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Hepatic fat changes with antisense oligonucleotide therapy targeting ANGPTL3
Andre Zimerman1, Stephen D Wiviott1, Jeong-Gun Park1
1Thrombolysis in Myocardial Infarction (TIMI) Study Group, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA (Drs. Zimerman, Wiviott, Park, Murphy, Ran, Jevne), Kuder, (Drs. Sabatine, Bergmark, and Marston).
Journal of Clinical Lipidology
|December 29, 2023
Summary
Vupanorsen treatment for hyperlipidemia increased hepatic fat fraction (HFF) in a dose-dependent manner. Liver enzymes like AST and ALT are imperfect indicators for detecting these increases in hepatic fat.
Area of Science:
- Cardiology
- Hepatology
- Pharmacology
Background:
- Angiopoietin-like protein 3 (ANGPTL3) is a novel target for hyperlipidemia.
- Vupanorsen, an ANGPTL3 inhibitor, reduced triglycerides but increased hepatic fat fraction (HFF).
Purpose of the Study:
- To assess HFF progression with escalating vupanorsen doses.
- To examine differential HFF increases in patient subgroups.
- To correlate HFF changes with liver enzymes.
Main Methods:
- TRANSLATE-TIMI 70 was a randomized, placebo-controlled trial.
- 286 adults with hyperlipidemia received 7 vupanorsen dosing regimens.
- 227 patients had HFF measured at baseline and 24 weeks.
Main Results:
- Vupanorsen caused dose-dependent HFF increases up to 76% (absolute 7.0%) at 24 weeks.
- HFF increases were greater in patients with elevated baseline HFF, BMI, triglycerides, or diabetes.
- HFF changes correlated moderately with AST (rho=0.49) and ALT (rho=0.50) elevations.
Conclusions:
- Vupanorsen increased HFF dose-dependently.
- Liver enzymes (AST, ALT) are imperfect indicators of increased hepatic fat.
- HFF monitoring is crucial in clinical trials for ANGPTL3 inhibitors targeting the liver.
