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

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

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Free PMC article
Clinical Trial

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

J R Colca et al. Clin Pharmacol Ther. .
Free PMC article

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.

Figures

Figure 1
Figure 1
Structures of medications and establishing of dosages. (a) Structures of pioglitazone and major active metabolites, and of MSDC-0160 and its major metabolite, the R-alcohol. (b) Pharmacokinetics of MSDC-0160 (parent plus hydroxymetabolite) in normal volunteers after the first and seventh doses. The compound was given once daily for 7 consecutive days, and the complete profile was generated on both days 1 (first dose) and 7. Trough levels were measured every day before the next dose. (c) Formulated tablets for use in the phase IIb trial were evaluated in normal volunteers. Data are shown for the combined area under the curve (AUC) of MSDC-0160 and its major metabolite at the three given doses, depicted by closed squares (q.d., mg/day). The dotted line shows the AUC of pioglitazone and its active metabolites (~60,000 ng ∙ hr/ml) after dosing with 45 mg of pioglitazone HCl (Actos). The three doses selected for the phase IIb study are shown by arrows.
Figure 2
Figure 2
Effect of 12 weeks of treatment on hemoglobin A1c (HbA1c). Data show the HbA1c changes from baseline (as a percentage) for each of the five treatment groups. (a) The change in HbA1c at each visit during the double-blind treatment period. Variations are not shown on the time curve but are similar to the data shown for the terminal 12-week time point shown in (b). The abscissa marks the time points of the visits (actual time points are baseline and weeks 2, 4, 8, and 12 during the double-blind treatment). (b) The placebo-adjusted least-squares change and SE at the 12-week end point for each of the treatment groups. The baseline HbA1c values and the number per group are shown below the bar chart. P values are given for the least-squares placebo-adjusted change from baseline. LS, least squares.
Figure 3
Figure 3
Effect of 12 weeks of treatment on total hemoglobin as a marker of fluid retention. Data show the change in total hemoglobin (g/dl) from baseline for each of the five treatment groups. (a) The change at each visit during the double-blind treatment period. (b) The placebo-adjusted least-squares change (mean and SE) at the 12-week end point (the last time point in (a)). The starting values of total hemoglobin and the number per group are shown below the bar chart. P values under the bars depict the least-squares change from baseline. P values below the panel show the differences between the MSDC-0160 groups and the pioglitazone group. LS, least squares.
Figure 4
Figure 4
Effect of 12 weeks of treatment on high-molecular-weight (HMW) adiponectin. Data show the change in HMW adiponectin from baseline for the five treatment groups. (a) The percentage change after 2 weeks and at the end point (12 weeks) for the five groups. (b) The placebo-adjusted least-squares change (mean and SE) at the 12-week end point. The starting values of HMW adiponectin (ng/ml) and the number per group are shown below the bar chart. P values above the bars depict the change from baseline. P values below the panel show the differences between the MSDC-0160 groups and pioglitazone. HMWA, HMW adiponectin; LS, least squares.
Figure 5
Figure 5
Effect of 12 weeks of treatment on body weight and waist circumference. Data show the (a,b) change in body weight and (c,d) waist circumference from baseline for each of the five treatment groups. (a) The change in body weight (kg) at each visit during the double-blind treatment period. (b) The adjusted least-squares change (mean and SE) at the 12-week end point for all five groups. The initial weight (kg) and N are shown below the bars. (c) The change in waist circumference at each visit during the double-blind treatment period. (d) The adjusted least-squares change (mean and SE) at the 12-week end point for all five groups. Data are expressed in cm (mean and SE). In each case, the 12-week time point (b,d) represents the last point on the time curves (a,c). BW, body weight; LS, least squares.
Figure 6
Figure 6
Effect of 12 weeks of treatment on lipoprotein particle size. Data show the change in the distribution of HDL particles (a: small, medium, large), LDL particles (c: small or large), and VLDL particles (d: small, medium, large). The data (mean and SEM) are presented as change from baseline for each of the five groups. The legend in the center panel presents the number of individuals in each group. (b) The changes in average size (nm) of HDL and LDL particles. Data are expressed as mean and SEM for the numbers shown in parentheses in the central panel. HDL, high-density lipoprotein; VLDL, very low-density lipoprotein.

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