New IRIS Data Shows Pioglitazone Slows Type 2 Diabetes Progression

New data from the Insulin Resistance Intervention after Stroke (IRIS) trial showed that pioglitazone, which belongs to the thiazolidinedione (TZD) drug class, reduced the likelihood of progression to diabetes by more than 50% in individuals with insulin resistance and cerebrovascular disease. The new findings were presented during the president’s oral abstract session at the ADA’s 76th Scientific Sessions (June 10-14, 2016; New Orleans, LA).

IRIS is a multicenter, double-blind, placebo-controlled trial that included 3876 individuals who recently had a stroke or heart attack, insulin resistance (defined as Homeostasis Model Assessment of Insulin Resistance [HOMA-IR) >3.0), and who did not have diabetes (defined as no prior history and fasting plasma glucose [FPG] of <126 mg/dL). The participants were randomized to pioglitazone (45 mg daily; n = 1939) or placebo (n = 1937). 

Results from IRIS on the primary endpoint, which were published in the New England Journal of Medicine [2016;374(14):1321-1331], showed that pioglitazone reduced the risk of fatal and nonfatal stroke and myocardial infarction by 24% in individuals with cerebrovascular disease. The secondary analysis examined pioglitazone’s effect on diabetes prevention in a large group of nondiabetic stroke patients with insulin resistance, including many who had prediabetes.

 “While previous studies have shown that TZD medications can reduce diabetes risk, this is the first to show they can do so in a group of patients with established cerebrovascular disease. It’s also the first time a glucose-lowering drug has been shown to both reduce diabetes and also reduce the risk of cardiovascular complications in the same study,” said lead investigator Silvio E Inzucchi, MD, director, Yale Diabetes Center, New Haven, CT, said in a press statement.

At baseline, participants exhibited mean FPG of 98.2 mg/dL, hemoglobin A1c (HbA1c) of 5.8%, and HOMA-IR of 5.4. They were assessed annually through interviews and FPG testing. After the first year, mean HOMA-IR decreased to 4.1 in the pioglitazone group and increased to 5.7 in the placebo group (P < .0001), while FPG decreased to 95.1 mg/dL in the pioglitazone group and increased to 99.7 mg/dL in the placebo group (P < .0001). During the follow-up period (mean, 4.8 years), progression to diabetes occurred in 3.8% of individuals (n = 73) in the pioglitazone group, compared with 7.7% (n = 149) in the placebo group, representing a significant 52% reduction in the time to diabetes onset (P < .0001).

The greatest reduction in risk occurred in patients who had prediabetes (FPG ≥ 100 mg/dL or HbA1c ≥ 5.7%) and those who had the worst insulin resistance (HOMA-IR ≥ 4.6). 

“Insulin resistance is very common after stroke,” said Dr Inzucchi. “Treating insulin resistance with pioglitazone cuts the risk of diabetes in half, while also reducing the risk of stroke and heart attack by a quarter. This is a potentially powerful dual effect to combat metabolic and cardiovascular disease.”

Pioglitazone was previously shown to reduce the risk of type 2 diabetes in the Actos Now for Prevention of Diabetes (ACT NOW) study, published in the New England Journal of Medicine [2011;364(12):1104-1115). A recent follow-up of ACT NOW to examine the effect of pioglitazone on incidence of diabetes after discontinuing therapy showed that pioglitazone’s protective effect persisted for at least 1 year after the study participants stopped taking the medicine [J Clin Endocrinol Metab. 2016;101(5):2056-2062].—Eileen Koutnik-Fotopoulos