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Interference RNA safely and effectively lowers blood cholesterol and triglyceride levels
Last reviewed: 02.07.2025
Small interfering RNA (siRNA), an experimental therapy that inhibits a gene involved in lipoprotein metabolism, has been shown in a clinical trial led by Mount Sinai researchers to significantly reduce levels of various types of cholesterol and triglycerides in people with mixed hyperlipidemia, a condition in which fats build up in the blood.
In addition to encouraging preliminary safety and efficacy results in clinical trials, Mount Sinai researchers have found that an RNA interference (RNAi) therapy called zodasiran may be a promising option for significantly lowering levels of a number of atherogenic lipoproteins while requiring less frequent dosing than traditional treatments. The results were presented as a late-stage clinical trial at the European Congress on Atherosclerosis in Lyon, France, and simultaneously published in The New England Journal of Medicine.
Zodasiran (Arrowhead Pharmaceuticals) targets a specific gene expressed in hepatocytes known as angiopoietin-like protein 3 (ANGPTL3), which plays a role in regulating levels of low-density lipoprotein (LDL), non-HDL cholesterol (a measure of all the "bad" cholesterol in the blood, including LDL), and triglycerides. Various studies have identified these compounds as increasing the risk of atherosclerotic cardiovascular disease.
"Our study represents one of the first trials of an ANGPTL3 RNA inhibitor with the advantages of long-term gene silencing and infrequent dosing," said lead study author Robert Rosenson, MD, professor of medicine (cardiology) at the Icahn School of Medicine at Mount Sinai and director of lipids and metabolism at the Mount Sinai Health System.
"For patients with mixed hyperlipidemia and persistently elevated LDL and non-HDL cholesterol, zodasiran may expand the options for lowering 'bad' cholesterol beyond traditional treatments such as statins, potentially leading to more favorable outcomes for patients."
Mixed hyperlipidemia is characterized by a buildup of fats in the blood and is often inherited. People with this condition may be overweight and more likely to have prediabetes or diabetes.
In a global phase 2b trial (known as ARCHES-2) of 204 patients with mixed hyperlipidemia who received zodasiran (50, 100, and 200 mg) and standard therapy including statins, researchers observed significant reductions in all lipid parameters.
This included a reduction in triglycerides by 54-74% compared with placebo, LDL cholesterol by 20%, non-HDL cholesterol by 36%, and remnant cholesterol by 73-82%. Remnant cholesterol measures the amount of "leftover" or residual very-low-density lipoprotein (VLDL) particles. It is measured by adding HDL and LDL and subtracting that sum from an individual's total cholesterol.
Reducing remnant cholesterol is especially important because these remnants can contain up to four times more cholesterol per particle than LDL. In addition, previous studies have shown a link between elevated remnant cholesterol levels and an increased risk of cardiovascular disease.
The Mount Sinai researchers hypothesized that, based on previous genetic studies, the magnitude of the reduction in remnant cholesterol seen with zodasiran in their study could translate into a 20% reduction in recurrent major cardiac events.
The ARCHES-2 study also found that zodasiran was effective in reducing apolipoprotein B, a lipid transport protein in the body that at high levels is associated with an increased risk of cardiovascular disease.
"Unlike fibrates and fish oil, zodasiran lowers apolipoprotein B and thus may be a more promising potential therapy for reducing the risk of cardiovascular events," notes Dr. Rosenson.
The results of this study in patients with mixed hyperlipidemia build on previous efforts to modulate ANGPTL3 using evinacumab, a fully human monoclonal antibody against the ANGPTL3 protein approved by the US Food and Drug Administration (FDA) for the treatment of patients with homozygous familial hypercholesterolemia (HoFH).
"We believe," Dr. Rosenson emphasizes, "that based on these promising results, further studies are needed to determine the potential of zodasiran, an investigational drug, to reduce the risk of cardiovascular events in a broad range of patients through a single therapy that targets all lipoprotein fractions."