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Pioglitazone First Medication to Prevent Diabetes Progression Including Cardiovascular Events

Study could not evaluate drug’s long-term effects on diabetes prevention, length of effects

The Insulin Resistance Intervention after Stroke trial (IRIS) recently found that the thiazolidinedione (TZD) drug pioglitazone reduced the risk of fatal and non-fatal stroke and myocardial infarction (heart attack) by 24 percent in people with cerebrovascular disease—a group of conditions that affects the flow of blood to the brain. This secondary analysis of the data collected in the IRIS trial examined pioglitazone’s effect on diabetes prevention in a large group of non-diabetic stroke patients with insulin resistance, including many people who had prediabetes. The analysis found that pioglitazone reduced progression to diabetes by 52 percent.

“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 cardiovascular 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 of the Yale Diabetes Center.

Recently, the IRIS trial found that pioglitazone was associated with decreased risk for stroke or myocardial infarction by 24% compared to placebo in nondiabetic, insulin resistant patients with ischemic stroke or TIA. Results also showed that pioglitazone was linked to decreased blood pressure, decreased CRP, and increased HDL cholesterol.

The study included 3,876 participants (mean age 63.5 years, 65% male, mean baseline HbA1c 5.8, mean baseline HOMA-IR 5.4). Fifty-two percent of participants met diagnostic criteria for metabolic syndrome at baseline. Participants were at least 40 years old and had had an ischemic stroke or TIA in the past six months. They had evidence of insulin resistance as defined by HOMA-IR >3.0 on a screening blood test, but had not yet developed diabetes. Participants were randomized to placebo or pioglitazone starting at 15 mg daily and titrated as tolerated up to 45 mg daily. Diabetes onset was assessed with periodic interviews and annual FPG tests. An independent committee of diabetes experts blinded to treatment assignment determined diabetes diagnosis based on 2004 ADA guidelines, or other pre-specified indicators of hyperglycemia.  The trial was conducted at 179 sites in Australia, Canada, Germany, Israel, Italy, the UK, and the US.

Some of the key results at one year showed that:

  • Pioglitazone: mean HOMA-IR decreased significantly by 24% from baseline, FPG also decreased significantly (both P<0.0001)
  • Placebo: At one year, mean HOMA-IR increased significantly by 7% from baseline, FPG also increased significantly FPG (both P<0.0001)
  • After a median follow-up of 4.8 years
    • Pioglitazone: 73 (3.8%) developed diabetes
    • Placebo: 149 (7.7%) developed diabetes
    • Pioglitazone was linked to 52% lower risk of developing diabetes (hazard ratio, 0.48 [95% CI 0.33–0.69]; P<0.0001)
  • A sensitivity analysis that accounted for updated 2010 ADA guidelines showed similar results
    • The pioglitazone group had more weight gain, edema, and bone fractures than placebo. Heart failure incidence or hospitalization for heart failure did not increase with pioglitazone.
    • No difference in cancer (including bladder cancer) existed between groups.

The authors highlighted that the preventive effect of pioglitazone was driven mainly by participants with increased risk of diabetes progression, such as those with metabolic syndrome, impaired FPG, increased HbA1c, and worse insulin resistance at baseline.  However, they added, “The absence of a statistically significant interaction between baseline FPG or baseline HbA1c and treatment effect does suggest that pioglitazone may prevent not only the conversion of prediabetes to diabetes, but also the development of diabetes in normoglycemic individuals who have insulin resistance. The absolute risk reduction in the latter category is, however, small.”

The results of the study could not evaluate whether pioglitazone has long-term effects on diabetes prevention or if its effects are temporary.

The authors concluded that, “Pioglitazone is the first pharmacological agent demonstrated in a single trial to both prevent diabetes and improve cardiovascular outcomes in patients at increased risk for these sequelae. More broadly, the results lend support to the notion that diabetes prevention through insulin sensitization could potentially be associated with important cardiovascular benefits.”

Practice Pearls:

  • Results from the Insulin Resistance after Stroke (IRIS) trial suggest that pioglitazone may be the first anti-diabetes agent to prevent diabetes progression and improve cardiovascular outcomes in patients with insulin resistance and recent stroke or TIA.
  • Past results from IRIS suggest pioglitazone is associated with 24% decreased risk for stroke or myocardial infarction compared to placebo.
  • Pioglitazone decreased the risk of diabetes progression by 52% compared to placebo.
  • The preventive effect of pioglitazone was driven mainly by participants with increased risk of diabetes progression, such as those with metabolic syndrome, impaired FPG, increased HbA1c, and worse insulin resistance at baseline.

References:

Inzucchi SE, et al. Pioglitazone prevents diabetes in insulin-resistant patients with cerebrovascular disease. Diabetes Care. 2016 Jul 27.

Kernan WN, et al; IRIS Trial Investigators. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. 2016;374:1321-1331.

Stroke (IRIS) trial published online in Diabetes Care.