BackgroundPioglitazone’s role in the induction of atheroma regression in diabetics was suggested by several RCT. The aim of our study was to evaluate this role through a systematic review of all RCT conducted on this subject.MethodsLiterature was searched for relevant studies. We included all RCT that compared pioglitazone versus other antidiabetic agents. Mean differences of either AV or CIMT, HbA1C, HDL, and LDL between the two groups were used to assess the effect of pioglitazone versus alternative therapies.ResultsSix RCT were included with a total of 1180 patients. Pioglitazone was significantly superior to glimepiride and gliclazide in improving IMT. No significant difference was observed in overall AV, HbA1C, and LDL.ConclusionThe latter findings confirm that anti-atheroma action of pioglitazone is not achieved through its antiglycemic or antidyslipidemia effects, but probably through a DNA-mediated effect, and may lead to its repurposing for reversal of organ fibrosis.