Updates in Small Interfering RNA for the Treatment of Dyslipidemias

Abstract

Purpose of Review Atherosclerotic cardiovascular disease (ASCVD) is still the leading cause of death worldwide. Despite excellent pharmacological approaches, clinical registries consistently show that many people with dyslipidemia do not achieve optimal management, and many of them are treated with low-intensity lipid-lowering therapies. Beyond the well-known association between low-density lipoprotein cholesterol (LDL-C) and cardiovascular prevention, the atherogenicity of lipoprotein(a) and the impact of triglyceride (TG)-rich lipoproteins cannot be overlooked. Within this landscape, the use of RNA-based therapies can help the treatment of difficult to target lipid disorders. Recent Findings The safety and efficacy of LDL-C lowering with the siRNA inclisiran has been documented in the open-label ORION-3 trial, with a follow-up of 4 years. While the outcome trial is pending, a pooled analysis of ORION-9, ORION-10, and ORION-11 has shown the potential of inclisiran to reduce composite major adverse cardiovascular events. Concerning lipoprotein(a), data of OCEAN(a)-DOSE trial with olpasiran show a dose-dependent drop in lipoprotein(a) levels with an optimal pharmacodynamic profile when administered every 12 weeks. Concerning TG lowering, although ARO-APOC3 and ARO-ANG3 are effective to lower apolipoprotein(apo)C-III and angiopoietin-like 3 (ANGPTL3) levels, these drugs are still in their infancy. Summary In the era moving toward a personalized risk management, the use of siRNA represents a blossoming armamentarium to tackle dyslipidaemias for ASCVD risk reduction.

Drug development advances in human genetics‐based targets

“…In addition, ANGPTL3 LOF mutations prevent CAD without serious adverse health consequences and are expressed predominantly in hepatocytes, several features that make nucleic acid therapy potentially more effective than monoclonal antibodies. In particular, inhibition of ANGPTL3 by siRNA may be a future panacea against hypertriglyceridemia in a variety of dyslipidemia conditions, 181 including residual LDL-C elevation in FH. 135,166,182 Similarly, ANGPTL3 is an attractive target for in vivo gene editing.…”

Lipid-lowering approaches to manage statin-intolerant patients

“…Furthermore, twice-yearly inclisiran provided sustained reductions in LDL-C and PCSK9 concentrations and was well tolerated over 4 years in the extension study. 15 …”

Differences in Stable and Unstable Atherosclerotic Plaque

“…58 Further understanding of signaling molecules that control blood lipids has also added a variety of targetable lipid-lowering therapies, including therapies not yet on the market such as lipoprotein(a) and apoCIII, as well as other monoclonal antibodies and antisense oligonucleotides. [59][60][61] Bempedoic acid is a novel nonstatin drug that inhibits cholesterol synthesis, targeting the same pathway as statins in the liver. The prodrug is converted into active coenzyme A in the liver and can lower cholesterol levels by 23% at higher doses (eg, 120 mg daily).…”