TZD use was not associated with the presence of clinically significant or any DME among ACCORD participants at baseline. The ACCORD Eye Substudy provided an opportunity to examine the relationship in a large sample with a comparable untreated group in whom retinopathy, including DME, was graded in a standardized fashion by a centralized reading center. Visual acuities were also collected in all patients using a common protocol. The analyses enabled adjustment for multiple potential confounding variables collected in a standardized protocol.
These findings are reassuring in that they do not support the concern from case reports of DME with TZD use. However there are limitations to this analysis. Perhaps longer-term exposure to a TZD is necessary for risk to develop; we only know that participants had TZD exposure for at least 3 months. It is also possible that there is an idiosyncratic association between TZD use and DME that occurs rarely. As others have previously reported, we observed relationships between HbA1c (9
), retinopathy (9
), and age (9
) with DME. We were unable to confirm previous reports of associations of DME with diabetes duration (9
), gender (9
), and race/ethnic category (10
), perhaps because participants with previous laser photocoagulation, representing the most severe end of the retinopathy scale, were excluded from the Eye Substudy. Additionally, ACCORD was restricted to people with fairly advanced diabetes and many had a fairly long duration of diabetes at randomization, thus we may not have the ability to detect an association with diabetes duration.
Adverse associations were found between DME and elevated cholesterol and non-smoking status and beneficial associations were found between DME and greater albumin/creatinine ratio and triglycerides. Others have reported an association between DME and both triglycerides and cholesterol (16
). We believe that the adverse relationship between DME and triglycerides seen in this study may be due to the high collinearity between cholesterol and triglycerides. The biological plausibility of current and former smokers having lower prevalence of DME is unclear and is perhaps due to chance or the inclusion process for ACCORD although the results are consistent with the unadjusted analysis (data not shown). However, a previous study (41
) showed an association between high-risk PDR and smoking, which is contrary to the results for DME in this study.
There was evidence of a positive association (0.79 letters) between TZD exposure and visual acuity. We do not know whether this finding is clinically significant.
The ACCORD Eye study exclusion criteria of previous laser photocoagulation or vitrectomy for diabetic retinopathy may have limited our analysis as laser is also a therapy for DME. It is possible that some ACCORD participants with laser-treated DME would have been excluded from the ACCORD-Eye study resulting in decreased power to detect an association. Unfortunately, no data on DME were collected in these participants. The possibility of recent prior exposure to TZD in some patients in the control group could potentially weaken any differences between groups cannot be excluded, but seems unlikely, because that exposure, if any, should have ended at least 3 months prior to baseline. However, there was no association observed between concurrent TZD exposure and any type of eye surgery including retinal laser photocoagulation and vitrectomy at baseline (data not shown).
The cross-sectional analysis presented here is likely to be less informative than an examination of incident macular edema which will be possible at the end of ACCORD, at which point the dose and duration of TZD exposure during the period between baseline and follow-up photographs can be examined. Other additional covariates could include post-baseline values of HbA1c, fasting plasma glucose, and exposure to insulin, diuretics, calcium channel blockers, oral steroids, niacin and nicotinic acid, and NSAIDs. The current analysis also does not take into account duration of exposure, past exposure, or type of TZD (rosiglitazone or pioglitazone), which could be important causal considerations.
Many recent clinical trials of DME have employed optical coherence tomography (OCT) measured central retinal thickness as an endpoint, which was not employed in this study. Historically, DME measured from stereoscopic fundus photographs has been well accepted as a clinical endpoint and is moderately correlated with OCT measurements (42
); therefore results would not likely have been different using OCT.