Effects of Pioglitazone on CV Outcome, Diabetes

Pioglitazone may be the first anti-diabetes medication shown to prevent both diabetes progression and major cardiovascular events, according to results from the Insulin Resistance after Stroke (IRIS) trial published online in Diabetes Care.¹

“In this clinical trial of nondiabetic, insulin-resistant patients with ischemic stroke or transient ischemic attack (TIA) during a median follow-up of 4.8 years, therapy with pioglitazone reduced the risk of diabetes by 52%,” wrote first author Silvio Inzucchi, MD, of the Yale School of Medicine, and colleagues.

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.²

The study included 3876 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. The trial was conducted at 179 sites in Australia, Canada, Germany, Israel, Italy, the UK, and the US between February 2005 and January 2013.

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. 

Key Results:

• At one year:

♦ 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 study could not evaluate whether pioglitazone has long-term effects on diabetes prevention, or whether its effects are temporary.

“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, our results lend support to the notion that diabetes prevention through insulin sensitization could potentially be associated with important cardiovascular benefits,” the authors concluded.

Take-home Points

• 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.

The IRIS study was funded by the US National Institute for Neurological Disorders and Stroke (NINDS) of the National Institutes of Health. Takeda Pharmaceuticals International, Inc, provided pioglitzone and matching placebo. One or more authors reports consulting, steering, advisory or other committee membership, research grant support, stock ownership, and/or expert consultant/witness for one or more of the following: AstraZeneca, Boehringer Ingelheim, Daichii Sankyo, Janssen, Lexicon, Merck, Poxel, Sanofi, Novo Nordisk, Intarcia, Takeda, Mifcor, Amgen, Janssen, Perle Bioscience, Response Scientific, Dance Pharma, Adams and Reese, LLP, Covance. Thermali Diabetes. R.E.P., Lexicon, Eli Lilly, Merck, Takeda, GlaxoSmithKline, Hanni, Janssen, Ligand, Cerenis, Roche, Resverlogix, The Medicines Company.

References:

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

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