OBJECTIVE: To determine the effects of volanesorsen (ISIS 304801), a 
second-generation 2'-O-methoxyethyl chimeric antisense inhibitor of 
apolipoprotein (apo)C-III, on triglyceride (TG) levels and insulin resistance in 
patients with type 2 diabetes.
RESEARCH DESIGN AND METHODS: A randomized, double-blind, placebo-controlled 
trial was performed in 15 adult patients with type 2 diabetes (HbA1c >7.5% [58 
mmol/mol]) and hypertriglyceridemia (TG >200 and <500 mg/dL). Patients were 
randomized 2:1 to receive volanesorsen 300 mg or placebo for a total of 15 
subcutaneous weekly doses. Glucose handling and insulin sensitivity were 
measured before and after treatment using a two-step hyperinsulinemic-euglycemic 
clamp procedure.
RESULTS: Treatment with volanesorsen significantly reduced plasma apoC-III 
(-88%, P = 0.02) and TG (-69%, P = 0.02) levels and raised HDL cholesterol 
(HDL-C) (42%, P = 0.03) compared with placebo. These changes were accompanied by 
a 57% improvement in whole-body insulin sensitivity (P < 0.001). Importantly, we 
found a strong relationship between enhanced insulin sensitivity and both plasma 
apoC-III (r = -0.61, P = 0.03) and TG (r = -0.68, P = 0.01) suppression. 
Improved insulin sensitivity was sufficient to significantly lower glycated 
albumin (-1.7%, P = 0.034) and fructosamine (-38.7 μmol/L, P = 0.045) at the end 
of dosing and HbA1c (-0.44% [-4.9 mmol/mol], P = 0.025) 3 months postdosing.
CONCLUSIONS: Volanesorsen reduced plasma apoC-III and TG while raising HDL-C 
levels. Importantly, glucose disposal, insulin sensitivity, and integrative 
markers of diabetes also improved in these patients after short-term treatment.