The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye Substudy recruitment flowchart. The ACCORD Eye Substudy began recruitment after initiation of the main trial.
Ambrosius WT, Danis RP, Goff DC, Greven CM, Gerstein HC, Cohen RM, Riddle MC, Miller ME, Buse JB, Bonds DE, Peterson KA, Rosenberg YD, Perdue LH, Esser BA, Seaquist LA, Felicetta JV, Chew EY. Lack of Association Between Thiazolidinediones and Macular Edema in Type 2 DiabetesThe ACCORD Eye Substudy. Arch Ophthalmol. 2010;128(3):312-318. doi:10.1001/archophthalmol.2009.310
Copyright 2010 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.2010
To assess the cross-sectional association of thiazolidinediones with diabetic macular edema (DME).
The cross-sectional association of DME and visual acuity with thiazolidinediones was examined by means of baseline fundus photographs and visual acuity measurements from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Visual acuity was assessed in 9690 participants in the ACCORD trial, and 3473 of these participants had fundus photographs that were centrally read in a standardized fashion by masked graders to assess DME and retinopathy from October 23, 2003, to March 10, 2006.
Among the subsample, 695 (20.0%) people had used thiazolidinediones, whereas 217 (6.2%) people had DME. Thiazolidinedione use was not associated with DME in unadjusted (odds ratio [OR], 1.01; 95% confidence interval [CI], 0.71-1.44; P = .95) and adjusted (OR, 0.97; 95% CI, 0.67-1.40; P = .86) analyses. Significant associations with DME were found for retinopathy severity (P < .001) and age (OR, 0.97; 95% CI, 0.952-0.997; P = .03) but not for hemoglobin A1c (P = .06), duration of diabetes (P = .65), sex (P = .72), and ethnicity (P = .20). Thiazolidinedione use was associated with slightly greater visual acuity (0.79 letter; 95% CI, 0.20-1.38; P = .009) of uncertain clinical significance.
In a cross-sectional analysis of data from the largest study to date, no association was observed between thiazolidinedione exposure and DME in patients with type 2 diabetes; however, we cannot exclude a modest protective or harmful association.
clinicaltrials.gov Identifier: NCT00542178
Diabetic macular edema (DME) is one of the main causes of visual impairment in persons with diabetic retinopathy. A small number of case reports have raised the possibility that use of thiazolidinediones, which can cause fluid retention, generally, might exacerbate DME.1,2 These observations led to physician alerts or label changes by manufacturers in Canada and the United States.3- 6 One report1 described a patient who developed vision loss and DME after an increase in the dosage of rosiglitazone maleate from 2 to 8 mg/d. After the dosage was reverted to 2 mg/d, the vision of the patient improved and his DME resolved itself. Ryan et al2 reported results from a retrospective medical record review of 30 patients who sought care at a single practice of retinal specialists with use of pioglitazone hydrochloride or rosiglitazone and both lower-extremity edema and DME. The authors contended that fluid overload owing to use of thiazolidinediones contributed to DME in at least 19 of 30 patients and that, in 2 patients, there was evidence of a direct cause-and-effect relationship. Finally, a case report7 of macular edema being resolved with systemic furosemide suggests that thiazolidinediones may exacerbate macular edema. In a larger study of 292 patients, Shen et al8 found no association of rosiglitazone with DME.
These reports are limited by the absence of comparison groups of patients who have not been exposed to thiazolidinediones and cannot control for confounding between thiazolidinedione exposure and other risk factors for DME, such as sex,9 age,9 ethnicity,10 long-standing diabetes,9,11 insulin use,12 increased severity of diabetic retinopathy,9,11 elevated serum cholesterol level,13- 16 hypertension,9 and poor glycemic control.9,11
Interest in this issue has been heightened by broader concerns about the safety of the currently available thiazolidinediones, pioglitazone and rosiglitazone. The PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) Study,17 which tested the hypothesis that pioglitazone can reduce cardiovascular risk, showed not only benefit in an important secondary cardiovascular end point but also significant increases of both peripheral edema and congestive heart failure. A meta-analysis18 of trials of pioglitazone suggested reductions of cardiovascular death, myocardial infarction, and stroke but also increased risk of congestive heart failure. Rosiglitazone has been associated in another meta-analysis19 with greater risk for myocardial infarction (odds ratio [OR], 1.43; P = .03) and death (OR, 1.64; P = .06). An unplanned interim analysis by the Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycaemia in Diabetes (RECORD) Study investigators followed,20 which yielded an estimated hazard ratio for the cardiovascular end point of 1.11 (95% confidence interval [CI], 0.93-1.32). A series of editorials21- 25 ensued. The Food and Drug Administration now requires that the package label for pioglitazone include a black-box warning about risk of congestive heart failure and that the package label for rosiglitazone include a similar warning about the risk of congestive heart failure or myocardial ischemia.26
The Eye Substudy of the Action to Control Cardiovascular Risk in Diabetes (ACCORD)27 trial was designed to test the effect of the ACCORD interventions (strategies to control blood glucose levels, blood lipid levels, and blood pressure) on the development and progression of diabetic retinopathy. This study provides us with the opportunity to evaluate the potential association of thiazolidinediones with DME. In addition, we report the relationship between thiazolidinedione use and visual acuity, which is assessed in all participants enrolled in the ACCORD study.
