We read with interest the results of the Insulin Resistance Intervention after Stroke (IRIS) trial prespecified secondary analysis for type 2 diabetes mellitus (T2DM) prevention, in which Inzucchi et al. (1) reported that pioglitazone almost halved the risk of T2DM development in insulin-resistant patients with cerebrovascular disease. This effect was driven by a larger impact in participants who at baseline had HbA1c >5.7% (39 mmol/mol), impaired fasting plasma glucose (>100 mg/dL [5.6 mmol/L]), higher HOMA of insulin resistance (≥4.6), and metabolic syndrome (1).
One of the potentially beneficial effects of thiazolidinediones is that they may decrease serum uric acid concentrations, which may in turn predict vascular risk (2). Therefore, it would be useful to evaluate this effect in the IRIS trial.
Nonalcoholic fatty liver disease, the hepatic manifestation of metabolic syndrome, has been associated with increased risk for T2DM and cardiovascular morbidity and mortality (3). In the earlier IRIS publication, significantly fewer patients on pioglitazone than those on placebo had alanine aminotransferase activity greater than the upper limit of the normal range (4). In this context, did the Inzucchi et al. (1) investigate whether pioglitazone affected development of nonalcoholic fatty liver disease?
Postprandial lipemia (PPL) has been related to increased cardiovascular risk (5). Pioglitazone was shown to reduce fasting triglyceride (TG) levels in the IRIS trial (4). As elevated fasting TGs increase the incidence of PPL (5), the TG-reducing effect of pioglitazone may decrease the prevalence of PPL.
Overall, multiple beneficial metabolic effects may account for the positive clinical outcomes observed with pioglitazone in the IRIS trial.
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Duality of Interest. N.K. has given talks, attended conferences, and participated in trials sponsored by Amgen, Angelini, AstraZeneca, Boehringer Ingelheim, Merck Sharp & Dohme, Novartis, Novo Nordisk, Sanofi, and WinMedica. D.P.M. has given talks and attended conferences sponsored by Merck Sharp & Dohme, AstraZeneca, and Libytec Pharmaceutical. No other potential conflicts of interest relevant to this article were reported.
