Can a Selective PPARγ Modulator Improve Glycemic Control in Patients With Type 2 Diabetes With Fewer Side Effects Compared With Pioglitazone?

Abstract

OBJECTIVEINT131 besylate is a potent, nonthiazolidinedione, selective peroxisome proliferatoractivated receptor g (PPARg) modulator (SPPARM) designed to improve glucose metabolism while minimizing the side effects of full PPARg agonists. This placebocontrolled study compared the efficacy and side effects of INT131 besylate versus 45 mg pioglitazone HCl in subjects with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODSThis was a 24-week randomized, double-blind, placebo-and active-controlled study of 0.5-3.0 mg INT131 versus 45 mg pioglitazone or placebo daily in 367 subjects with T2D on sulfonylurea or sulfonylurea plus metformin. The primary efficacy analysis was the comparison of change from baseline to week 24 in hemoglobin A 1c (HbA 1c ) across treatment groups. Fluid status was assessed with a prospective scoring system for lower-extremity pitting edema. RESULTSINT131 had a steep dose response for efficacy as measured by changes in HbA 1c . After 24 weeks' treatment, the 0.5-mg dose demonstrated minimal efficacy (HbA 1c 20.3 6 0.12%) and the 2-mg dose demonstrated near-maximal efficacy (HbA 1c 21.1 6 0.12%), which was not statistically different from the efficacy of 45 mg pioglitazone (HbA 1c 20.9 6 0.12%; P < 0.01 for noninferiority). With the 1-mg dose, INT131 provided significant improvements in glycemic control (HbA 1c 0.8 6 0.12; P < 0.001 vs. placebo) but with less edema, weight gain, and hemodilution than observed with 45 mg pioglitazone. CONCLUSIONSINT131 demonstrated dose-dependent reductions in HbA 1c , equivalent to 45 mg pioglitazone, but with less fluid accumulation and weight gain, consistent with its SPPARM design.Insulin resistance is a key etiologic factor in type 2 diabetes (T2D). Peroxisome proliferator-activated receptor (PPAR)g activation is associated with significant improvement in insulin resistance, hyperglycemia, endothelial function, and markers of inflammation (1,2). However, clinical use of thiazolidinediones (TZDs) has been limited by their side effect profile, namely, fluid retention, congestive

Thiazolidinediones and the Promise of Insulin Sensitization in Type 2 Diabetes

“…The diarysulfonamide non-TZD class of PPARγ partial agonists, which includes the drug INT-131, is structurally distinct from TZDs with different binding properties (Bajare et al, 2012). In mouse models, INT-131 failed to cause volume expansion and actually increased bone density, and a recent 24-week trial of 362 patients with T2DM showed equal glucose lowering efficacy to 45mg pioglitazone with evidence for less fluid retention (DePaoli et al, 2014). MBX-102 and GW1929 are two other structurally distinct non-TZD agonists with promising results in animal and cell models (Brown et al, 1999; Gregoire et al, 2009).…”

Selective Tissue Distribution Mediates Tissue-Dependent PPARγ Activation and Insulin Sensitization by INT131, a Selective PPARγ Modulator

“…A phase IIb clinical trial has been completed for INT131, a promising non-TZD sPPARγM that improves hyperglycaemia in both animal diabetes models and T2DM patients, with effects comparable to those of TZDs but with fewer side effects than full PPARγ agonists (Motani et al, 2009; Dunn et al, 2011; Lee et al, 2012; DePaoli et al, 2014). INT131 binds to the ligand-binding pocket of PPARγ receptor, partly overlapping with the TZD binding site, but does not directly contact with Tyr 473 in helix H12, which is the binding site associated with full PPARγ agonism (Bruning et al, 2007; Einstein et al, 2008; Motani et al, 2009).…”

The multifaceted factor peroxisome proliferator-activated receptor γ (PPARγ) in metabolism, immunity, and cancer

“…To separate the beneficial metabolic effects from the unwanted side effects, highly potent and selective PPARa modulators (SPPARMa) and PPARc modulators (SPPARMc) are being investigated (Balint and Nagy 2006;DePaoli et al 2014;Feldman et al 2008). Dual PPAR-a/c agonists were also studied and have displayed some promising metabolic effects.…”