Thiazolidinedione drugs (TZDs) such as pioglitazone have been used to improve insulin sensitivity and glycemic control in patients with type 2 diabetes mellitus (DM), and now pioglitazone (Actos) has been shown to reduce the risk of developing DM in patients with insulin resistance who had a previous ischemic stroke or transient ischemic attack (TIA), according to findings published in Diabetes Care. Treatment with pioglitazone decreased the risk of developing diabetes by 52% in these patients as compared to placebo.1
“Our data extend the diabetes prevention effects of pioglitazone to patients at high cardiovascular risk,” said the lead author, Silvio Inzucchi, MD, director of the Yale Diabetes Center at the Yale University School of Medicine in New Haven, Connecticut. “It also demonstrates that even if just insulin resistance is present without prediabetes, pioglitazone has a benefit, although the event rates are much lower even in the control group.”
It is important to prevent diabetes from developing in patients with insulin resistance or prediabetes, in part, because patients who have diabetes are at 1.5 fold higher risk for having a stroke, according to data from the American Diabetes Association. Pioglitazone appears effective in preventing progression to diabetes in these high-risk patients.1 Previous trials have not included patients with cerebrovascular disease, so this study is the first to show that pioglitazone is able to prevent progression to diabetes in a population at risk for future cardiovascular events.
These results build on previous studies showing that TZDs prevent diabetes in patients with insulin resistance2,3 by demonstrating a protective effect in patients with cerebrovascular disease,1 as well.
“Pioglitazone is now the only oral diabetes medication to demonstrate a clear preventative effect on cardiovascular events as well as diabetes,” said Dr. Inzucchi. “This drug should be considered for high-risk patients who do not have contraindications such as heart failure.”
Based on the study design, IRIS did not complete glycemic assessments after the conclusion of treatment, so it is not possible to infer whether the effect of pioglitazone to prevent the development of diabetes is temporary or sustained.1,2 Also, adherence to the pioglitazone regimen by study patients was relatively low--76% of patients were still taking the drug after 1 year but only 60% remained on the medication at the final consultation.1 The authors attribute this attrition to the side effect profile of pioglitazone, especially edema and weight gain, as well as safety concerns.
“[The IRIS] study really is the first to associate a TZD with benefit for cardiovascular events, at least in those with insulin resistance but not diabetes, and at higher risk of developing diabetes,” said Caroline Apovian, MD, a professor of medicine and pediatrics at Boston University School of Medicine in Boston, Massachusetts, who was not involved in the study but commented as a member of the EndocrineWeb editorial board. “Pioglitazone also was associated with a lower risk of diabetes progression compared to placebo, something that has been found with other TZDs as well as metformin.”
“These findings show that, if used early in the onset of disease, perhaps pioglitazone can actually be protective against development of diabetes and cardiovascular events,” said Dr. Apovian. She noted that several questions remain including, “Why does rosiglitazone associate with cardiovascular risk [while] pioglitazone the opposite? Pioglitazone like other TZDs has been shown to cause edema and weight gain,” side effects that are risk factors for cardiovascular disease.
This study used data obtained in the Insulin Resistance Intervention after Stroke IRIS trial.1,2 A total of 3,876 patients with insulin resistance, but not diabetes, and incident ischemic stroke or TIA in the previous 6 months were randomized to receive pioglitazone or placebo then monitored for the development of diabetes.1 Thresholds used to select patients with insulin resistance without diabetes were fasting blood glucose (FBG) <126 mg/dL and homeostasis model assessment of insulin resistance (HOMA-IR) scores >3.0. The median follow-up was 4.8 years.
The aim of this analysis was to determine the effects of pioglitazone on metabolic measures and the secondary trial outcome of diabetes prevention. Previously published results from the IRIS trial showed that pioglitazone decreased the risk of subsequent stroke or myocardial infarction in this population at high risk for cardiovascular events.2
During the follow-up period, the rate of developing diabetes was 3.8% (73) of patients in the pioglitazone treatment group as compared with 7.7% (149) of the placebo group (hazard ratio [HR] 0.48; P <.0001). The greatest effect was observed in patients with initial FPG >100 mg/dL (HR 0.41) or Hemaglobin A1c >5.7% (HR 0.46).
1. Inzucchi SE, Viscoli CM, Young LH. Pioglitazone Prevents Diabetes in Patients With Insulin Resistance and Cerebrovascular Disease. Diabetes Care. 2016;39(10): 1684-1692.
2. Kernan WN, Viscoli CM, Furie KL, et al for the IRIS Trial Investigators. Pioglitazone after Ischemic Stroke or Transient Ischemic Attack. N Engl J Med. 2016; 374:1321-1331.
3. Kendall DM. Thiazolidinediones. Diabetes Care. 2006;29(1):154-157.