-TIMI 70
Abstract
Background and Aims
VLDL and remnant cholesterol are increasingly recognized risk factors for MI with few targeted therapeutic options. Vupanorsen is an antisense oligonucleotide that inhibits the synthesis of ANGPTL3, a regulator of cholesterol metabolism.
Methods
TRANSLATE-TIMI 70 was a double-blind, randomized controlled trial testing 7 dose regimens of vupanorsen (SC Q4W: 80, 120, 160 mg; SC Q2W: 60, 80, 120, 160 mg) in adults with elevated triglycerides (150-500 mg/dl) and non-HDL-C ≥100 mg/dl on statin therapy. ANGPTL3, direct VLDL-C, and remnant cholesterol (calculated as total cholesterol - direct LDL-C - HDL-C) were assessed over 24 weeks.
Results
286 patients were enrolled with a median age of 64 years (IQR 58-69) and 44% female. Mean baseline VLDL and remnant cholesterol levels were 35 and 45 mg/dl, respectively (both normally <30 mg/dl). Vupanorsen lowered VLDL-C by up to 66-88% over placebo (p<0.001) at 16-24 weeks in the 160 mg Q2W arm (Figure, A), achieving a mean level of 7-8 mg/dl. Over the same time frame, remnant cholesterol was also significantly reduced by up to 57-59% over placebo (p<0.001). The magnitude of VLDL and remnant cholesterol reduction was directly related to the degree of ANGPTL3 protein synthesis inhibition (Figure, B), which occurred in a dose-dependent manner and by as much as 95% compared with placebo (p<0.001).
Conclusions
Inhibition of ANGPTL3 protein synthesis significantly lowers VLDL and remnant cholesterol, with the magnitude of reduction directly related to degree of ANGPTL3 lowering. ANGPTL3 inhibition may have a role in patients with residual dyslipidemia despite LDL-lowering therapy.