• Diabetes care · Aug 2016

    Randomized Controlled Trial

    Antisense-Mediated Lowering of Plasma Apolipoprotein C-III by Volanesorsen Improves Dyslipidemia and Insulin Sensitivity in Type 2 Diabetes.

    • Andres Digenio, Richard L Dunbar, Veronica J Alexander, Marcus Hompesch, Linda Morrow, Richard G Lee, Mark J Graham, Steven G Hughes, Rosie Yu, Walter Singleton, Brenda F Baker, Sanjay Bhanot, and Rosanne M Crooke.
    • Akcea Therapeutics, Cambridge, MA adigenio@akceatx.com.
    • Diabetes Care. 2016 Aug 1; 39 (8): 1408-15.

    ObjectiveTo 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 MethodsA 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.ResultsTreatment 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.ConclusionsVolanesorsen 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.© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

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