The ACCORD study28,29 and the ACCORD Eye Substudy have been described previously. In brief, ACCORD is a multicenter, randomized, controlled, double, 2 × 2 factorial trial with 10 251 patients with type 2 diabetes. The trial was designed to test the effects of intensive glycemia control, treatment to increase high-density lipoprotein cholesterol levels and lower levels of triglycerides, and intensive blood pressure control on major cardiovascular disease. Visual acuity was assessed at baseline in 9690 people by means of a standardized Early Treatment Diabetic Retinopathy Study (ETDRS) logarithmic chart.30
The ACCORD Eye Substudy recruited 3537 participants in whom baseline stereoscopic retinal photographs of 7 standard fields were obtained and ophthalmologic examinations were performed between October 23, 2003, and March 10, 2006. Participants were eligible to enroll in the ACCORD Eye Substudy if they had not undergone laser photocoagulation or vitrectomy for diabetic retinopathy in either eye. A summary of recruitment of ACCORD participants into the ACCORD Eye Substudy is shown in the Figure. Masked evaluators (including B.A.E.) at the Fundus Photograph Reading Center (University of Wisconsin, Madison) graded all photographs for the severity of diabetic retinopathy and the presence of DME. The severity of diabetic retinopathy was graded by means of the ETDRS letter scale31 and categorized into the following 5 levels using the International Clinical Diabetic Retinopathy Severity scale: none, mild, moderate nonproliferative, severe nonproliferative, and proliferative.32 We scored DME separately for each eye on a scale of 0 through 3: 0, none; 1, questionable; 2, zone of retinal thickness 1 disc area or greater and within 1 disc diameter or less from the center of the macula; and 3, retinal thickness or adjacent hard exudates within 500 μm of the center of the macula. This scale was collapsed into absence (0) or presence (1-3) of DME. Those eyes graded as levels 2 or 3 would be considered to have clinically significant macular edema (CSME) because the center of the fovea is involved or threatened.33
Thiazolidinedione use was assessed on the basis of self-report at the baseline examination and included current use of rosiglitazone or pioglitazone on a regular basis. The duration of thiazolidinedione exposure before baseline is not known, but the ACCORD inclusion criteria required that no new antihyperglycemic drugs were added within 3 months of baseline.
Ethnicity was categorized into nonexclusive categories of white, African American/African Canadian, and Hispanic. Other therapy for diabetes, a surrogate for severity, was measured by the number of types of diabetes medications used at baseline, with the exclusion of thiazolidinediones and insulin. These medications included (1) sulfonylureas, (2) α-glucosidase inhibitors, (3) biguanides, and (4) meglitinides. The number of medications ranged from 0 through 4 and was treated as a categorical variable. Insulin and diuretic use at baseline were recorded. Mean arterial pressure was calculated as [Systolic + (2 × Diastolic)]/3.
Pretibial edema in either foot was assessed at the time of clinical examination. A history of foot ulcer that required antibiotics or presence of ulceration on either foot by examination was documented. Foot amputation secondary to diabetes was assessed by examination.
