IRIS Trial Examines CV and Diabetes Risks

A pre-specified secondary analysis of data from the Insulin Resistance Intervention after Stroke trial (IRIS) examined pioglitazone’s effect on diabetes prevention. Study participants were non-diabetic stroke patients with insulin resistance, including many people with pre-diabetes (about 64%).

The primary results from IRIS found that the thiazolidinedione drug reduced the risk of fatal and non-fatal stroke and myocardial infarction by 24% in people with cerebrovascular disease, essentially a major adverse cardiovascular events (MACE) composite outcome.¹ “Just to put this in context, this effect in stroke patients is actually larger than had been published with aspirin therapy, which is considered the routine therapy in patients with stroke,” stated Silvio E. Inzucchi, MD, Director of the Yale Diabetes Center and lead author of the study.

The trial included 3876 people who recently had a stroke or heart attack and insulin resistance (Homeostasis Model Assessment of Insulin Resistance [HOMA-IR] >3.0) but not diabetes (no prior history and fasting plasma glucose [FPG] of <126 mg/dl). Participants were randomly assigned to 45 mg of pioglitazone daily (n=1939) or placebo (n=1937). At baseline patients had a mean fasting plasma glucose level of 98.2 mg/dl, A1c of 5.8%, and HOMA-IR score of 5.4. All participants were assessed annually through interviews and FPG testing.

Overall, pioglitazone reduced progression to diabetes by 52%. At one year, mean HOMA-IR decreased to 4.1 in the pioglitazone group and increased to 5.7 in the control group (P<0.0001). After 4.8 years of follow up, 3.8% (n=73) of the pioglitazone group developed type 2 diabetes and 7.7% (n=149) of the placebo group developed the disease (HR 0.48; 95% CI 0.33, 0.69; P<0.0001). Patients with pre-diabetes (FPG≥100 mg/dl or A1c≥5.7%) and those who had the worst insulin resistance (HOMA-IR≥4.6) experienced the greatest risk reduction. The absolute risk reduction in the two groups was 8.5%, compared to 0.8% in those with FPG <100 mg/dl; and 5.6%, in those compared to 1% for those with A1c<5.7%; and 6.3%, compared to 1.4% in those with HOMA-IR less than 4.6.

Pioglitazone is the only oral glucose lowering drug to reduce atherosclerotic events and to prevent diabetes and improve cardiovascular outcomes in the same trial. “Those two events are not necessarily linked, but one of the holy grails in terms of diabetes prevention is to try to find strategies that will be demonstrated not only to reduce the biochemical diagnosis of diabetes but also the cardiovascular complications that are so common in diabetes…I think it was more likely the drug acting on arthrosclerosis itself that also happened to be preventing diabetes.”

“Usually the way we look at it is that if you reduce diabetes you will reduce cardiovascular disease because these risk factors occur in a cluster. For example, the DPP certainly showed that you will get a reduction in blood pressure as well as weight and to some degree lipids, and prevent type 2 diabetes. It’s just the fact that these really occur as a cluster, and on one hand that's good because by nicking at some of these interventions you’re actually impacting a number of risk factors and we like to be able to get that bang for the buck, if you will. There’s a lot of benefit to participating in these interventions beyond just preventing diabetes,” added moderator Ann Albright, PhD, RD, Centers for Disease Control and Prevention.

1. Kernan WN, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. 2016;37:1321-1331.