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

J Clin Endocrinol Metab. 2007 Feb;92(2):527-31. doi: 10.1210/jc.2006-1740. Epub 2006 Nov 21.

Abstract

Objective: Our objective was to test the safety and metabolic effects of a novel beta(3)-adrenoreceptor agonist (TAK-677) in humans.

Design, setting, and participants: 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.

Intervention: 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.

Outcomes: 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.

Conclusion: 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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abdominal Fat / drug effects
  • Acetates / administration & dosage*
  • Adrenergic beta-3 Receptor Antagonists*
  • Adrenergic beta-Antagonists / administration & dosage*
  • Adult
  • Body Weight / drug effects
  • Circadian Rhythm
  • Double-Blind Method
  • Energy Metabolism / drug effects*
  • Fasting
  • Female
  • Homeostasis / drug effects
  • Humans
  • Indoles / administration & dosage*
  • Longitudinal Studies
  • Male
  • Obesity / drug therapy*
  • Obesity / metabolism*
  • Placebos
  • Treatment Failure

Substances

  • ((3-((2R)-(((2R)-3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1H-indol-7-yloxy)acetic acid
  • Acetates
  • Adrenergic beta-3 Receptor Antagonists
  • Adrenergic beta-Antagonists
  • Indoles
  • Placebos