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

Diabetes Care. 2016 Aug;39(8):1408-15. doi: 10.2337/dc16-0126. Epub 2016 Jun 6.

Abstract

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.

Trial registration: ClinicalTrials.gov NCT01647308 NCT02211209.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Anticholesteremic Agents / pharmacology*
  • Apolipoprotein C-III / blood*
  • Biomarkers / blood
  • Blood Glucose / metabolism
  • Cholesterol, HDL / blood
  • Cholesterol, LDL / blood
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Glycated Hemoglobin A / metabolism
  • Humans
  • Hypertriglyceridemia / blood
  • Hypertriglyceridemia / drug therapy*
  • Insulin Resistance*
  • Male
  • Middle Aged
  • Oligonucleotides, Antisense / pharmacology*
  • Triglycerides / blood

Substances

  • Anticholesteremic Agents
  • Apolipoprotein C-III
  • Biomarkers
  • Blood Glucose
  • Cholesterol, HDL
  • Cholesterol, LDL
  • Glycated Hemoglobin A
  • Oligonucleotides, Antisense
  • Triglycerides

Associated data

  • ClinicalTrials.gov/NCT01647308
  • ClinicalTrials.gov/NCT02211209