title: Efficacy and safety of the PPARγ partial agonist balaglitazone compared with pioglitazone and placebo: a phase III, randomized, parallel-group study in patients with type 2 diabetes on stable insulin therapy.
abstract: BACKGROUND
  Treatment of patients with perioxisome proliferator-activated receptor-γ full agonists are associated with weight gain, heart failure, peripheral oedema, and bone loss. However, the safety of partial perioxisome proliferator-activated receptor-γ agonists has not been established in a clinical trial. The BALaglitazone glucose Lowering Efficacy Trial aimed to establish the glucose-lowering effects and safety parameters of the perioxisome proliferator-activated receptor-γ partial agonist balaglitazone in diabetic patients on stable insulin therapy.
  
  
  METHODS
  Four hundred and nine subjects from three countries with type 2 diabetes on stable insulin therapy were randomized to 26 weeks of double-blind treatment with once daily doses of 10 or 20 mg balaglitazone, 45 mg pioglitazone, or matching placebo (n ≥ 99 in each group). The primary endpoint was the efficacy of balaglitazone 10 and 20 mg versus placebo on the absolute change in haemoglobin A(1c) . Secondary endpoints included levels of fasting serum glucose, and changes in body composition and bone mineral density as measured by dual energy X-ray absorptiometry, in comparison to pioglitazone 45 mg. This study is registered with Clinicaltrials.gov identifier: NCT00515632.
  
  
  RESULTS
  In the 10- and 20-mg balaglitazone groups, and in the 45-mg pioglitazone group, significant reductions in haemoglobin A(1c) levels were observed (−0.99, −1.11, and −1.22%, respectively; p < 0.0001) versus placebo. Fasting serum glucose was similarly reduced in all treatment arms. Dual energy X-ray absorptiometry analyses showed that, while balaglitazone at 10 mg caused weight gain and fluid retention compared to placebo, the magnitude of these effects was significantly smaller than that of pioglitazone 45 mg and balaglitazone 20mg. Balaglitazone at either dose did not appear to reduce bone mineral density, while Pioglitazone showed a trend towards a reduction.
  
  
  CONCLUSIONS
  Patients treated with balaglitazone at 10 mg and 20 mg and pioglitazone at 45 mg showed clinically meaningful improvements in glucose levels and HbA(1c) . With the 10 mg dose, the benefits (glucose & HgA(1c) lowering) and untoward effects (fluid and fat accumulation) were less, results that encourage further studies of this drug candidate.
authors.affiliation: Nordic Bioscience A/S, Herlev, Denmark. kh@nordicbioscience.com
authors.forename: Kim
authors.initials: K
authors.lastname: Henriksen
authors.forename: Inger
authors.initials: I
authors.lastname: Byrjalsen
authors.forename: Per
authors.initials: P
authors.lastname: Qvist
authors.forename: Henning
authors.initials: H
authors.lastname: Beck-Nielsen
authors.forename: Gitte
authors.initials: G
authors.lastname: Hansen
authors.forename: Bente J
authors.initials: BJ
authors.lastname: Riis
authors.forename: Hans
authors.initials: H
authors.lastname: Perrild
authors.forename: Ole Lander
authors.initials: OL
authors.lastname: Svendsen
authors.forename: Jeppe
authors.initials: J
authors.lastname: Gram
authors.forename: Morten A
authors.initials: MA
authors.lastname: Karsdal
authors.forename: Claus
authors.initials: C
authors.lastname: Christiansen
mesh_terms: D000368:Aged; D001786:Blood Glucose / Q000032:analysis; D001823:Body Composition / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination / Q000009:adverse effects; D005260:Female; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D007328:Insulin / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D047495:PPAR gamma / Q000037:antagonists & inhibitors*; D000077205:Pioglitazone; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014882:Water-Electrolyte Balance / Q000187:drug effects; D015430:Weight Gain / Q000187:drug effects
chemical_list: D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D047495:PPAR gamma; D000077205:Pioglitazone; D011799:Quinazolines; D045162:Thiazolidinediones; C517652:hemoglobin A1c protein, human; C497232:balaglitazone