Clinical Proof-of-Concept Study With MSDC-0160, a Prototype mTOT-Modulating Insulin Sensitizer

• Published in: Clinical pharmacology and therapeutics Vol. 93; no. 4; pp. 352 - 359
• Main Authors: Colca, J R, VanderLugt, J T, Adams, W J, Shashlo, A, McDonald, W G, Liang, J, Zhou, R, Orloff, D G
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01-04-2013; Nature Publishing Group
• Subjects: 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; Pyridines - adverse effects; Pyridines - therapeutic use; Thiazolidinediones - adverse effects; Thiazolidinediones - therapeutic use
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1038/clpt.2013.10

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.
Clinical Pharmacology & Therapeutics (2013); 93 4, 352–359. doi:10.1038/clpt.2013.10