Pioglitazone taken prophylactically provided marked protection against the onset of type 2 diabetes in persons at high risk of the disease. In a double-blind study, 602 subjects with impaired glucose tolerance and a body mass index of 25 kg/m2 or greater were randomized to pioglitazone (30 mg/day for the first month, increased to 45 mg/day thereafter) or placebo. After a median of 2.4 years, the annual average incidence of diabetes was 2.1% in patients assigned to pioglitazone and 7.6% in those assigned to placebo, corresponding to a 72% reduction in conversion to type 2 diabetes in the pioglitazone group. Pioglitazone recipients also experienced a 31% decline carotid intima-media thickness. Weight gain and edema were the major side effects of pioglitazone.