Injectable medications are emerging as a promising treatment option for lowering cholesterol and reducing cardiovascular risk.
“This started around 20 years ago with key genetic studies of individuals with a family history of high cholesterol,” explains chief of the Division of Cardiology at UCLA Health.
Researchers identified mutations and genes associated with low cholesterol levels and low incidence of cardiovascular disease. Thanks to those initial findings, strategies such as monoclonal antibodies to target the proprotein convertase subtilisin/kexin type 9 (PCSK9) molecule have been developed, notes Dr. Hsue.
“Today we have two FDA-approved agents that have been tested in large clinical trials showing safety and benefit in clinical outcomes,” she adds. There is another agent that is FDA-approved and trials to evaluate impact on clinical events are ongoing.
Two of the agents, alirocumab and evolocumab, are monoclonal antibodies that inhibit PCSK9, which binds to LDL receptors on the surface of liver cells. PCSK9 prevents the LDL receptor from being recycled back to the cell surface.
“The LDL receptors bind to LDL cholesterol and usher cholesterol out of the blood circulation,” explains Dr. Hsue. “Inhibiting PCSK9 means that there will be more LDL receptors on the hepatocyte cell surface, thus increasing their ability to clear LDL from the plasma.” Both agents are injected approximately once or twice a month.
The third agent, inclisiran, is a small interfering RNA (siRNA) that inhibits expression of PCSK9 by binding specifically to the mRNA precursor of PCSK9 and causing its degradation. It is injected only twice a year.
“Looking to the future, a patient might come for a flu shot, a COVID shot and a cholesterol-lowering shot at the same time,” says Dr. Hsue.
Who benefits?
While the injectable agents typically are used in combination with statins, they can be used independently as well.
“Some patients cannot be on a statin for some reason. They may get muscle soreness or rhabdomyolysis,” says Dr. Hsue. “Others with severe liver disease may not be able to take statins. Some people may be on other medications that interact with statins.
“Injectables are reasonable to consider for someone whose LDL level remains elevated despite statin therapy.”
She notes injectables are primarily used for individuals who could gain significant clinical benefit, particularly those at high risk for (or with known) cardiovascular disease. Pinpointing prime candidates for injectable therapies depends on patients’ clinical characteristics.
“Do they have known cardiovascular disease? What is their LDL while on a statin?” says Dr. Hsue. “People with very severe liver disease, hypersensitivity to the drugs or fear of injections would not be good candidates.”
Large clinical trials — with tens of thousands of participants — show these agents generally are safely tolerated. Side effects are minimal. The most common is localized soreness near the injection site.
Most importantly, while standard statin therapy typically lowers LDL to around 100 mg/dL, “Injectables can lower LDL cholesterol to 15 mg/dL, levels we have not been able to achieve with statins alone. It’s really incredible,” says Dr. Hsue.
“They also are associated with significant reduction in clinical events.”
Therapy adoption
Because the injectable agents are costly (about $6,000 per year out-of-pocket, which is a sizeable drop from $14,000 a year when they first became available), the uptake has been challenging, explains Dr. Hsue.
“Although we are seeing costs decreasing, it is an expensive medication; insurance regulates who can get it. Usually, it is reserved for individuals who have failed with other therapy or are at extremely high risk. Secondly, some individuals just don't like injectable medication, and that may decrease acceptance, too.”
However, with increasing use of injectables (such as with weight-loss drugs), people are becoming more accepting of injections, says Dr. Hsue. And benefits certainly outweigh the prick of a needle.
“With LDL cholesterol, we know that the lower the level you achieve, the more benefit you get, even at a very low level. Perhaps as a society we should think more about prevention of cardiovascular disease and use these agents to reach that objective,” says Dr. Hsue.
“Once a person has a cardiovascular event, there is great impact on their clinical disease and a lot of costs. And there’s no turning back the clock. We cannot make their risk equivalent to someone who’s never had an event. It would be far better to prevent cardiovascular disease up front.”
It’s an exciting time for the cardiometabolic field and drug development, Dr Hsue says.
“Looking back to 2005, we thought statins would be as good as it gets. Now we have effective injectable agents developed for obesity which may represent the statins of the future.
“Looking forward we could see in vivo gene editing to knock out PCSK9 molecules — a one-time infusion to target cholesterol for the rest of your life.”
UCLA continues to be a trailblazer in research and treatment for cardiovascular disease.
“(We have) a cardiovascular prevention clinic, a lipid clinic, a cardiology clinic for persons with HIV who are at high risk and a cardiometabolic clinic,” says Dr. Hsue. “We’re screening for individuals who would benefit from this therapy, continuing with important research and helping lead the way in this expanding field.”
