Balaglitazone is a novel
thiazolidinedione in clinical development for the treatment of
type 2 diabetes. Common side effects associated with
PPARgamma receptor agonists are
weight gain, oedema and adipogenesis.
Balaglitazone is a selective partial
PPARgamma 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
PPARgamma 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
PPARgamma agonist,
rosiglitazone, induces more pronounced body fluid retention and
heart enlargement than seen for the partial
PPARgamma agonist,
balaglitazone. Thus, partial agonists may pose safer alternative to current anti-diabetic
therapy with full
PPARgamma agonist.