Angiopoietin-Like Protein 3 (ANGPTL3) Inhibitors in the Management of Refractory Hypercholesterolemia

Abstract

Cardiovascular disease (CVD) is the most common cause of death in a global scale and significantly depends on the elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) and the subsequent formation of atherosclerotic plaques. While physicians have several LDL-C-lowering agents with diverse mechanisms of action, including statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and inclisiran, angiopoietin-like protein 3 (ANGPTL3) inhibitors have recently emerged as a powerful addition in the armamentarium of lipid-lowering strategies, especially for patients with refractory hypercholesterolemia, as in the case of patients with homozygous familial hypercholesterolemia (HoFH). ANGPTL3 protein is a glycoprotein secreted by liver cells that is implicated in the metabolism of lipids along with other ANGPTL proteins. These proteins inhibit lipoprotein lipase (LPL) and endothelial lipase (EL) in tissues. Loss-of-function mutations affecting the gene encoding ANGPTL3 are linked with lower total cholesterol, LDL-C, and triglyceride (TG) levels. Evinacumab is a monoclonal antibody that targets, binds to, and pharmacologically inhibits ANGPTL3, which was recently approved by the United States Food and Drug Administration (FDA) as a complementary agent to other LDL-C lowering regimens for patients aged 12 or older with HoFH, based on clinical trial evidence that confirmed its safety and efficacy in those patients. Antisense oligonucleotides (ASOs) also represent an interesting class of agents that target and inhibit the mRNA derived from the transcription of ANGPTL3 gene. This review aims to present and discuss the current clinical and scientific data pertaining to the role of ANGPTL3 inhibitors, a novel lipid-modifying class of agents capable of reducing LDL-C levels via a mechanism independent of LDL receptors.

Drug development advances in human genetics‐based targets

“…identified 13 different LOF variants of ANGPTL3 , the presence of which was associated with a 41% lower risk of CAD in 13,102 patients with CAD and 40,430 controls. In addition, carriers of the ANGPTL3 LOF variant were found to have 27% lower levels of TG, 9% lower levels of LDL‐C, and 4% lower levels of high‐density lipoprotein cholesterol (HDL‐C) compared with noncarriers 141 . Similar results were reported by Stitziel et al 142 .…”

“…In addition, carriers of the ANGPTL3 LOF variant were found to have 27% lower levels of TG, 9% lower levels of LDL-C, and 4% lower levels of high-density lipoprotein cholesterol (HDL-C) compared with noncarriers. 141 Similar results were reported by Stitziel et al 142 Musunuru et al 143 found by WES that two mutations (S17X and E129X) in human ANGPTL3 resulted in decreased plasma LDL-C, TG, and HDL-C levels, and also minimized the rate of very low-density lipoprotein (VLDL)-apo B production and increased the rate of LDL-apo B catabolism. Robciuc et al 144 reported that ANGPTL3 LOF carriers exhibit low plasma FFA levels and strong insulin sensitivity.…”

“…141,164 Currently, evinacumab is used primarily in patients with HoFH (both children and adults over the age of 5 years), 165 and several studies have validated the long-term safety and efficacy of evinacumab. 141 Second, there are several ANGPTL3 inhibitors in the development stages (Table 2), among which the more hotly researched ones are ASO and siRNA drugs targeting ANGPTL3 mRNA, such as ARO-ANG3 and Vupanorsen. 166,167 Based on the LDL-C regulatory mechanism of ANGPTL3 independent of LDLR, it is expected to make up for the inadequacy of current PCSK9 inhibitors in lowering LDL-C and TG to address the residual risk of ASCVD.…”

“…One ANGPTL3 inhibitor is currently approved for marketing, the human monoclonal antibody evinacumab developed by Regeneron 141,164 . Currently, evinacumab is used primarily in patients with HoFH (both children and adults over the age of 5 years), 165 and several studies have validated the long‐term safety and efficacy of evinacumab 141 .…”

High producer variant of lipoprotein lipase may protect from hepatocellular carcinoma in alcohol-associated cirrhosis

“…2 A–C). LPL activity is tightly controlled also on a post-transcriptional level, 43 for example by the inhibitor ANGPTL3, which is mainly expressed in the liver, 44 so that the effect of a single C allele might be diminished considerably. In addition, our study may be underpowered to show an additive effect: studies showing an additive effect on lipid levels in the blood included more than 27,000 10 or more than 7,100 18 individuals.…”