October 01, 2013

BARCELONA, Spain — Treating type 2 diabetic patients with pioglitazone significantly increases the risk for macular edema, according to the results of a new Japanese study. For those who received the thiazolidinedione, the risk for macular edema was 5 times greater than in those who did not receive pioglitazone.

In addition, combining pioglitazone with insulin was associated with an even greater risk for macular edema, with patients having a more than 11-fold increased risk compared with diabetic patients who did not receive the 2 drugs.

The results, presented here last week at the European Association for the Study of Diabetes (EASD) 2013 Meeting, are from a retrospective cohort analysis of patients with type 2 diabetes and no history of macular edema treated at a single center in Osaka, Japan.

The study was led by Kanta Fujimoto, MD, from the Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan. Presenting the results at the EASD meeting, Fujimoto said several studies have highlighted the adverse effects of pioglitazone, particularly several analyses that have suggested an increased risk for bladder cancer with the drug. Other studies have suggested pioglitazone causes fluid retention, and this can increase the risk for macular edema, said Fujimoto.

These studies, however, have been limited by missing data, particularly information about confounding variables, such as the presence/absence of renal and heart failure. Both renal and heart failure are often associated with diabetic macular edema, he said.

Between 2000 and 2012, there were 22,115 patients with type 2 diabetes treated at Kitano Hospital. Of these, 953 were treated with pioglitazone. The pioglitazone-treated patients were sicker than those not treated with pioglitazone and were significantly more likely to be treated with insulin, have renal failure, have congestive heart failure, be treated with ACE inhibitors and antiplatelet medications, and have higher HbA1c levels.

In the entire cohort, there were 99 new cases of diabetic macular edema, a prevalence of 0.45%. For those treated with pioglitazone, 11 patients developed macular edema, for a prevalence of 1.15%. After adjustment for confounding variables, the hazard ratio for macular edema at 2 years was 5.28 (95% confidence interval [CI], 1.55–17.92) and 5.06 (95% CI, 2.59–9.91) at 12 years.

For those who received insulin and pioglitazone, the 12-year adjusted hazard ratio for macular edema was 11.86 (95% CI, 4.70–29.93) when compared with patients not treated with pioglitazone or insulin.

Not surprisingly, Fujimoto called for further large-scale studies to address this particular safety signal in type 2 diabetic patients treated with the thiazolidinedione. During the question-and-answer session at the EASD meeting, one criticism raised about the analysis was the lack of adjustment in the model for body mass index (BMI). Patients treated with pioglitazone have typically failed to lower HbA1c levels with metformin and tend to be obese and have more insulin resistance. Fujimoto agreed with the criticism, telling the audience the data on BMI simply weren't available.

Dr. Fujimoto has reported no relevant financial relationships.


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