👤 Ioanna Gouni-Berthold

The PROLONG-ANG3 trial demonstrated that two doses of solbinsiran, an siRNA targeting hepatic ANGPTL3, given 90 days apart, decreased concentrations of apoB, triglycerides, LDL-C, non-HDL-C, ANGPTL3, and hepatic fat content at day 180 in adults with mixed dyslipidemia. Show less

The Essence-TIMI 73b trial demonstrated that monthly injections of olezarsen, an antisense oligonucleotide targeting hepatic APOC3, over 6 months increased HDL cholesterol and significantly decreased the concentrations of triglycerides, apolipoprotein C-III, apolipoprotein B, non-HDL-C, VLDL cholesterol, and remnant cholesterol in adults with moderate hypertriglyceridemia. Show less

To provide an insight into the new pharmacological options for the treatment of severe hypertriglyceridemia (sHTG). 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. Show less

According to current guidelines, the selection and intensity of lipid-effective therapies are based on the risk to be treated. The sole clinical categories of primary and secondary prevention of cardiovascular diseases result in over- and under-treatment, which may be a contributory cause of incomplete implementation of current guidelines in everyday practice. For the extent of benefit in cardiovascular outcome studies with lipid-lowering drugs, the importance of dyslipdemia for the pathogenesis of atherosclerosis-related diseases is crucial. Primary lipid metabolism disorders are characterized by life-long increased exposure to atherogenic lipoproteins. This article describes the relevance of new data for low density lipoprotein-effective therapy: inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9), adenosine triphosphate (ATP) citrate lyase with bempedoic acid, and ANGPTL3 with special consideration of primary lipid metabolism disorders, which are insufficiently taken into account, or not taken into account at all, in current guidelines. This is due to their apparently low prevalence rate and thus the lack of large outcome studies. The authors also discuss the consequences of increased lipoprotein (a), which cannot be sufficiently reduced until the ongoing intervention studies examining antisense oligonucleotides and small interfering RNA (siRNA) against apolipoprotein (a) are completed. Another challenge in practice is the treatment of rare, massive hypertriglyceridemia, especially with the aim of preventing pancreatitis. For this purpose, the apolipoprotein C3 (ApoC3) antisense oligonucleotide volenasorsen is available, which binds to the mRNA for ApoC3 and lowers triglycerides by around three quarters. Show less

Elevated triglyceride levels (higher than ~1000 mg/dL) are associated with an increased risk for pancreatitis. Apolipoprotein-CIII (apoC-III) plays a key role in the metabolism of triglycerides and triglyceride-rich lipoproteins. Loss of function mutations in the gene encoding apoC-III (APOC3) is associated with low triglyceride levels and a decreased risk for cardiovascular disease (CVD) while overexpression of APOC3 is associated with hypertriglyceridemia. Although many drugs such as fibrates, statins and omega-3 fatty acids modestly decrease triglyceride levels (and apoC-III concentrations), there are many patients who still have severe hypertriglyceridemia and are at increased risk for pancreatitis and potentially for CVD. The antisense oligonucleotide (ASO) against APOC3 mRNA volanesorsen (previously called ISIS 304801, ISIS-ApoCIIIRx and IONIS-ApoCIIIRx) robustly decreases both, apoC-III production and triglyceride concentrations and is being currently evaluated in phase 3 trials. In this narrative review, we present the currently available clinical evidence on the efficacy and safety of volanesorsen for the treatment of hypertriglyceridemia. Show less

Increased triglyceride levels (higher than ∼1000 mg/dL) are associated with an increased risk for pancreatitis. Apolipoprotein-CIII (apo-CIII) plays a key role in the metabolism of triglycerides and triglyceride-rich lipoproteins. While loss of function mutations in the gene encoding apo-CIII (APOC3) are associated with low triglyceride levels and a decreased risk for cardiovascular disease (CVD), overexpression of APOC3 is associated with hypertriglyceridemia. Although many drugs such as fibrates, statins and omega-3 fatty acids modestly decrease triglyceride levels (and apo-CIII concentrations), there are many patients who still have severe hypertriglyceridemia and are at risk for pancreatitis and potentially CVD. The antisense oligonucleotide (ASO) against APOC3 mRNA volanesorsen (previously called ISIS 304801, ISIS-ApoCIIIRx and IONIS-ApoCIIIRx) robustly decreases both, apo-CIII production and triglyceride concentrations and is being currently evaluated in phase 3 trials. In this narrative review we present the currently available clinical evidence on the efficacy and safety of volanesorsen for the treatment of hypertriglyceridemia. Show less