August 29, 2023Open Access
Updates in Drug Treatment of Severe Hypertriglyceridemia
Resultado clave
Novel therapies targeting APOC3 and ANGPTL3 robustly decrease triglyceride levels in severe hypertriglyceridemia, though definitive reduction in acute pancreatitis risk remains unproven.
PICO estructurado
Do novel pharmacological agents (ASO and siRNA targeting APOC3 and ANGPTL3) reduce triglyceride levels and the risk of acute pancreatitis in patients with severe hypertriglyceridemia?
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Población
Patients with severe hypertriglyceridemia (sHTG) and familial chylomicronemia syndrome (FCS)
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Intervención
Novel pharmacological agents including antisense oligonucleotides (ASO) and small interfering RNA (siRNA) targeting APOC3 and ANGPTL3 (e.g., volanesorsen, olezarsen, ARO-APOC3, ARO-ANG3)
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Resultado
Decrease in triglyceride levels and reduction in the incidence of acute pancreatitis
While novel RNA-targeted therapies offer promising triglyceride-lowering efficacy for severe hypertriglyceridemia, definitive evidence for reducing acute pancreatitis risk remains lacking.
Limitaciones
- Lack of definitive evidence that any pharmacotherapy decreases the risk of acute pancreatitis
- Off-target side effects such as injection-site reactions and drug-induced thrombocytopenia with volanesorsen
- Hepatic side effects observed with vupanorsen leading to its discontinuation
Resumen
PURPOSE OF REVIEW: To provide an insight into the new pharmacological options for the treatment of severe hypertriglyceridemia (sHTG). RECENT FINDINGS: sHTG is difficult to treat. The majority of the traditional pharmacological agents available have limited success in both robustly decreasing triglyceride levels and/or in reducing the incidence of acute pancreatitis (AP), the most severe complication of sHTG. Therapeutic options with novel mechanisms of action have been developed, such as antisense oligonucleotides (ASO) and small interfering RNA (siRNA) targeting APOC3 and ANGPTL3. The review discusses also 2 abandoned drugs for sHTG treatment, evinacumab and vupanorsen. The ASO targeting APOC3, volanesorsen, is approved for use in patients with familial chylomicronemia syndrome (FCS) in Europe. Olezarsen, an N-acetylgalactosamine (GalNAc)-conjugated ASO with the same target, seems to have a better safety and efficacy profile. siRNA targeting APOC3 and ANGPTL3, namely ARO-APOC3 and ARO-ANG3, are also promising for the treatment of sHTG. However, the ultimate clinical goal of any sHTG treatment, the decrease in the risk of AP, has not been definitively achieved till now by any pharmacotherapy, either approved or in development.