ApoC3 Inhibitors: Hope for High Triglycerides?
- Emerging therapies targeting apolipoprotein C-III (ApoC3) are changing how hypertriglyceridemia and associated cardiovascular risks are managed, according to Dr.
- ApoC3,a small glycoprotein crucial in triglyceride (TG) metabolism,was identified 50 years ago as a potent inhibitor of lipoprotein lipase (LPL) and a contributor to remnant lipoprotein accumulation.
- ApoC3,encoded by the APOC3 gene,inhibits LPL and hepatic lipase,Gaudet explained.
New therapies are transforming hypertriglyceridemia treatment. ApoC3 inhibitors,like olezarsen and plozasiran,are showing promise in reducing cardiovascular risk and elevated triglyceride levels,the chief takeaway,according to recent findings shared at the NLA 2025. professor Daniel Gaudet highlights how these treatments, targeting the ApoC3 protein, are offering new hope, especially for those with familial chylomicronemia syndrome (FCS). Clinical trials reveal significant reductions in triglycerides, with potential FDA approvals anticipated. News Directory 3 reports on these advancements, exploring how ApoC3 inhibition coudl fundamentally change lipid management. Discover what’s next for patients.
ApoC3 Inhibitors Transform Hypertriglyceridemia Treatment, CVD Risk
Updated May 31, 2025
Emerging therapies targeting apolipoprotein C-III (ApoC3) are changing how hypertriglyceridemia and associated cardiovascular risks are managed, according to Dr. Daniel gaudet, a professor of medicine at the Université de Montréal in Canada. Gaudet spoke at the 2025 National Lipid Association (NLA) Scientific Sessions in Miami, Fla.
ApoC3,a small glycoprotein crucial in triglyceride (TG) metabolism,was identified 50 years ago as a potent inhibitor of lipoprotein lipase (LPL) and a contributor to remnant lipoprotein accumulation. Recent clinical trials have renewed interest in ApoC3 inhibition for patients with severe hypertriglyceridemia (sHTG) and rare disorders like familial chylomicronemia syndrome (FCS), Gaudet said.
ApoC3,encoded by the APOC3 gene,inhibits LPL and hepatic lipase,Gaudet explained. By interfering with the breakdown of TG-rich lipoproteins, including chylomicrons and very-low-density lipoproteins, ApoC3 increases circulating TG levels. It also hinders the hepatic clearance of lipoprotein remnants, which is increasingly linked to cardiovascular disease (CVD) risk. Studies suggest ApoC3 is not just a contributor to hypertriglyceridemia but also an independant risk factor for atherosclerotic CVD (ASCVD), Gaudet noted.
“The clinical interest in inhibiting ApoC3 in preventing CVD or pancreatitis stems primarily from the identification quite recently—published 17 years ago—of naturally occurring loss-of-function variants in the APOC3 gene, the carriers [of which] were presenting favorable lipid profiles,” Gaudet said. “A lot of carriers were not exhibiting features of CVD over many years…large cohorts are available now showing the same pattern of negative association with CVD.”
Carriers of these loss-of-function variants consistently show lower TG levels and a reduced incidence of ASCVD, Gaudet said. This genetic evidence supports pharmacologically inhibiting ApoC3 to mimic this protective effect.
ApoC3 inhibition is effective in sHTG populations,including patients with FCS,where LPL activity is virtually absent. Gaudet emphasized that ApoC3 inhibitors can lower TG levels in these patients,highlighting the existence of LPL-independent pathways.
Currently, the most advanced ApoC3 inhibitors are GalNAc conjugated antisense oligonucleotides (ASOs) and small interfering RNA (siRNA) agents, Gaudet said. Two leading candidates are olezarsen (Tryngolza; Ionis Pharmaceuticals), a GalNAc-conjugated ASO, and plozasiran (ARO-APOC3; Arrowhead Pharmaceuticals), a GalNAc-conjugated siRNA. Both target ApoC3 mRNA in hepatocytes, using GalNAc conjugation to enhance delivery via the asialoglycoprotein receptor. This liver-targeting strategy ensures efficient uptake, reduced systemic exposure, and prolonged action compared to earlier agents like volanesorsen (Waylivra; Ionis Pharmaceuticals), a non-GalNAc-conjugated ASO that required frequent injections and carried a thrombocytopenia risk.
Olezarsen and plozasiran have shown consistent efficacy across a range of TG disorders. Clinical trials have reported ApoC3 reductions of about 70%, with corresponding TG reductions from 40% to 80%. Gaudet highlighted data from the BALANCE trial (NCT02795676), which assessed olezarsen in FCS patients; the SHASTA-2 trial (NCT04720534), which assessed plozasiran in sHTG; and the MUIR trial (NCT04998201), which assessed plozasiran in mixed dyslipidemia. In the BALANCE trial,olezarsen achieved a 92% reduction in ApoC3 levels and a 74% reduction in TG in FCS patients.Plozasiran showed similar results, with TG reductions of up to 81% in the SHASTA-2 trial and 74% in the MUIR study.
These agents are also progressing in terms of regulatory approval. On Dec. 19, 2024, the FDA approved olezarsen for treating adults with FCS. on Jan. 17, 2025, the FDA accepted the new drug application for plozasiran to treat persistent chylomicronemia, with approval expected later in 2025. Phase 3 trials are ongoing for both agents, exploring expanded indications across hypertriglyceridemic disorders.
Gaudet also discussed the adverse effects of ApoC3 inhibitors. While thrombocytopenia was a concern with earlier agents like volanesorsen, it has not been observed with GalNAc-conjugated therapies. Though, an increase in low-density lipoprotein cholesterol (LDL-C) levels has been reported, likely due to the accelerated hydrolysis of TG-rich lipoproteins, leading to the formation of LDL particles. Gaudet explained that these LDL particles are typically larger,depleted of ApoC3,and potentially less atherogenic. Mild hyperglycemia has also been observed in some trials, notably in patients with Type 2 diabetes, though the mechanisms are still under investigation.
The evidence supporting ApoC3 inhibition marks a significant advancement in treating hypertriglyceridemia and related cardiovascular risks, offering hope to patients with rare and severe lipid disorders. As olezarsen enters clinical practice and plozasiran nears potential approval, these therapies are poised to transform lipid management.
“The most advanced ApoC3 inhibitors are plozasiran and olezarsen… and their efficacy and tolerability profiles are very, very similar,” Gaudet said. “I would like to dedicate this presentation to all patients affected with severe disorders,and to the health care providers and those pioneers who have made [these therapies] possible.”
What’s next
Ongoing Phase 3 trials will further define the role of ApoC3 inhibitors in managing a spectrum of hypertriglyceridemic conditions,potentially expanding treatment options for a broader patient population.