Selective modulation of PPARγ activity can lower plasma glucose without typical thiazolidinedione side-effects in patients with Type 2 diabetes

• Published in: Journal of diabetes and its complications Vol. 25; no. 3; pp. 151 - 158
• Main Authors: Dunn, Fredrick L, Higgins, Linda S, Fredrickson, Jill, DePaoli, Alex M
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-05-2011
• Subjects: Adult; Aged; Blood Glucose - drug effects; Blood Glucose - metabolism; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Dose-Response Relationship, Drug; Endocrinology & Metabolism; Female; Humans; Hyperglycemia - drug therapy; Hyperglycemia - metabolism; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - adverse effects; Insulin Resistance; Insulin sensitization; INT131; Male; Middle Aged; Non-thiazolidinedione; PPAR gamma - agonists; PPARγ; Quinolines - administration & dosage; Quinolines - adverse effects; SPPARM; Sulfonamides - administration & dosage; Sulfonamides - adverse effects; Thiazolidinediones - administration & dosage; Thiazolidinediones - adverse effects; Treatment Outcome; Non-thiazolidinedione; Insulin sensitization; INT131; PPARγ; SPPARM
• ISSN: 1056-8727; 1873-460X
• DOI: 10.1016/j.jdiacomp.2010.06.006

Abstract Objective INT131 besylate is a potent non-thiazolidinedione selective peroxisome proliferator-activated receptor γ (PPARγ)  modulator (SPPARM) designed to improve insulin sensitivity and glucose metabolism while minimizing the side effects of full agonist thiazolidinediones. This study was conducted to determine short-term efficacy and safety of INT131 besylate in patients with Type 2 diabetes mellitus (T2DM). Research Design and Methods This was a 4-week randomized, double-blind, placebo-controlled multi-center study with 1 or 10mg INT131 besylate or placebo daily in subjects with T2DM not receiving pharmacotherapy for their hyperglycemia. The primary efficacy analysis was the comparison of treatment groups with respect to least square mean change from baseline to Week 4 of fasting plasma glucose (FPG). Results Baseline mean (±S.D.) FPG for the study population was 171±42 mg/dl. Change in FPG (±S.E., mg/dl) from baseline after 4 weeks was 8±8 ( P =NS) with placebo, -22±8 with 1mg INT131 besylate ( P =.0056) and −46±7 with 10mg INT131 besylate ( P <.0001). Modeling of available data from the literature of the effect of rosiglitazone under similar study conditions suggested that 1 mg of INT131 besylate had a similar reduction in FPG as expected with 8 mg of rosiglitazone. INT131 besylate was well tolerated, and the 1 mg dose demonstrated no evidence of fluid retention or weight gain. Conclusions INT131 besylate demonstrated a dose dependent reduction in FPG. The FPG reduction with 1mg INT131 besylate was comparable to the modeled 8 mg dose of rosiglitazone, and did not cause fluid retention or weight gain. These results are consistent with the INT131 SPPARM design.