Possible link between thiazolidinediones, macular edema

Patients with type 2 diabetes who are treated with a thiazolidinedione may have an increased risk for diabetic macular edema, according to a recent study.

To evaluate whether an association existed between thiazolidinediones and development of diabetic macular edema, researchers performed a retrospective cohort study of U.K. patients who had type 2 diabetes but no macular edema at baseline. Data from Jan. 1, 2000 through Nov. 30, 2009 on patients' clinical, biochemical and demographic characteristics were obtained from The Health Improvement Network (THIN) database, which includes anonymous information from some general practices in the United Kingdom. One- and 10-year outcomes were analyzed. The study results were published online June 11 by Archives of Internal Medicine.

A total of 103,368 patients were included in the study. Overall, 3,227 took thiazolidinediones and 100,141 did not. At one year, 1.3% of the thiazolidinedione users had developed diabetic macular edema compared with 0.2% of nonusers (odds ratio, 5.7; 95% CI, 4.1 to 7.9). After Cox multiple regression analysis, multiple imputation analysis and propensity score analysis, thiazolidinedione use was found to be associated with higher risk for diabetic macular edema after one year (odds ratio, 2.3; 95% CI, 1.5 to 3.6) and after 10 years (hazard ratio, 2.3; 95% CI, 1.7 to 3.0). Insulin plus a thiazolidinedione also appeared to be associated with increased risk (hazard ratio, 3.0; 95% CI, 1.5 to 5.9), while aspirin (hazard ratio, 0.6; 95% CI, 0.4 to 0.9) and angiotensin-converting enzyme inhibitors (hazard ratio, 0.4; 95% CI, 0.2 to 0.7) each appeared to be associated with decreased risk.

The authors stressed that they did not have information about patients' diabetes duration or individual exposure to thiazolidinediones. However, they concluded that risk for diabetic macular edema appears to be higher in patients taking a thiazolidinedione, particularly those who are also receiving insulin. They called for additional larger trials to more accurately determine the risks and benefits of thiazolidinediones in patients with type 2 diabetes who have or are at risk for diabetic macular edema.

An invited commentary pointed out additional study limitations that would make definitive conclusions difficult. The study authors did not consider whether between-group differences could have been due to diabetes severity, since thiazolidinediones are usually second-line drugs, and did not control for risk factors that would have been affected by thiazolidinedione therapy. In addition, the commentary authors noted, some patients may have been misclassified.

“[W]e can neither be certain that thiazolidinediones cause macular edema nor be reassured that such a risk does not exist,” the commentary authors wrote. “Future studies using new-user incipient cohort designs with validated exposure and outcome definitions and appropriate adjustment for diabetes severity may provide additional information on this potential association.”

In the meantime, they wrote, physicians should base therapy on individual risk-benefit profiles and should follow current drug labeling, promptly evaluating patients on thiazolidinediones for possible diabetic macular edema if visual symptoms are reported.