New late-breaking science presented at AHA 2025 in New Orleans highlights new treatments for patients with severe hypertriglyceridemia (500-2,000 mg/dL), who may be at high risk of cardiovascular disease or pancreatitis.

In one trial, a first-of-its-kind medication called DR10624, which works by activating FGF21, glucagon and GLP-1 receptors, reduced both triglyceride levels and liver fat in most patients by more than 60%, respectively.

The double-blind study randomly assigned 79 adults with very high triglyceride levels (between 500 and 2,000 mg/dL) to receive either a weekly, subcutaneous injection of DR10624 at one of three doses (12.5 mg, 25 mg or 50 mg titration) or a placebo for 12 weeks.

Early results after 12 weeks found that patients receiving the 12.5 mg dose of DR10624 experienced the greatest reduction in triglycerides at 74.5%, followed by a 66.2% reduction among those receiving the 25mg dose, and a 68.9% reduction among those receiving the 50 mg titration dose. Individuals in the placebo group saw an 8% reduction in triglycerides.

Overall, nearly 90% of patients receiving DR10624 achieved triglyceride levels below 500 mg/dL, compared to 25% of patients receiving a placebo, researchers said. They also noted a 63.5% reduction in liver fat among those in the DR10624 group compared with an 8.4% reduction in the placebo group. Significant improvements in other important lipid measures, including total cholesterol, HDL cholesterol, non-HDL cholesterol and triglyceride-rich lipoprotein cholesterol were also observed.

"DR10624 could become a game-changer for patients with severe hypertriglyceridemia by reducing long-term risks of pancreatitis, as well as conditions like MASLD and cardiovascular disease," said lead study author Jianping Li, MD, PhD. "Severe hypertriglyceridemia is often difficult to manage with existing treatments, so access to more treatment choices are crucial for improving patient outcomes as well as quality of life."

The trial had some limitations, including its size, short duration and that it was only conducted in Mainland China. "Additional clinical studies are needed, which should include more participants from diverse parts of the world and last for a longer period in order to confirm the findings in this Phase 2 trial," said Li.

In another presentation, researchers shared results from the CORE-TIMI 72a and CORE-TIMI 72b trials, which were simultaneously published in NEJM. They found that olezarsen significantly reduced triglyceride levels at six months, as well as decreased the incidence of acute pancreatitis.

The two double-blind trials randomly assigned a total of 1,061 patients with severe hypertriglyceridemia in a 1:1:1 ratio to receive either olezarsen (50 mg), olezarsen (80 mg) or placebo for 12 months. The primary outcome was the percent change from baseline in the triglyceride level at six months. Acute pancreatitis events were also assessed across both trials.

Results showed the placebo-adjusted least-squares mean change from baseline in the triglyceride level was −62.9 percentage points in the olezarsen 50-mg group and −72.2 percentage points in the olezarsen 80-mg group in the CORE-TIMI 72a trial and was −49.2 percentage points in the olezarsen 50-mg group and −54.5 percentage points in the olezarsen 80-mg group in the CORE2-TIMI 72b trial (p<0.001 for all comparisons of olezarsen with placebo).

In presenting the findings, Nicholas A. Marston, MD, said greater decreases in the levels of triglycerides, apolipoprotein C-III, remnant cholesterol, and non-HDL cholesterol were also observed among those assigned to olezarsen compared with placebo. Similarly, the incidence of acute pancreatitis was lower with olezarsen than with placebo.

"The primary purpose of triglyceride lowering in patients with severe hypertriglyceridemia is to reduce the risk of acute pancreatitis, which can be life-threatening," Marston and colleagues write. "Current therapies have more modest triglyceride-lowering effects in patients with severe hypertriglyceridemia and have not been shown to reduce the incidence of pancreatitis in this population. Our trials showed that olezarsen reduced the incidence of acute pancreatitis by 85% among patients with severe hypertriglyceridemia."

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia

Keywords: AHA Annual Scientific Sessions, AHA25, Dyslipidemias, Metabolic Syndrome