Lack of an effect of a novel beta3-adrenoceptor agonist, TAK-677, on energy metabolism in obese individuals: a double-blind, placebo-controlled randomized study.
OBJECTIVE
Our objective was to test the safety and metabolic effects of a novel beta(3)-adrenoreceptor agonist (TAK-677) in humans.


METHODS
Sixty-five obese (body mass index = 33.9 +/- 2.1 kg/m2, mean +/- se) men and women (31.4 +/- 0.9 yr) participated in a double-blind placebo-controlled study at an institutional research center.


METHODS
Participants were randomized to 0.1 mg TAK-677 twice daily (BID) (n = 21), 0.5 mg TAK-677 BID (n = 22), or placebo BID (n = 22) for 29 d.


RESULTS
Drug safety, 24-h respiratory quotient (RQ), 24-h energy expenditure (EE), body composition, fat distribution, and fasting plasma concentration of substrates and hormones were assessed. An acute-response study was also conducted.


RESULTS
The drug was well tolerated by all participants; however, heart rate was elevated (9 +/- 2 beats per minute) with the 0.5-mg BID dose. After 28 d of treatment and when compared with placebo, there was no change in 24-h RQ with either 0.1-mg BID (P = 0.1) or 0.5-mg BID (P = 1.0) doses of TAK-677. However, TAK, 0.5 mg BID, resulted in a small increase in 24-h EE that was significantly different from placebo [change from baseline, 13 +/- 17 (0.5 mg BID) vs.-39 +/- 18 (placebo) kcal/d, P < 0.05]. Changes in weight, fat-free mass, and abdominal fat depots (visceral or sc) were not different between the three groups, nor were changes in fasting insulin, free fatty acid, or glucose concentrations.


CONCLUSIONS
TAK-677 has no effect on 24-h RQ or fat oxidation but does slightly increase 24-h EE at the highest dose (0.5 mg BID). The acute studies showed large interindividual variability in plasma concentrations of TAK-677 indicating some possible problems with bioavailability and therefore efficacy.
Redman
Leanne M
LM
Pennington Biomedical Research Center, Louisiana 70808, USA.
de Jonge
Lilian
L
Fang
Xiaobing
X
Gamlin
Betsy
B
Recker
David
D
Greenway
Frank L
FL
Smith
Steven R
SR
Ravussin
Eric
E
D050153:Abdominal Fat / Q000187:drug effects; D000085:Acetates / Q000008:administration & dosage*; D058673:Adrenergic beta-3 Receptor Antagonists; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage*; D000328:Adult; D001835:Body Weight / Q000187:drug effects; D002940:Circadian Rhythm; D004311:Double-Blind Method; D004734:Energy Metabolism / Q000187:drug effects*; D005215:Fasting; D005260:Female; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D008137:Longitudinal Studies; D008297:Male; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism*; D010919:Placebos; D017211:Treatment Failure
C418363:((3-((2R)-(((2R)-3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1H-indol-7-yloxy)acetic acid; D000085:Acetates; D058673:Adrenergic beta-3 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D007211:Indoles; D010919:Placebos