Can a selective PPARγ modulator improve glycemic control in patients with type 2 diabetes with fewer side effects compared with pioglitazone?
OBJECTIVE
INT131 besylate is a potent, nonthiazolidinedione, selective peroxisome proliferator-activated receptor γ (PPARγ) modulator (SPPARM) designed to improve glucose metabolism while minimizing the side effects of full PPARγ agonists. This placebo-controlled study compared the efficacy and side effects of INT131 besylate versus 45 mg pioglitazone HCl in subjects with type 2 diabetes (T2D).


METHODS
This 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 A1c (HbA1c) across treatment groups. Fluid status was assessed with a prospective scoring system for lower-extremity pitting edema.


RESULTS
INT131 had a steep dose response for efficacy as measured by changes in HbA1c. After 24 weeks' treatment, the 0.5-mg dose demonstrated minimal efficacy (HbA1c -0.3 ± 0.12%) and the 2-mg dose demonstrated near-maximal efficacy (HbA1c -1.1 ± 0.12%), which was not statistically different from the efficacy of 45 mg pioglitazone (HbA1c -0.9 ± 0.12%; P < 0.01 for noninferiority). With the 1-mg dose, INT131 provided significant improvements in glycemic control (HbA1c 0.8 ± 0.12; P < 0.001 vs. placebo) but with less edema, weight gain, and hemodilution than observed with 45 mg pioglitazone.


CONCLUSIONS
INT131 demonstrated dose-dependent reductions in HbA1c, equivalent to 45 mg pioglitazone, but with less fluid accumulation and weight gain, consistent with its SPPARM design.
InteKrin Therapeutics, Inc., Los Altos, CA.
Alex M
AM
DePaoli
InteKrin Therapeutics, Inc., Los Altos, CA.
Linda S
LS
Higgins
Center for Metabolic Research, VA San Diego Healthcare System and University of California, San Diego, School of Medicine, San Diego, CA.
Robert R
RR
Henry
Boston VA Healthcare System, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
Christos
C
Mantzoros
Center for Human Nutrition, University of Texas Southwestern Medical Center and VA North Texas Healthcare System, Dallas, TX fredrick.dunn@utsouthwestern.edu.
Fredrick L
FL
Dunn
D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000627:therapeutic use; D008875:Middle Aged; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D011446:Prospective Studies; D011804:Quinolines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D013449:Sulfonamides / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D013453:Sulfonylurea Compounds / Q000627:therapeutic use; D045162:Thiazolidinediones / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D015430:Weight Gain / Q000187:drug effects
D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D008687:Metformin; D047495:PPAR gamma; D000077205:Pioglitazone; D011804:Quinolines; D013449:Sulfonamides; D013453:Sulfonylurea Compounds; D045162:Thiazolidinediones; C541917:INT 131