title: Effects of triple antioxidant therapy on measures of cardiovascular autonomic neuropathy and on myocardial blood flow in type 1 diabetes: a randomised controlled trial.
abstract: OBJECTIVE
  We evaluated the effects of a combination triple antioxidant therapy on measures of cardiovascular autonomic neuropathy (CAN) and myocardial blood flow (MBF) in patients with type 1 diabetes.
  
  
  METHODS
  This was a randomised, parallel, placebo-controlled trial. Participants were allocated to interventions by sequentially numbered, opaque, sealed envelopes provided to the research pharmacist. All participants and examiners were masked to treatment allocation. Participants were evaluated by cardiovascular autonomic reflex testing, positron emission tomography with [(11)C]meta-hydroxyephedrine ([(11)C]HED) and [(13)N]ammonia, and adenosine stress testing. Markers of oxidative stress included 24 h urinary F2-isoprostanes. Diabetic peripheral neuropathy (DPN) was evaluated by symptoms, signs, electrophysiology and intra-epidermal nerve fibre density. Randomised participants included 44 eligible adults with type 1 diabetes and mild-to-moderate CAN, who were aged 46 ± 11 years and had HbA1c 58 ± 5 mmol/mol (7.5 ± 1.0%), with no evidence of ischaemic heart disease. Participants underwent a 24-month intervention, consisting of antioxidant treatment with allopurinol, α-lipoic acid and nicotinamide, or placebo. The main outcome was change in the global [(11)C]HED retention index (RI) at 24 months in participants on the active drug compared with those on placebo.
  
  
  RESULTS
  We analysed data from 44 participants (22 per group). After adjusting for age, sex and in-trial HbA1c, the antioxidant regimen was associated with a slight, but significant worsening of the global [(11)C]HED left ventricle RI (-0.010 [95% CI -0.020, -0.001] p = 0.045) compared with placebo. There were no significant differences at follow-up between antioxidant treatment and placebo in the global MBF, coronary flow reserve, or in measures of DPN and markers of oxidative stress. The majority of adverse events were of mild-to-moderate severity and did not differ between groups
  
  
  CONCLUSIONS
  In this cohort of type 1 diabetes patients with mild-to-moderate CAN, a combination antioxidant treatment regimen did not prevent progression of CAN, had no beneficial effects on myocardial perfusion or DPN, and may have been detrimental. However, a larger study is necessary to assess the underlying causes of these findings.
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA. rpbusui@umich.edu
authors.forename: R
authors.initials: R
authors.lastname: Pop-Busui
authors.forename: M J
authors.initials: MJ
authors.lastname: Stevens
authors.forename: D M
authors.initials: DM
authors.lastname: Raffel
authors.forename: E A
authors.initials: EA
authors.lastname: White
authors.forename: M
authors.initials: M
authors.lastname: Mehta
authors.forename: C D
authors.initials: CD
authors.lastname: Plunkett
authors.forename: M B
authors.initials: MB
authors.lastname: Brown
authors.forename: E L
authors.initials: EL
authors.lastname: Feldman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000493:Allopurinol / Q000494:pharmacology; D000975:Antioxidants / Q000627:therapeutic use*; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000503:physiopathology; D003929:Diabetic Neuropathies / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism*; D009536:Niacinamide / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects; D055815:Young Adult
chemical_list: D000975:Antioxidants; D009536:Niacinamide; D000493:Allopurinol