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A recent phase 2 randomized controlled trial reported that short-term treatment with ISIS 304801, a second-generation antisense inhibitor of apolipoprotein C-III (APOC3) synthesis, reduced triglyceride levels in patients with severe or uncontrolled hypertriglyceridemia. High triglyceride levels can cause insulin resistance, metabolic syndrome, diabetes, cardiovascular disease. Reducing APOC3, a key regulator of plasma triglyceride levels, may be cardioprotective and lower the risk of pancreatitis in patients with very high triglyceride levels, according to the investigators (Gaudet D et al. N Engl J Med. 2015;373:438-447).
An antisense inhibitor of APO3 synthesis reduced triglyceride levels in patients with hypertriglyceridemia.
The trial evaluated 2 cohorts of patients: 57 untreated patients with fasting triglyceride levels between 350 mg/dL and 2000 mg/dL (monotherapy cohort) and 28 patients receiving stable-dose fibrate therapy to lower their triglycerides and increase high-density lipoprotein (HDL) cholesterol levels (fibrate cohort). Participants received either ISIS 304801 at doses ranging from 100 to 300 mg or placebo, once weekly for 13 weeks.
When administered as monotherapy, ISIS 304801 produced dose-dependent mean reductions of 80% in APOC3 levels and of 71% in triglyceride levels. A similar reduction in APOC3 and triglyceride levels was seen in patients receiving ISIS 304801 as an add-on to fibrate therapy. Levels of “good” HDL cholesterol increased and elevated very low-density lipoprotein cholesterol levels normalized in patients who received the 300-mg dose of ISIS 304801 in both groups.
There were no safety issues related to treatment. Limitations of the study include a short treatment duration and small sample size composed mostly of white men.