Effect of Long Term α-Lipoic Acid Treatment on Endothelial Function in Patients With Type 2 Diabetes
Condition: Type 2 Diabetes
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 2

Summary: 
      In the present study, endothelium dependent vasodilation will be induced by administration of
      acetylcholine (ACh). To ascertain whether the vascular effects, if any, of α-lipoic acid are
      limited to the endothelium, endothelium independent vasodilation will also be assessed by
      administration of glyceroltrinitrate (GTN).

      Study objectives To investigate the effect of α-lipoic acid therapy on endothelium dependent
      and independent vasodilation, assessed by forearm blood flow (FBF), in patients with type 2
      diabetes mellitus

      Study design

      Randomized, double-blinded, parallel group study for 23 days:

      Day 1: FBF responses to acetylcholine and glyceroltrinitrate Day 2-22: intravenous infusion
      of 600 mg α-lipoic acid or placebo Day 23: FBF responses to acetylcholine and
      glyceroltrinitrate

      Study population 30 subjects with type 2 diabetes

      Study medication Acetylcholine (ACh) - intraarterial infusion, 25, 50, 100 nmol/min, infusion
      period 3 minutes/dose level Glyceroltrinitrate (GTN) - intraarterial infusion, 4, 8, 16
      nmol/min, infusion period 3 minutes/dose level α-lipoic acid - intravenous infusion of 600 mg
      in 250 ml saline solution over 30 minutes

      Main outcome variables Forearm blood flow (Ratio between intervention and control arm)
      Additional outcome variables Arterial blood pressure, pulse rate, markers of inflammation and
      oxidative stress, Insulin plasma levels, Glucose plasma levels

      Risk/benefit assessment The insertion of intravenous cannula may cause mild and transient
      pain. A minor hematoma may occur at the site of cannula insertion. The insertion of the
      intraarterial cannula is performed under local anaesthesia and causes mild pain. The
      meassurement of forearm bloodflow, espacialy the wrist cuff (>200 mmHG) may be uncomfortably.
      Local administration of drugs through a needle in the brachial artery allows the study of
      direct vascular effects of the drugs. Drug doses are 100 to 1000 times lower than a systemic
      effective dose, therefore no systemic adverse events are expected. There is experience in
      brachial artery infusions at our institution, and it is considered a safe technique. α-lipoic
      acid was well tolerated in healthy volunteers and subjects with diabetes at doses up to 600
      mg intravenously and 1800 mg orally with side effects comparable with placebo. Altogether 50
      ml blood will be collected throughout the study.
    

Detailed description: 
      Background

      Type 2 (non-insulin-dependent) diabetes is associated with a marked increase in the risk of
      cardiovascular disease. Before overt cardiovascular disease occurs, impairment of vascular
      endothelial function is detectable. Endothelium-dependent vasodilation is impaired in
      patients with type 2 diabetes, indicating that diabetes is associated with endothelial
      dysfunction. Recently, formation of reactive oxygen species (ROS) has been linked to
      diabetes. These heterogeneous group of highly reactive compounds interact with NO and thereby
      inhibit vasodilation caused by NO. Formation of ROS is therefore thought to be an important
      mechanism by which type 2 diabetes induces endothelial dysfunction. α-Lipoic acid, which has
      been used for the treatment of diabetic neuropathy, was shown to have antioxidant capacities
      in vitro and animal experiments. Short term treatment with intraarterial α-lipoic acid was
      shown to improve endothelium dependent vasodilation in type 2 diabetics. However, to date, no
      data exists about the long term effcts of α-lipoic acid on vascular function in type 2
      diabetics. In the present study, endothelium dependent vasodilation will be induced by
      administration of acetylcholine (ACh). To ascertain whether the vascular effects, if any, of
      α-lipoic acid are limited to the endothelium, endothelium independent vasodilation will also
      be assessed by administration of glyceroltrinitrate (GTN).

      Study objectives To investigate the effect of α-lipoic acid therapy on endothelium dependent
      and independent vasodilation, assessed by forearm blood flow (FBF), in patients with type 2
      diabetes mellitus

      Study design

      Randomized, double-blinded, parallel group study for 23 days:

      Day 1: FBF responses to acetylcholine and glyceroltrinitrate Day 2-22: intravenous infusion
      of 600 mg α-lipoic acid or placebo Day 23: FBF responses to acetylcholine and
      glyceroltrinitrate

      Study population 30 subjects with type 2 diabetes

      Study medication Acetylcholine (ACh) - intraarterial infusion, 25, 50, 100 nmol/min, infusion
      period 3 minutes/dose level Glyceroltrinitrate (GTN) - intraarterial infusion, 4, 8, 16
      nmol/min, infusion period 3 minutes/dose level α-lipoic acid - intravenous infusion of 600 mg
      in 250 ml saline solution over 30 minutes

      Main outcome variables Forearm blood flow (Ratio between intervention and control arm)
      Additional outcome variables Arterial blood pressure, pulse rate, markers of inflammation and
      oxidative stress, Insulin plasma levels, Glucose plasma levels

      Risk/benefit assessment The insertion of intravenous cannula may cause mild and transient
      pain. A minor hematoma may occur at the site of cannula insertion. The insertion of the
      intraarterial cannula is performed under local anaesthesia and causes mild pain. The
      meassurement of forearm bloodflow, espacialy the wrist cuff (>200 mmHG) may be uncomfortably.
      Local administration of drugs through a needle in the brachial artery allows the study of
      direct vascular effects of the drugs. Drug doses are 100 to 1000 times lower than a systemic
      effective dose, therefore no systemic adverse events are expected. There is experience in
      brachial artery infusions at our institution, and it is considered a safe technique. α-lipoic
      acid was well tolerated in healthy volunteers and subjects with diabetes at doses up to 600
      mg intravenously and 1800 mg orally with side effects comparable with placebo. Altogether 50
      ml blood will be collected throughout the study.
    

Intervention name(s): Alpha lipoic acid
Intervention type(s): Drug
Intervention MeSH terms: Thioctic Acid
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Treatment