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Antisense-Mediated Lowering of Plasma Apolipoprotein C-III by Volanesorsen Improves Dyslipidemia and Insulin Sensitivity in Type 2 Diabetes.
- Source :
- Diabetes Care; Aug2016, Vol. 39 Issue 8, p1408-1415, 8p, 1 Chart, 3 Graphs
- Publication Year :
- 2016
-
Abstract
- <bold>Objective: </bold>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.<bold>Research Design and Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>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. [ABSTRACT FROM AUTHOR]
- Subjects :
- APOLIPOPROTEINS
BLOOD lipoproteins
BLOOD plasma
DYSLIPIDEMIA
TYPE 2 diabetes
DRUG therapy for hyperlipidemia
ANTILIPEMIC agents
BLOOD sugar
COMPARATIVE studies
DOSE-effect relationship in pharmacology
GLYCOSYLATED hemoglobin
HIGH density lipoproteins
HYPERLIPIDEMIA
INSULIN resistance
LOW density lipoproteins
RESEARCH methodology
MEDICAL cooperation
NUCLEOTIDES
RESEARCH
STATISTICAL sampling
TRIGLYCERIDES
EVALUATION research
RANDOMIZED controlled trials
BLIND experiment
PHARMACODYNAMICS
Subjects
Details
- Language :
- English
- ISSN :
- 01495992
- Volume :
- 39
- Issue :
- 8
- Database :
- Complementary Index
- Journal :
- Diabetes Care
- Publication Type :
- Academic Journal
- Accession number :
- 116951666
- Full Text :
- https://doi.org/10.2337/dc16-0126