Abstract 16993: An Antisense Inhibitor of Apolipoprotein C-III Significantly Decreases Nonesterified Fatty Acid Levels in Severe Hypertriglyceridemic Patients
Background: Apolipoprotein C-III (apoC-III), a CV risk factor, plays a pivotal role in regulating plasma triglyceride (TG) levels. Elevated TG and its nonesterified fatty acid (NEFA) derivatives are associated with insulin resistance and type 2 diabetes. ISIS-APOCIIIRx selectively inhibits apoC-III protein synthesis in the liver and studies show it may improve insulin sensitivity in patients with type 2 diabetes. Treatment with ISIS-APOCIIIRx results in significant dose-dependent decreases in apoC-III and TG levels (Table) in patients with severe hypertriglyceridemia (SHTG) as monotherapy or add on to a stable dose of fibrate. The present study assessed the potential resulting change in NEFA levels in these patients.
Methods: Adult patients with SHTG treated or untreated with fibrate were enrolled in a double-blind Phase 2 study to receive ISIS-APOCIIIRx (up to 300 mg) or placebo as weekly SC injections for 13 weeks. Baseline and end-of-treatment fasting serum samples were analyzed for NEFA levels.
Results: Results show significant reductions in NEFA levels in line with reductions in TG levels at the 300 mg/week dose (the Phase 3 dose) of ISIS-APOCIIIRx (Table). ISIS-APOCIIIRx was generally safe and well tolerated. There were no clinically meaningful changes in liver tests or other laboratory values.
Conclusions: Treatment with ISIS-APOCIIIRx reduces NEFA levels together with decreases in TG in patients with treated or untreated SHTG suggesting the potential for improvement in peripheral insulin sensitivity in these patients.
Author Disclosures: V. Alexander: Employment; Significant; Isis Pharmaceuticals. D. Brisson: None. J. Flaim: Employment; Significant; Isis Pharmaceuticals. S. Hughes: Employment; Significant; Isis Pharmaceuticals. W. Singleton: Employment; Significant; Isis Pharmaceuticals. R. Geary: Employment; Significant; Isis Pharmaceuticals. D. Gaudet: Consultant/Advisory Board; Modest; Isis Pharmaceuticals.
- © 2014 by American Heart Association, Inc.