Interference RNA safely and effectively reduces blood cholesterol and triglyceride levels
Last reviewed: 14.06.2024
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Small interfering RNA (siRNA), an experimental therapy that inhibits a gene involved in lipoprotein metabolism, showed in a clinical trial conducted by Mount Sinai researchers to significantly reduce levels of various types of cholesterol and triglycerides in people with mixed hyperlipidemia, a condition associated with where fats accumulate 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)-based therapy called zodasiran may be a promising option for significantly reducing levels of a number of atherogenic lipoproteins, requiring This requires less frequent dosing compared to traditional treatments. The results were presented as a late clinical study 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 “bad” cholesterol) in the blood, including LDL) and triglycerides. Various studies have identified these components as increasing the risk of atherosclerotic cardiovascular disease.
"Our study represents one of the first trials of an RNA inhibitor for ANGPTL3 with the benefits of long-term gene silencing and infrequent dosing," said lead study author Robert Rosenson, MD, professor of medicine (cardiology) at the Mount Icahn School of Medicine. Sinai and Director of Lipids and Metabolism at Mount Sinai Health System."For patients with mixed hyperlipidemia and persistently elevated levels of LDL cholesterol and non-HDL cholesterol, zodasiran may expand the ability to lower 'bad' cholesterol beyond traditional treatments such as statins, potentially leading to more favorable patient outcomes."
Mixed hyperlipidemia is characterized by the accumulation of fats in the blood and is often a hereditary disease. 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) involving 204 patients with mixed hyperlipidemia treated with zodasiran (50, 100 and 200 mg) and standard therapy including a statin, investigators observed significant reductions in all lipid parameters.
This included reductions in triglycerides by 54-74% compared to placebo, LDL-cholesterol by up to 20%, non-HDL cholesterol by 36%, and remnant cholesterol by 73-82%. Residual 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 the 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 an association between elevated levels of residual cholesterol and an increased risk of cardiovascular disease.
The Mount Sinai researchers suggested that, based on previous genetic studies, the magnitude of the reduction in residual cholesterol seen by zodasiran in their study could lead to 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, in high concentrations, is associated with an increased risk of cardiovascular disease.
"Unlike fibrates and fish oils, zodasiran reduces 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 research is needed to determine the potential of zodasiran, an investigational drug that may reduce the risk of cardiovascular events in a wide range of patients through a single therapy targeting all fractions of lipoproteins."