Effects of triple antioxidant therapy on measures of cardiovascular autonomic neuropathy and on myocardial blood flow in type 1 diabetes: a randomised controlled trial

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. 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 [C-11]meta-hydroxyephedrine ([C-11]HED) and [N-13]ammonia, and adenosine stress testing. Markers of oxidative stress included 24 h urinary F-2-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 HbA(1c) 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, alpha-lipoic acid and nicotinamide, or placebo. The main outcome was change in the global [C-11]HED retention index (RI) at 24 months in participants on the active drug compared with those on placebo. We analysed data from 44 participants (22 per group). After adjusting for age, sex and in-trial HbA(1c), the antioxidant regimen was associated with a slight, but significant worsening of the global [C-11]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 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. ClinicalTrials.gov NCT00116207 The study was funded by the JDRF Centre for the Study of Complications in Diabetes; and by grants P60DK020572 and P30DK092926 to the Michigan Diabetes Research and Training Centre (MDRTC) and the Michigan Center for Diabetes Translational Research (MCDTR) from the National Institute of Diabetes and Digestive and Kidney Diseases.