One shot lowered LDL cholesterol and triglycerides

Clinical takeaway: Continue established lipid-lowering treatment for patients with mixed hyperlipidemia while awaiting larger trials of ARO-DIMER-PA. The investigational therapy produced substantial, dose-dependent lipid reductions after one dose, but long-term safety and cardiovascular benefit remain unproven.

Lipid-directed RNA interference (RNAi) therapies typically silence a single gene. In this first-in-human trial, ARO-DIMER-PA used a single RNAi molecule to silence two genes, potentially simplifying treatment for patients who need both LDL cholesterol and triglyceride lowering.

The investigational therapy targets two genes in the liver: PCSK9 to lower LDL cholesterol and APOC3 to lower triglycerides. Interim findings presented at the American Heart Association’s Scientific Sessions 2026 showed dose-dependent reductions in both, but the data have not yet been peer reviewed.

The single-ascending-dose part of a randomized, double-blind, placebo-controlled phase 1/2a study enrolled 31 adults with mixed hyperlipidemia: 21 received one of five single doses ranging from 25 to 400 mg, and 10 received placebo. Safety and tolerability were the primary focus, with secondary outcomes assessing changes in lipid levels and the targeted proteins.

After a single dose, LDL cholesterol fell by an average of 26% to 65% across dose groups, while median triglyceride reductions ranged from 56% to 78%. ApoB and remnant cholesterol also declined, suggesting an effect across several atherogenic lipoprotein measures.

These interim results reflect changes from baseline across different dose groups and assessment times, rather than placebo-adjusted treatment effects.

Most participants had mild or moderate adverse events. Injection-site redness was the most common adverse effect, occurring in 20 of 21 treated participants and none on placebo.

No serious adverse events or deaths were reported. The highest dose, 400 mg, produced more side effects, and one participant in that group had grade 3 syncope six hours after dosing, underscoring the need to establish an appropriate dose in further studies.

An ongoing part of the trial is evaluating repeated doses over time to help guide dose selection for a pivotal trial. Further evaluation will need to establish duration of effect, characterize long-term safety, and determine whether lowering both lipid pathways reduces cardiovascular events.

“These findings support continued evaluation of dual PCSK9/APOC3 inhibition as a potential single-agent strategy for mixed hyperlipidemia,” said study author Luke Laffin, MD, medical director of the Cleveland Clinic Coordinating Center for Clinical Research.

Sources: Cleveland Clinic. (2026 Nov 7). Cleveland Clinic First-in-Human Trial Shows Gene-Silencing Therapy for High Cholesterol to Be Safe and Effective; Arrowhead Pharmaceuticals, Inc. (2026 Nov 7). Arrowhead Pharmaceuticals Presents Plozasiran Data Highlighting Sustained Triglyceride Reductions and Reduced Acute Pancreatitis Rates