Reductions in remnant cholesterol and VLDL cholesterol through inhibition of ANGPTL3 protein synthesis: an analysis from the TRANSLATE-TIMI 70 trial.

Aims: Remnant cholesterol and very low-density lipoprotein cholesterol (VLDL-C) are increasingly recognized risk factors for atherosclerotic disease with few therapeutic options. Angiopoietin-like 3 (ANGPTL3), a key protein in the metabolism of triglyceride-rich lipoproteins, is a promising target.
Methods and Results: TRANSLATE-TIMI 70 was a double-blind, placebo-controlled randomized trial testing seven dose regimens of vupanorsen, an antisense oligonucleotide against ANGPTL3, in adults with non-HDL-C ≥ 100 mg/dL and triglycerides 150-500 mg/dL. The primary endpoint of this analysis was percentage change in remnant cholesterol (total cholesterol minus directly measured LDL-C minus HDL-C) and VLDL-C (directly measured) over 24 weeks. Two hundred eighty-six patients were enrolled, with a median age of 64 years and 44% female. Median baseline remnant cholesterol and VLDL-C were 42 and 31 mg/dL, respectively (reference: <30 mg/dL). Vupanorsen lowered remnant cholesterol by 42-59% at 24 weeks over placebo (P < 0.001), achieving a median level of 18 mg/dL at the highest dose. Over the same period, VLDL-C was reduced by 52-67% over placebo (P < 0.001), with a median achieved level of 2.5 mg/dL at the highest dose. The effect of vupanorsen on remnant cholesterol and VLDL-C reduction was dose-dependent and directly associated with the degree of ANGPTL3 inhibition: at 90% ANGPTL3 reduction, there was a 61% and 81% decrease in remnant cholesterol and VLDL-C, respectively.
Conclusion: Inhibition of ANGPTL3 protein synthesis significantly lowered remnant cholesterol and VLDL-C in patients with hypertriglyceridaemia. The magnitude of reduction was associated with the degree of ANGPTL3 inhibition. These findings support ANGPTL3 inhibition as a promising target for lowering cholesterol on triglyceride-rich lipoproteins.
Competing Interests: Conflict of interest: A.Z., S.D.W., J.-G.P., S.A.M., X.R., A.J., J.F.K., M.S.S., B.A.B., and N.A.M. are members of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Abiomed, Inc., Amgen, Anthos Therapeutics, ARCA Biopharma, Inc., AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Ionis Pharmaceuticals, Inc., Janssen Research and Development, LLC, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Roche, Saghmos Therapeutics, Inc., Siemens Healthcare Diagnostics, Inc., Softcell Medical Limited, The Medicines Company, Verve Therapeutics, Inc., and Zora Biosciences. S.D.W. reports grants from Amgen, Arena, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, Janssen, Merck, and Sanofi; and consulting fees from Arena, AstraZeneca, Aegerion, Allergan, AngelMed, Boehringer Ingelheim, Boston Clinical Research Institute, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, Icon Clinical, Janssen, Lexicon, Merck, Servier, St Jude Medical, and Xoma. His spouse, Dr Caroline Fox, is an employee of Merck. C.R.B., M.C., V.R., and S.G.T. are employees and shareholders of Pfizer. S.V. holds a Tier 1 Canada Research Chair in Cardiovascular Surgery; and reports receiving research grants and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Janssen, Novartis, Novo Nordisk, Pfizer, PhaseBio, S & L Solutions Event Management Inc., and Sanofi. He is the President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. W.W. reports lecture fees from Pfizer, Astra Zeneca, and Boehringer Ingelheim. M.S.S. reports research grant support through Brigham and Women’s Hospital from: Abbott; Amgen; Anthos Therapeutics; AstraZeneca; Boehringer Ingelheim; Daiichi-Sankyo; Eisai; Intarcia; Ionis; Medicines Company; MedImmune; Merck; Novartis; Pfizer; Saghmos Therapeutics; and Verve Therapeutics. M.S.S. reports consulting for: Althera; Amgen; Anthos Therapeutics; AstraZeneca; Beren Therapeutics; Bristol-Myers Squibb; DalCor; Dr. Reddy’s Laboratories; Fibrogen; Intarcia; Merck; Moderna; Novo Nordisk; and Silence Therapeutics. B.A.B. reports grant support through the Brigham and Women’s Hospital: Pfizer, Ionis, AstraZeneca, and Abbott Vascular; and consulting/personal fees from Abiomed, CSI, Philips, Abbott Vascular, Servier, DaiichiSankyo, Janssen, and Quark. N.A.M. reports funds through a National Institutes of Health grant (K08HL153950) and is involved in clinical trials with Amgen, Pfizer, Ionis, Novartis, and AstraZeneca without personal fees, payments, or increase in salary. The other authors report no conflicts.
(© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)