All analyses were prespecified before analysis began. Descriptive statistics were calculated, with the inclusion of proportions for categorical variables and means, medians, standard deviations, and ranges for continuous variables. Comparisons of proportions between 2 groups were made by means of a χ2 test. Almost all participants had measurements performed for both eyes. To account for the within-participant correlation and thus to use data from both eyes, our primary model was a generalized estimating equation model34,35 that predicted DME, with thiazolidinedione use at baseline as a predictor. The ORs, P values, and 95% CIs are reported. P values were calculated using generalized score statistics, and the CIs presented are Wald intervals. Six factors known to be associated with DME were included as covariates: hemoglobin A1c (HbA1c) level,9,11 diabetes duration,9,11 retinopathy severity,9,11 sex,9 age,9 and ethnicity.10 In a secondary analysis, a modified version of the model selection approach presented by Hosmer and Lemeshow36 was used to examine other potential covariates (Table 1 and Table 2). Included in all models were thiazolidinedione use at baseline, sex, ethnicity, diabetes duration, age, HbA1c level, and retinopathy. All other variables were examined for possible inclusion by means of the variable selection method described herein. Three interactions of thiazolidinedione use were specified a priori and were examined in order: thiazolidinedione use with diabetes duration, insulin use (only if insulin was in the model as a main effect), and HbA1c level. We screened potential covariates at P ≤ .25 in a series of unadjusted models and compared patients who used thiazolidinedione with those who did not. These variables and those in the primary model were included, and backward selection (P > .10) was used to delete variables from this model. Linearity was examined by means of generalized additive models37,38 and by categorization of the covariates at their quartiles. Interactions were examined at P ≤ .05. Model adequacy was examined via the techniques of Lin et al39,40 to assess linearity and adequacy of the logit link. We examined 2 additional sets of generalized estimating equation models: one for moderate or severe CSME (defined as scores of 2 or 3) and another for severe CSME (defined as a score of 3). The relationship of baseline visual acuity with thiazolidinedione exposure was analyzed with a mixed model of covariance with HbA1c level, diabetes duration, sex, and age. A random effect for individual was used to account for within-person correlation.
Table 1 gives the baseline characteristics of the 3473 participants included in the primary analysis. No adjustment for multiple testing was made. These results are presented as guides to potential relationships. A difference in pretibial edema prevalence was observed by exposure to thiazolidinediones (P < .001). Eye-specific prevalence of DME and retinopathy on the 6875 eyes included in the primary analysis are presented by thiazolidinedione exposure in Table 2. All subsequent results use both eyes in statistical models accounting for correlation.
The analyses are summarized in Table 3. In the unadjusted analysis, thiazolidinedione was not associated with DME. The primary analysis provided consistent results. Retinopathy and age were associated with, and HbA1c level marginally associated with, DME. There was evidence that the relationship of HbA1c level to DME was nonlinear, but this evidence had no effect on the estimated effect of thiazolidinedione (data not shown). After the variable selection procedure described herein for the secondary analysis, 4 additional variables were added to the primary model: the logarithm of triglyceride level, cholesterol level, the logarithm of the albumin-creatinine ratio, and smoking status. There was no association between thiazolidinedione use and DME. Those who formerly and currently smoked had lower prevalence of DME than did those who never smoked (with smoking status determined by self-report). Interestingly, the association of HbA1c level with DME was attenuated from the primary (OR, 1.15; P = .06) to the secondary model (OR, 1.08; P = .29), perhaps because of confounding by other variables. As in the primary analysis, there was evidence that the relationship between HbA1c level and DME was nonlinear (data not shown). When we fit the HbA1c level as a 4-level category, the estimated association between thiazolidinedione use and DME was essentially unchanged (data not shown). When the primary and unadjusted models were refit by the use of only the data available for the secondary model, the results were substantially unchanged (data not shown). The examination of outcomes other than any DME (ie, moderate-severe or severe) did not substantially change the results in any model (data not shown).
In the adjusted analysis, thiazolidinedione use was associated with marginally better visual acuity (0.79 letter; 95% CI for the difference in means, 0.20-1.38; P = .009) in 9690 participants (19 239 eyes). That is, those who used thiazolidinediones before baseline had, on average, visual acuity scores less than 1 letter (0.79) better on the 0 to 100 scale. Diabetes duration (β = −0.18 per year; 95% CI, −0.21 to −0.15; P < .001), HbA1c level (β = −0.85 per 1%; 95% CI, −1.08 to −0.63; P < .001), female sex (β = −2.66; 95% CI, −3.14 to −2.18; P < .001), and age (β = −0.28 per year; 95% CI, −0.32 to −0.25; P < .001) were all inversely associated with visual acuity. That is, a 10-year-longer diabetes duration is associated with a worse visual acuity by 1.8 ETDRS letters. Similarly, a 10-year-older age is associated with worse acuity by 2.8 letters. A 1% higher HbA1c level (>7.5%, the lower inclusion limit) is associated with a worse acuity by 0.85 letter. That is, a 2% greater HbA1c level is approximately equivalent to a 10-year-older age (1.9 vs 1.8 letters). Thiazolidinedione use is approximately equivalent to a 3-year-younger age (0.79 vs 0.84). In an unadjusted model in 9795 participants (19 446 eyes), the association between visual acuity and use of thiazolidinedione was similar (0.90 letter; 95% CI, 0.30-1.51; P = .004).
Thiazolidinedione use was not associated with the presence of CSME 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, with the inclusion of DME, was graded in a standardized fashion by a centralized reading center. Visual acuities were also measured in all patients by means of a common protocol. The analyses enabled adjustment for information with regard to multiple potential confounding variables collected in a standardized protocol.
