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



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.



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.



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.
Akcea Therapeutics, Cambridge, MA adigenio@akceatx.com.
Andres
A
Digenio
University of Pennsylvania, Philadelphia, PA.
Richard L
RL
Dunbar
Ionis Pharmaceuticals, Inc., Carlsbad, CA.
Veronica J
VJ
Alexander
Profil Institute for Clinical Research, San Diego, CA.
Marcus
M
Hompesch
Profil Institute for Clinical Research, San Diego, CA.
Linda
L
Morrow
Ionis Pharmaceuticals, Inc., Carlsbad, CA.
Richard G
RG
Lee
Ionis Pharmaceuticals, Inc., Carlsbad, CA.
Mark J
MJ
Graham
Ionis Pharmaceuticals, Inc., Carlsbad, CA.
Steven G
SG
Hughes
Ionis Pharmaceuticals, Inc., Carlsbad, CA.
Rosie
R
Yu
Ionis Pharmaceuticals, Inc., Carlsbad, CA.
Walter
W
Singleton
Ionis Pharmaceuticals, Inc., Carlsbad, CA.
Brenda F
BF
Baker
Ionis Pharmaceuticals, Inc., Carlsbad, CA.
Sanjay
S
Bhanot
Ionis Pharmaceuticals, Inc., Carlsbad, CA.
Rosanne M
RM
Crooke
D000368:Aged; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D053305:Apolipoprotein C-III / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D015228:Hypertriglyceridemia / Q000097:blood / Q000188:drug therapy*; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood
D000924:Anticholesteremic Agents; D053305:Apolipoprotein C-III; D015415:Biomarkers; D001786:Blood Glucose; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D006442:Glycated Hemoglobin; D016376:Oligonucleotides, Antisense; D014280:Triglycerides