Article

Diabetologia

, 52:715

First online:

A copper(II)-selective chelator ameliorates left-ventricular hypertrophy in type 2 diabetic patients: a randomised placebo-controlled study

  • G. J. S. CooperAffiliated withLevel 4, School of Biological Sciences, Faculty of Science, University of AucklandMaurice Wilkins Centre for Molecular Biodiscovery, Faculty of Science, University of AucklandDepartment of Medicine, School of Medicine, Faculty of Medical and Health Sciences, University of Auckland Email author 
  • , A. A. YoungAffiliated withDepartment of Anatomy with Radiology, School of Medicine, Faculty of Medical and Health Sciences, University of Auckland
  • , G. D. GambleAffiliated withDepartment of Medicine, School of Medicine, Faculty of Medical and Health Sciences, University of Auckland
  • , C. J. OccleshawAffiliated withDepartment of Cardiology, Greenlane Hospital
  • , A. M. DissanayakeAffiliated withSouth Auckland Diabetes Service, Middlemore Hospital
  • , B. R. CowanAffiliated withDepartment of Medicine, School of Medicine, Faculty of Medical and Health Sciences, University of AucklandDepartment of Anatomy with Radiology, School of Medicine, Faculty of Medical and Health Sciences, University of Auckland
  • , D. H. BruntonAffiliated withLevel 4, School of Biological Sciences, Faculty of Science, University of Auckland
  • , J. R. BakerAffiliated withSouth Auckland Diabetes Service, Middlemore Hospital
  • , A. R. J. PhillipsAffiliated withLevel 4, School of Biological Sciences, Faculty of Science, University of AucklandMaurice Wilkins Centre for Molecular Biodiscovery, Faculty of Science, University of Auckland
    • , C. M. FramptonAffiliated withDepartment of Medicine, Christchurch Clinical School, University of Otago
    • , S. D. PoppittAffiliated withLevel 4, School of Biological Sciences, Faculty of Science, University of AucklandDepartment of Medicine, School of Medicine, Faculty of Medical and Health Sciences, University of Auckland
    • , R. N. DoughtyAffiliated withDepartment of Medicine, School of Medicine, Faculty of Medical and Health Sciences, University of Auckland

Abstract

Aims/hypothesis

Cu(II)-selective chelation with trientine ameliorates cardiovascular and renal disease in a model of diabetes in rats. Here, we tested the hypothesis that Cu(II)-selective chelation might improve left ventricular hypertrophy (LVH) in type 2 diabetic patients.

Methods

We performed a 12 month randomised placebo-controlled study of the effects of treatment with the Cu(II)-selective chelator trientine (triethylenetetramine dihydrochloride, 600 mg given orally twice daily) on LVH in diabetic patients (n = 15/group at baseline) in an outpatient setting wherein participants, caregivers and those assessing outcomes were blinded to group assignment. Using MRI, we measured left ventricular variables at baseline, and at months 6 and 12. The change from baseline in left ventricular mass indexed to body surface area (LVMbsa) was the primary endpoint variable.

Results

Diabetic patients had LVH with preserved ejection fraction at baseline. Trientine treatment decreased LVMbsa by 5.0 ± 7.2 g/m2 (mean ± SD) at month 6 (when 14 trientine-treated and 14 placebo-treated participants were analysed; p = 0.0056 compared with placebo) and by 10.6 ± 7.6 g/m2 at month 12 (when nine trientine-treated and 13 placebo-treated participants were analysed; p = 0.0088), whereas LVMbsa was unchanged by placebo treatment. In a multiple-regression model that explained ~75% of variation (R 2 = 0.748, p = 0.001), cumulative urinary Cu excretion over 12 months was positively associated with trientine-evoked decreases in LVMbsa.

Conclusions/interpretation

Cu(II)-selective chelation merits further exploration as a potential pharmacotherapy for diabetic heart disease.

Trial registration: Australian New Zealand Clinical Trials Registry ACTRN 12609000053224

Funding: The Endocore Research Trust; Lottery Health New Zealand; the Maurice and Phyllis Paykel Trust; the Foundation of Research, Science and Technology (New Zealand); the Health Research Council of New Zealand; the Ministry of Education (New Zealand) through the Maurice Wilkins Centre for Molecular Biodiscovery; and the Protemix Corporation.

Keywords

Cardiac magnetic resonance imaging Copper Diabetic cardiomyopathy Left-ventricular hypertrophy Oral copper chelation Triethylenetetramine