These findings are reassuring in that they do not support concern based on the case reports of DME associated with thiazolidinedione use. However, this analysis has limitations. Perhaps longer-term exposure to a thiazolidinedione is necessary for risk to develop; we only know that participants had thiazolidinedione exposure for at least 3 months. It is also possible that there is an idiosyncratic association between thiazolidinedione use and DME that occurs rarely. As others9,11 have previously reported, we observed relationships between DME and each of the following: HbA1c level, retinopathy, and age. We were unable to confirm previous reports of associations of DME with diabetes duration,9,11 sex,9 and ethnic category,10 perhaps because participants who had undergone previous laser photocoagulation, which represents the most severe end of the retinopathy scale, were excluded from the ACCORD Eye Substudy. In addition, participation in the ACCORD trial was restricted to people with fairly advanced diabetes, many of whom 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 level and nonsmoking status, and beneficial associations were found between DME and greater albumin-creatinine ratio and a higher level of triglycerides. Others16 have reported an association between DME and both triglyceride and cholesterol levels.We believe the adverse relationship between DME and triglyceride levels seen in this study may be owing to the high collinearity between cholesterol and triglyceride levels. The biological plausibility that those who currently and had formerly smoked would have a lower prevalence of DME is unclear and is perhaps attributable to chance or the inclusion process for the ACCORD Study, although the results are consistent with the unadjusted analysis (data not shown). However, a previous study41 showed an association between high-risk proliferative diabetic retinopathy and smoking, a result that is contrary to those for DME in this study. There was evidence of a positive association (0.79 letter) between thiazolidinedione exposure and visual acuity. We do not know whether this finding is clinically significant.
The exclusion criteria of the ACCORD Eye Substudy of previous laser photocoagulation or vitrectomy for diabetic retinopathy may have limited our analysis because laser photocoagulation is also a type of therapy for DME. It is possible that some ACCORD participants with laser-treated DME would have been excluded from the ACCORD Eye Substudy, which would result in decreased power to detect an association. Unfortunately, no data with regard to DME were collected in these participants. The possibility that recent prior exposure to thiazolidinedione 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 before baseline. However, no association was observed between concurrent thiazolidinedione exposure and any type of eye surgery, with the inclusion of retinal laser photocoagulation and vitrectomy at baseline (data not shown).
The cross-sectional analysis presented herein 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 thiazolidinedione exposure during the period between baseline and follow-up photographs can be examined. Other additional covariates could include postbaseline values of HbA1c and fasting plasma glucose levels and exposure to insulin, diuretics, calcium channel blockers, oral steroids, niacin and nicotinic acid, and nonsteroidal anti-inflammatory drugs. The current analysis also does not take into account duration of exposure, past exposure, or type of thiazolidinedione (rosiglitazone or pioglitazone), which could be important causal considerations.
Many recent clinical trials of DME have used optical coherence tomography–measured central retinal thickness as an end point, which was not used in this study. Historically, DME measured from stereoscopic fundus photographs has been well accepted as a clinical end point and is moderately correlated with optical coherence tomography measurements;42 therefore, results would not likely have been different with the use of optical coherence tomography.
In conclusion, no association between recent thiazolidinedione exposure and DME was observed in the baseline population of the ACCORD Eye Substudy. Because of the size of the CI of the OR (0.67-1.40) and the uncertain duration of exposure, we cannot rule out the possibility of either a modest protective or deleterious association of thiazolidinedione exposure with DME. A more definitive answer may be provided from the 4-year follow-up data, which will enable us to examine prospectively the relationship between thiazolidinedione exposure and DME incidence.
Correspondence: Walter T. Ambrosius, PhD, Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC 27157 (email@example.com).
Submitted for Publication: November 4, 2008; final revision received April 13, 2009; accepted April 13, 2009.
Financial Disclosure: Dr Gerstein has received honoraria for providing advice and for speaking on the topic of thiazolidinediones and rosiglitazone maleate (Avandia) from GlaxoSmithKline. He has also received research grants from this company for independent research related to this drug. Since 2005, the University of North Carolina School of Medicine, Chapel Hill, has contracted with a variety of companies, including GlaxoSmithKline, Hoffman–La Roche Inc, InteKrin Therapeutics Inc, and Merck & Co Inc, for Dr Buse's services as an investigator or consultant with regard to thiazolidinediones and related compounds. Dr Goff has received research funding from Merck and Co, Inc. for a trial that involved the glucose-lowering medication sitagliptin (Januvia).
Funding/Support: This study was funded by the National Eye Institute and the National Heart, Lung, and Blood Institute of the National Institutes of Health.
Group Information: A list of the ACCORD Study Group investigators was published in AM J Cardiol. 2007;99(12)(suppl):S4-S20.