Clinical Proof-Of-Concept Study With MSDC-0160, a Prototype mTOT-modulating Insulin Sensitizer

Clin Pharmacol Ther. 2013 Apr;93(4):352-9. doi: 10.1038/clpt.2013.10. Epub 2013 Jan 18.

Abstract

It may be possible to achieve insulin sensitivity through the recently identified mitochondrial target of thiazolidinediones (mTOT), thereby avoiding peroxisome proliferator-activated receptor-γ (PPAR-γ)-dependent side effects. In this phase IIb clinical trial, 258 patients with type 2 diabetes completed a 12-week protocol with 50, 100, or 150 mg of MSDC-0160 (an mTOT modulator), 45 mg pioglitazone HCl (a PPAR-γ agonist), or a placebo. The two active treatments lowered fasting glucose levels to the same extent. The decreases in glycated hemoglobin (HbA1c) observed with the two higher doses of MSDC-0160 were not different from those associated with pioglitazone. By contrast, fluid retention as evidenced by reduction in hematocrit, red blood cells, and total hemoglobin was 50% less in the MSDC-0160-treated groups. There was also a smaller increase in high-molecular-weight (HMW) adiponectin with MSDC-0160 than with pioglitazone (P < 0.0001), suggesting that MSDC-0160 produces less expansion of white adipose tissue. Thus, mTOT modulators may have glucose-lowering effects similar to those of pioglitazone but without the adverse effects associated with PPAR-γ agonists.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Adiponectin / metabolism
  • Blood Glucose / drug effects
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Dose-Response Relationship, Drug
  • Edema / blood
  • Edema / complications
  • Female
  • Glycated Hemoglobin A / metabolism
  • Humans
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / therapeutic use*
  • Insulin Resistance*
  • Male
  • Middle Aged
  • Mitochondrial Proteins / drug effects*
  • Pioglitazone
  • Pyridines / adverse effects
  • Pyridines / therapeutic use*
  • Thiazolidinediones / adverse effects
  • Thiazolidinediones / therapeutic use*

Substances

  • Adiponectin
  • Blood Glucose
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • MSDC-0160
  • Mitochondrial Proteins
  • Pyridines
  • Thiazolidinediones
  • Pioglitazone