A copper(II)-selective chelator ameliorates left-ventricular hypertrophy in type 2 diabetic patients: a randomised placebo-controlled study.
OBJECTIVE
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 (LVM(bsa)) was the primary endpoint variable.


RESULTS
Diabetic patients had LVH with preserved ejection fraction at baseline. Trientine treatment decreased LVM(bsa) by 5.0 +/- 7.2 g/m(2) (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/m(2) at month 12 (when nine trientine-treated and 13 placebo-treated participants were analysed; p = 0.0088), whereas LVM(bsa) 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 LVM(bsa).


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


BACKGROUND
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.
Cooper
G J S
GJ
Level 4, School of Biological Sciences, Faculty of Science, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand. g.cooper@auckland.ac.nz
Young
A A
AA
Gamble
G D
GD
Occleshaw
C J
CJ
Dissanayake
A M
AM
Cowan
B R
BR
Brunton
D H
DH
Baker
J R
JR
Phillips
A R J
AR
Frampton
C M
CM
Poppitt
S D
SD
Doughty
R N
RN
D000328:Adult; D000368:Aged; D001794:Blood Pressure / Q000187:drug effects; D001830:Body Surface Area; D002614:Chelating Agents / Q000627:therapeutic use*; D003404:Creatinine / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D003925:Diabetic Angiopathies / Q000188:drug therapy* / Q000503:physiopathology; D004452:Echocardiography; D004562:Electrocardiography; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D006352:Heart Ventricles / Q000033:anatomy & histology; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy* / Q000503:physiopathology; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D018579:Patient Selection; D010919:Placebos; D014266:Trientine / Q000627:therapeutic use*
D002614:Chelating Agents; D003404:Creatinine; D006442:Glycated Hemoglobin; D010919:Placebos; D014266:Trientine