Dissociation of antihyperglycaemic and adverse effects of partial perioxisome proliferator-activated receptor (PPAR-γ) agonist balaglitazone

• Published in: European journal of pharmacology 2008-10, Vol.596 (1), p.173-179
• Main Authors: Larsen, Philip J., Lykkegaard, Kirsten, Larsen, Leif K., Fleckner, Jan, Sauerberg, Per, Wassermann, Karsten, Wulff, Erik Max
• Format: Article
• Language: English
• Subjects: Adipogenesis - drug effects; Adipose Tissue - drug effects; Animals; Balaglitazone; Biological and medical sciences; Blood Volume - drug effects; Body Weight - drug effects; Diabetes; Diabetes. Impaired glucose tolerance; Drinking - drug effects; Eating - drug effects; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fluid retention; Haemodilution; Heart - anatomy & histology; Heart - drug effects; Heart weight; Humans; Hypoglycemic Agents - adverse effects; Hypoglycemic Agents - pharmacology; Male; Medical sciences; Mice; Oedema; Organ Size - drug effects; Pharmacology. Drug treatments; PPAR gamma - agonists; PPAR gamma - genetics; Quinazolines - adverse effects; Quinazolines - pharmacology; Rats; Rosiglitazone; Thiazolidinediones - adverse effects; Thiazolidinediones - pharmacology
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2008.08.004

Balaglitazone is a novel thiazolidinedione in clinical development for the treatment of type 2 diabetes. Common side effects associated with PPARγ receptor agonists are weight gain, oedema and adipogenesis. Balaglitazone is a selective partial PPARγ agonist and it has been speculated that such compounds have a more favourable safety margin than full agonists. We have compared impact of equi-efficacious antihyperglycaemic doses of balaglitazone with full PPARγ agonist rosiglitazone on body fluid accumulation, cardiac enlargement, and adipogenesis. Equi-efficacious antihyperglycaemic doses (ED 90) of balaglitazone (3 mg/kg/day) and rosiglitazone (6 mg/kg/day) were determined in male diabetic db/db mice. In adult male rats treated for up to 42 days, feeding, drinking, anthropometry, and plasma volumes were measured. Total plasma volume was measured with dye dilution technique. Compared to vehicle, rosiglitazone consistently increased food intake throughout the 42 day treatment period. In contrast, balaglitazone increased food intake in the last week of the experiment. However, both rosiglitazone and balaglitazone increased water intake. After 42 days, rosiglitazone treated rats displayed significantly elevated adiposity. Rosiglitazone increased total blood and plasma volumes throughout the treatment. Twenty-one days of balaglitazone treatment had no significant impact on blood or plasma volumes, whilst 42 days of balaglitazone increased plasma volume but to a significantly lesser extent than seen for rosiglitazone (vehicle: 46.1 ± 1.5; balaglitazone: 50.8 ± 1.21; rosiglitazone: 54.6 ± 1.6 ml/kg). Heart weight was significantly elevated only in rosiglitazone treated animals. At doses inducing comparable antihyperglycaemic control, the full PPARγ agonist, rosiglitazone, induces more pronounced body fluid retention and heart enlargement than seen for the partial PPARγ agonist, balaglitazone. Thus, partial agonists may pose safer alternative to current anti-diabetic therapy with full PPARγ agonist.