Inhibition of apoliprotein lowers triglyceride levels


1. ISIS 304801 is an antisense oligonucleotide that targets APOC3 mRNA to decrease plasma levels of APOC3.

2. Patients who received ISIS 304801 had decreased levels of APOC3 as well as reduced levels of triglycerides as compared to those who received placebo.

Evidence Rating Level: 1 (Excellent)      

Study Rundown: Apolipoprotein C-IIIs (APOC3) are proteins produced from the liver to bind lipids and form lipoproteins. High levels of APOC3 have been found to be associated with increased risk for cardiovascular disease. It was previously found that patients with a loss of function mutation in the APOC3 gene had low levels of the protein and reduced risk of coronary heart disease.

This phase 2 randomized controlled trial evaluated the effect of the antisense oligonucleotide, ISIS 304801, on APOC3 levels in patients with hypertriglyceridemia. After 13 weeks of treatment, the authors found that patients treated with ISIS 304801 had decreased levels of plasma APOC3  as well as decreased levels of triglycerides in a dose dependent manner. ISIS 304801 was also effective when used in conjunction with fibrate therapy. Although promising, the study was greatly limited by the small sample size of 57 patients. Larger studies with longer follow up are needed to further evaluate the efficacy of ISIS 304801 and its impact on the development of cardiovascular disease.

Click to read the study, published today in NEJM 


Relevant Reading: Apolipoprotein C-III as a Potential Modulator of the Association Between HDL-Cholesterol and Incident Coronary Heart Disease

In-Depth [randomized controlled trial]: This study randomized 57 patients to treatment with different doses of ISIS 304801(100, 200, 300 mgs) or treatment with ISIS 304801 and fibrate or placebo. The primary endpoint was the change in APOC3 levels at the end of treatment.

As compared to placebo, the patients who received ISIS 304801 alone had significant dose dependent decreases in APOC3 levels (decrease of 40.0±32.0% in the 100 mg group, 63.8±22.3% in the 200 mg group, and 79.6±9.3% in the 300 mg group versus an increase of 4.2±41.7% in the placebo group). At 300mg of ISIS 304801, patients experienced a decrease of 70.9% in triglyceride levels from baseline as compared to an increase of 20.1% in the placebo group (p<0.001). Six patients discontinued treatment with ISIS due to adverse effects. No relationship was found between discontinuation and dosage of the study drug.

Image: PD

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