Zodasiran Effectively Lowers Triglycerides and Improves Lipid Profile in Patients with Mixed Hyperlipidemia on Statin Therapy

Core Concepts

Zodasiran, a hepatocyte-targeted small interfering RNA, significantly reduces triglycerides, LDL cholesterol, and other lipid markers in patients with mixed hyperlipidemia on stable statin therapy, with a favorable safety profile.

Abstract

The ARCHES-2 study investigated the efficacy and safety of the drug zodasiran (formerly ARO-ANG3) in patients with mixed hyperlipidemia who were on optimal statin therapy. Zodasiran is a hepatocyte-targeted small interfering RNA (siRNA) designed to silence the expression of the ANGPTL3 gene, which regulates lipid metabolism.
The study found that all three doses of zodasiran (50 mg, 100 mg, and 200 mg) were associated with substantial and durable reductions in ANGPTL3 levels, triglycerides, remnant cholesterol, non-HDL cholesterol, LDL cholesterol, and apolipoprotein B levels compared to placebo. These reductions were largely maintained at 36 weeks. Zodasiran also led to a decrease in liver fat content in patients with hepatic steatosis.
The safety profile of zodasiran was favorable, with no significant changes in platelet concentrations or HbA1c levels. Apart from one death in the placebo group, serious adverse events were rare and manageable.
The study results support the further development of zodasiran, including in a cardiovascular outcomes trial, to treat residual atherosclerotic cardiovascular disease risk in patients with elevated triglycerides. The progress with zodasiran and other siRNA-based therapies also highlights the importance of studying diverse populations to identify exceptional genetic variants that may influence disease risk and treatment response.

Stats

Zodasiran 50 mg dose led to a 51% reduction in triglycerides compared to placebo at 24 weeks.
Zodasiran 100 mg dose led to a 57% reduction in triglycerides compared to placebo at 24 weeks.
Zodasiran 200 mg dose led to a 63% reduction in triglycerides compared to placebo at 24 weeks.
In patients with hepatic steatosis, zodasiran 50 mg, 100 mg, and 200 mg doses led to a 10%, 16%, and 27% decrease in liver fat content, respectively, compared to placebo at 24 weeks.

Quotes

"The reductions in serum lipids and lipoproteins and the favorable safety profile seen in ARCHES-2 support the potential for zodasiran to treat residual atherosclerotic cardiovascular disease in patients with elevated triglycerides."
"The combination of reductions in triglycerides, low-density lipoprotein (LDL) cholesterol, remnant cholesterol, and apolipoprotein B, among others, should be, based on our current knowledge, decrease the cardiovascular risk of patients with mixed dyslipidemia quite significantly."

Key Insights Distilled From

Gene Silencing Benefit of Zodasiran in Hyperlipidemia

by Liam Davenpo... at www.medscape.com 06-28-2024

https://www.medscape.com/viewarticle/gene-silencing-benefit-zodasiran-hyperlipidemia-2024a1000c4n

Deeper Inquiries

How might the efficacy and safety of zodasiran compare to other emerging lipid-lowering therapies, such as those targeting PCSK9 or other novel mechanisms?

Zodasiran's efficacy in lowering triglyceride and lipoprotein levels in patients with mixed hyperlipidemia, especially when combined with optimal statin therapy, shows promising results. Compared to other emerging lipid-lowering therapies like PCSK9 inhibitors, zodasiran's mechanism of action targeting the ANGPTL3 gene offers a unique approach. While PCSK9 inhibitors work by increasing the liver's ability to clear LDL cholesterol from the bloodstream, zodasiran's gene silencing effect on ANGPTL3 leads to reductions in triglycerides and various lipoproteins. The safety profile of zodasiran, as indicated by the ARCHES-2 study, appears favorable with manageable adverse events, making it a potentially attractive option for patients with hyperlipidemia.

What potential limitations or concerns might arise regarding the long-term use of gene silencing therapies like zodasiran, and how could these be addressed in future research?

One potential limitation of long-term use of gene silencing therapies like zodasiran could be the unknown effects on off-target gene silencing or unintended consequences on gene expression. Continuous monitoring and follow-up studies are essential to assess any unforeseen impacts on gene regulation or potential adverse effects over extended treatment periods. Additionally, the durability of zodasiran's effects and the need for ongoing dosing regimens should be evaluated to ensure sustained efficacy without compromising safety. Future research should focus on elucidating the long-term safety profile of zodasiran, including its impact on liver function, metabolic parameters, and cardiovascular outcomes to address any concerns regarding its extended use.

Given the importance of studying diverse populations highlighted in the editorial, what strategies could be employed to ensure equitable representation and access to these novel therapies across different racial and ethnic groups?

To ensure equitable representation and access to novel therapies like zodasiran across diverse racial and ethnic groups, several strategies can be implemented. Firstly, clinical trials should actively recruit participants from various racial and ethnic backgrounds to reflect the real-world patient population. Collaborating with community organizations, healthcare providers, and advocacy groups can help reach underrepresented groups and increase awareness about participation in clinical research. Moreover, culturally sensitive approaches, language support, and tailored outreach efforts can enhance inclusivity and engagement among diverse populations. Transparency in trial recruitment, data collection, and reporting of outcomes stratified by race and ethnicity is crucial to address disparities and ensure that the benefits of novel therapies are accessible to all individuals, regardless of their background.