Olezarsen Significantly Reduces Triglycerides and Pancreatitis Risk in Severe Hypertriglyceridemia

At the American Heart Association Scientific Sessions 2025 in New Orleans, Nicholas Marston, MD, MPH, discussed new data evaluating olezarsen as a treatment for severe hypertriglyceridemia. He noted that existing therapies—such as fibrates, omega-3 fatty acids, and statins—typically reduce triglycerides by only 20% to 30%, leaving many patients above the 500 mg/dL threshold where the risk of acute pancreatitis becomes significant. In two recently published trials, olezarsen achieved triglyceride reductions of 60% to 65% and enabled 86% of patients to move out of the severe range despite already being on background therapy. Marston highlighted that this translated to an 85% reduction in acute pancreatitis, representing a substantial clinical benefit rarely seen with lipid-lowering therapies. He emphasized that olezarsen may offer an important new option for both primary and secondary prevention of pancreatitis in patients whose triglyceride levels remain dangerously elevated despite diet, lifestyle changes, and currently available treatments.

Pharmacy Times: Pharmacists are often on the front lines of managing patients with severe hypertriglyceridemia. How do you see their role evolving with an agent like olezarsen—particularly in counseling patients on adherence, injection technique, and monitoring for potential lab abnormalities?

Nicholas Marston, MD, MPH: I mean, so right now, when we have patients with severe hypertriglyceridemia, which is triglycerides of 500 milligrams per deciliter or higher, we have some therapeutic options. We have fibrates that we'll use, we have fish oils—omega-3 fatty acid fish oils like icosapent ethyl—and statins can lower triglycerides as well. So we do currently have some therapies available, but they're overall pretty modest in their effect.

As a result, a lot of people don't get out of that severe hypertriglyceridemia range. The reason that's important is because when they are in the severe hypertriglyceridemia range, there's this risk of acute pancreatitis. That's what we want to avoid because that can be life-threatening and lead to hospitalization and ICU admissions.

So olezarsen is a new triglyceride-lowering therapy. We just published these two trials for it, and it reduces triglycerides significantly—more effective than the other therapies that I mentioned—and it significantly reduces acute pancreatitis.

So this is going to be, I think, a very nice option to give to patients who can't get out of that severe range with diet, lifestyle, or the currently available therapies. It is an injectable, as you note and I think more and more of our therapies are becoming injectables. People are becoming more comfortable with them. In the cardiology and prevention space, we have PCSK9 inhibitors that are injectables and we have the GLP-1s, which are injectables. Obviously, a lot of the other diabetes therapies are injectables, or insulin is, so I think we're becoming more comfortable with them as providers and as patients, and this falls in that category.

The plus side is it's just dosed every four weeks, so you only have to do it every four weeks. The patients tolerate it quite well. It's occasional—just a little redness in the area—but it's mild and self-limited. Most patients don't experience that at all.

So from a pharmacy perspective, this is an exciting addition, and it's something we're going to be seeing more and more of as this medicine and others like it are approved.

Pharmacy Times: Olezarsen achieved substantial triglyceride reductions and a notable decrease in acute pancreatitis events. From a clinician’s perspective, how meaningful are these results in changing how we approach triglyceride management in high-risk patients?

Marston: I think it's a big step forward because the other therapies that I had mentioned—the fibrates, the omega-3 fatty acids—are lowering triglycerides on the order of 20 or 30%. For some, that might be enough, but for others who are very high in their TG levels, maybe over 880 or a thousand, they need more than that. So a 60%, 65% reduction, like we're seeing with olezarsen, gets a lot more patients down below 500 and out of the severe range.

In fact, in these two trials, 86% of patients got out of the severe range with olezarsen. That's much better than occurred in the placebo arm, and that placebo arm was on good background therapy. So I think a lot more patients get out of the severe range, and as a result, a lot fewer patients had acute pancreatitis. It was an 85% reduction in acute pancreatitis. That's a major, major treatment effect.

There are very few therapies that we have that reduce such an important outcome by such a large amount. So, you know, I think it's going to have a big impact for patients in preventing pancreatitis, especially in those who have already had pancreatitis and we want to prevent it from happening again—so kind of secondary prevention.