Study: Olezarsen Effective Treatment for High Triglycerides

Many people monitor their heart health by tracking blood pressure and cholesterol. But there’s another important number: triglycerides, which are usually tested along with cholesterol. High triglycerides, or hypertriglyceridemia, can increase risk of cardiovascular disease and cause serious damage to the pancreas. 

For people with hypertriglyceridemia, options are limited — mostly lifestyle modifications and medications to try to reduce the risk of heart attack. Although some medicines that lower cholesterol also have a small impact on triglycerides, there are no approved treatments that can substantially lower triglyceride levels. 

A Mass General Brigham research group recently found that an investigational drug called olezarsen reduced triglyceride levels up to 50%. The medication also lowered two other substances that are strong indicators of cardiovascular risk. 

“Olezarsen effectively reduced triglyceride levels to a degree that is not currently possible with approved medications on the market,” says Brian Bergmark, MD, a Mass General Brigham interventional cardiologist who cares for patients at Brigham and Women’s Hospital and is an investigator in the TIMI Study Group. “This is an active area of research with a lot of potential new agents coming down the line that could lead to many options for patients in the near future.”

Dr. Bergmark and colleagues published the results in the New England Journal of Medicine and presented their findings at the American Academy of Cardiology annual conference.

What causes hypertriglyceridemia?

When you eat or drink calories but don’t use them, your body converts those calories into triglycerides. They are a kind of fat (lipid) that your body stores and uses for energy between meals. If you often consume more calories than your body uses, you may have a high level of triglycerides in your bloodstream. This is called hypertriglyceridemia. 

Your doctor can measure triglycerides during a routine blood test called a lipid panel, which also measures your cholesterol. The test will tell you whether you have normal or high levels of triglycerides:

• Normal is less than 150 milligrams per deciliter (mg/dL) or less than 1.7 millimoles per liter (mmol/L) 
• Borderline high is 150 to 199 mg/dL or 1.8 to 2.2 mmol/L
• High is 200 to 499 mg/dL or 2.3 to 5.6 mmol/L
• Very high is greater than or equal to 500 mg/dL or 5.7 mmol/L

“When your triglycerides are elevated at all, that increases your risk of the things we often think about with high cholesterol — heart attack and stroke,” Dr. Bergmark says. “Once they are severely elevated, that of 500 mg/dL or higher, there is a risk for direct clinical consequences. For example, it can cause acute pancreatitis, inflammation of the pancreas, which is life-threatening. It also can lead to damage to the heart, brain, and blood vessels.”

Severe hypertriglyceridemia may be caused by several factors, including:

• Diet that has been too high in calories and fat
• Genetic disorder passed down in families (called familial hypertriglyceridemia or familial combined hyperlipidemia)
• Lack of exercise
• Medications (such as hormones, steroids, diuretics, and beta blockers)
• Other medical conditions (including diabetes, kidney disease, and autoimmune diseases such as HIV and lupus)
• Regular consumption of alcohol

How to lower triglycerides: Gaps in treatment 

If your blood test reveals a high number, you may wonder how to lower triglycerides. However, options are limited. Your doctor will recommend that you:

• Exercise more.
• Improve your diet, including limiting alcohol and fatty foods, similar to dietary changes to lower cholesterol.
• Lose weight.
• Reduce stress.
• Take all medications prescribed by your doctors, such as statins, to reduce risk of cardiovascular events.
• Test your triglycerides regularly to see if they are getting higher or lower.

“All of those things are helpful to manage risk, but they do not, in a meaningful way, target high triglycerides or lower triglycerides,” Dr. Bergmark says. “And for somebody who has severely high levels and is hospitalized, there’s not a lot out there that’s effective.”

He is the principal investigator on studies examining a new treatment that may bridge this treatment gap. 

Olezarsen as a promising new treatment for hypertriglyceridemia

Olezarsen is a new drug that targets a protein produced in the liver that’s involved in triglyceride metabolism and processing. The medication is self-injected under the skin monthly.

“There is a protein called apolipoprotein C3 (apoC-III), which slows down the body's ability to break down and get rid of triglycerides,” Dr. Bergmark explains. “Olezarsen inhibits apolipoprotein C3. It stops this protein that’s putting a brake on the system, and it allows the body to break down and clear these triglyceride-rich particles out of the body.”

Dr. Bergmark and colleagues found that 6 months of 50 mg or 80 mg olezarsen reduced levels of triglycerides by about 50% in people with hypertriglyceridemia and elevated cardiovascular risk. 

The hypertriglyceridemia medication also reduced by about 20% to 25% two other components of a lipid panel that are strong markers of cardiovascular risk. One is apolipoprotein B, which helps transport lipids (including cholesterol) around the body. The other is non-high-density lipoprotein (non-HDL) cholesterol. Non-HDL cholesterol indicates the amount of cholesterol that can build up in the arteries. Both of those are strong markers of a person’s risk for cardiovascular disease.

“Olezarsen effectively reduced triglyceride levels to a degree that is not currently possible with approved medications on the market,” Dr. Bergmark says. “The drug was not only effective, but it was also safe, with no major safety problems or side effects.”

Ongoing research to test olezarsen

Dr. Bergmark believes that continued research will lead to review and approval of olezarsen by the U.S. Food and Drug Administration (FDA).

“We have three ongoing trials here at Mass General Brigham. Two of them involve patients with severe hypertriglyceridemia, and those should finish next year. Those findings will likely lead to the approval of the drug for lowering triglycerides in that more severe patient population,” Dr. Bergmark says. 

“As for those with moderate hypertriglyceridemia,” he adds, “the question is going to be, not simply does it lower triglycerides, but can you actually show that it reduces the risk of a heart attack or stroke? In order to test that, we need a much larger trial of many thousands of patients over several years.”

As a step in that direction, the research group is conducting a larger trial that compares coronary CT scans before and after olezarsen treatment. “We’ll be looking to see if there are changes in cholesterol plaques in the heart arteries over the course of a year,” Dr. Bergmark says. “If the coronary arteries look healthier after a year of treatment, then that would be a compelling reason to move ahead with a very large trial to really show that this can reduce cardiovascular risk.”

Cardiovascular research at Mass General Brigham

This research was sponsored by olezarsen’s manufacturer, Ionis Pharmaceuticals, Inc., and conducted through the TIMI Study Group at Mass General Brigham. TIMI is an academic research organization dedicated to conducting innovative clinical trials that enhance the understanding of cardiovascular disease and improve the care of patients.