Response to Comment on Inzucchi et al. Pioglitazone Prevents Diabetes in Patients With Insulin Resistance and Cerebrovascular Disease. Diabetes Care 2016;39:1684–1692

Katsiki and Mikhailidis (1) raise the possibility that reduced uric acid may have been a mechanism of the cardiovascular benefits of pioglitazone in the Insulin Resistance Intervention after Stroke (IRIS) trial. Unfortunately, we did not measure urate levels during the trial, so the question cannot be answered. One small trial suggested modest reductions in hyperuricemia from pioglitazone, on the order of 14% (<1 mg/dL) (2). Data regarding the association between uric acid and cardiovascular disease remain highly controversial, however, and whether lowering urate confers a cardiovascular advantage remains to be demonstrated convincingly. The issue of effects of pioglitazone on nonalcoholic fatty liver disease is also raised. As Katsiki and Mikhailidis (1) describe, modest decreases in alanine aminotransferase levels were in fact measured in IRIS participants assigned to the pioglitazone group. Because we did not measure liver fat directly, …