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

• DOI: 10.2337/dc16-0126
• Publication Date: 2016-06-07T03:33:51Z
• Authors: Andres Digenio; Richard L. Dunbar; Veronica J. Alexa...; Marcus Hompesch; Linda Morrow; Richard G. Lee; Mark J. Graham; Steven G. Hughes; Rosie Yu; Walter Singleton; Brenda F. Baker; Sanjay Bhanot; Rosanne M. Crooke
• Keywords: Blood Glucose; Male; 0301 basic medicine; 03 medical and health sciences; 0302 clinical medicine; Double-Blind Method; Humans; Triglycerides; Aged; Glycated Hemoglobin; Hypertriglyceridemia; Apolipoprotein C-III; Dose-Response Relationship, Drug; Anticholesteremic Agents; Cholesterol, HDL; Cholesterol, LDL; Middle Aged; Oligonucleotides, Antisense; 3. Good health; Diabetes Mellitus, Type 2; Female; Insulin Resistance; Biomarkers

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.