ANGPTL3 Inhibition: A Potential Breakthrough in Protecting Against Coronary Artery Disease

Inhibition of ANGPTL3 and Its Impact on Lipid Levels

Overview of ANGPTL3

Recent research indicates that inhibiting angiopoietin-like 3 (ANGPTL3), a liver protein involved in lipoprotein metabolism, may significantly reduce plasma levels of triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. This inhibition could also lower the risk of atherosclerotic coronary artery disease.

Coronary Artery Disease and Lipid Levels

Patients with coronary artery disease remain at high risk for heart attacks and strokes, even when treated with LDL cholesterol-lowering medications like statins or ezetimibe. Many of these patients exhibit elevated levels of triglyceride-rich lipoproteins, which are regulated by lipoprotein lipase (LPL). This enzyme breaks down triglycerides into fatty acids and glycerol, enabling their delivery to muscles and adipose tissues. ANGPTL3 inhibits LPL, contributing to elevated levels of triglyceride-rich lipoproteins.

Genetic Insights into ANGPTL3

Individuals with mutations in both copies of the ANGPTL3 gene that lead to a dysfunctional protein experience significantly lower levels of triglyceride-rich lipoproteins, LDL cholesterol, and HDL cholesterol, a condition known as familial combined hypolipidemia. Additionally, ANGPTL3 plasma levels correlate with arterial wall thickness, which is associated with high blood pressure and lipid levels. Consequently, inhibiting ANGPTL3 presents a viable strategy for lowering blood lipid levels and potentially mitigating the risk of atherosclerotic coronary artery disease.

Recent Research Findings

Two research teams recently published studies in The New England Journal of Medicine that support the role of ANGPTL3 inhibition in lowering lipid levels.

In the first study, researchers sequenced the exons of the ANGPTL3 gene from 58,335 participants. They identified that individuals with mutations leading to dysfunctional ANGPTL3 had significantly lower serum levels of triglycerides, HDL cholesterol, and LDL cholesterol. They tested evinacumab, an antibody that inhibits ANGPTL3, in mice and healthy humans with high triglycerides or LDL cholesterol. Results showed that evinacumab reduced atherosclerotic plaque in mice and led to a dose-dependent decrease in fasting triglycerides and LDL cholesterol by up to 76% and 23%, respectively, in humans.

The second study utilized antisense oligonucleotides in mice to block ANGPTL3 protein production. This approach demonstrated lower triglyceride and LDL cholesterol levels, improved insulin sensitivity, and slowed atherosclerosis progression. In humans, the injection of antisense ANGPTL3 RNA resulted in significant reductions in triglycerides, LDL cholesterol, very low-density lipoprotein (VLDL) cholesterol, non-HDL cholesterol, apolipoprotein B, and apolipoprotein C-III.

Combination Therapy and Future Directions

A third study reported that when combined with existing cholesterol-lowering medications, a single dose of the anti-ANGPTL3 antibody could further reduce LDL cholesterol levels by an additional 49% in individuals with homozygous familial hypercholesterolemia caused by mutations in the LDLR gene.

Thus, targeting ANGPTL3 to enhance lipoprotein lipase activity represents a promising strategy for lowering plasma lipid levels and addressing hypertriglyceridemia and atherosclerotic coronary artery disease, potentially paving the way for clinical applications in the future.

References

1. Hatsuda S, et al. Association between plasma angiopoietin-like protein 3 and arterial wall thickness in healthy subjects. J Vasc Res. 2007;44(1):61-6.
2. Tall AR. Increasing Lipolysis and Reducing Atherosclerosis. N Engl J Med. 2017;377(3):280-283.
3. Dewey FE, et al. Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease. N Engl J Med. 2017;377(3):211-221.
4. Graham MJ, et al. Cardiovascular and Metabolic Effects of ANGPTL3 Antisense Oligonucleotides. N Engl J Med. 2017;377(3):222-232.
5. Gaudet D, et al. ANGPTL3 Inhibition in Homozygous Familial Hypercholesterolemia. N Engl J Med. 2017;377(3):296-297.