DIABETIC MACULAR EDEMA

ASSOCIATED WITH GLITAZONE USE

EDWIN H. RYAN JR, MD,* DENNIS P. HAN, MD,†
ROBERT C. RAMSAY, MD,* HERBERT L. CANTRILL, MD,*
STEVEN R. BENNETT, MD,* SUNDEEP DEV, MD,*
DAVID F. WILLIAMS, MD*

Purpose: To describe diabetic macular edema (DME) in patients who developed fluid
retention as a consequence of glitazone use.
Methods: A chart review identified 30 patients who used pioglitazone or rosiglitazone
and had both lower extremity edema and macular edema. Clinical reports, photographs,
and fluorescein angiograms were reviewed. Patients followed for ⬎3 months were ana-
lyzed separately.
Results: Seventeen patients took oral pioglitazone, 11 took rosiglitazone, and 2 took
both drugs at different times. Eleven patients were observed for ⬎3 months after cessation
of glitazones. Mean weight gain during drug administration in this group was 30 lb, and
mean weight loss after drug discontinuation was 19 lb. Rapid reduction in macular edema
off drug occurred in only 4 of 11 patients, but 8 of 11 had reduced edema over 2 years.
Mean visual acuity in this group at the initial visit was 20/60, and at the final visit, it was
20/85. Four eyes of three patients had resolution of diffuse macular edema with improved
vision after cessation of glitazones without laser treatment.
Conclusions: Fluid retention occurs in 5% to 15% of patients taking glitazones. In some
of these patients, glitazone use appears to be a cause of macular edema, and drug
cessation appears to result in rapid resolution of both peripheral and macular edema. Fluid
retention associated with glitazone use should be considered when assessing treatment
options for patients with DME, especially those with concomitant peripheral edema.
RETINA 26:562–570, 2006

G litazones (thiazolidinediones) are commonly used

oral agents that reduce insulin resistance in type 2
diabetes and include rosiglitazone and pioglitazone.
deaths due to liver toxicity.2 Fluid retention and pe-
ripheral edema are described in 5% to 7% of patients
using glitazones alone3–5 or in conjunction with other
Glitazones are effective for glycemic control as mono- oral agents or up to 15% of patients using pioglitazone
therapy in combination with other oral agents or with with insulin.5 This fluid retention is refractory to treat-
insulin.1 The two drugs currently on the market in- ment with diuretics.6 Systemic fluid retention, usually
clude pioglitazone and rosiglitazone, with troglitazone caused by congestive heart failure or renal disease,
having been withdrawn from the market in 2000 after can aggravate diabetic macular edema (DME) and
complicate its management.7–9 We suspect that fluid
From *VitreoRetinal Surgery, P.A., Minneapolis, Minnesota; retention associated with glitazone use in some cases
and †The Eye Institute, Medical College of Wisconsin, Milwaukee,
Wisconsin. leads to worsening of DME.
Presented at the American Academy of Ophthalmology Annual To our knowledge, this association has been iden-
Meeting; Anaheim, CA; November 2003. tified in one case report.10 The two clinical objectives
None of the authors have financial interest in the subject matter.
Reprint requests: Edwin H. Ryan Jr, MD, 7760 France Avenue of the current study were to identify patients in our
South, Suite 310, Minneapolis, MN 55435. clinical practice who were noted to have both clini-

562
 Table 1. Glitazones and Peripheral Edema—Grouped by Diffuse Versus Focal Macular Edema
Initial
Examination Study Weight Weight Macular
Date (Date Entry Present Gain Loss Con- Edema
Glitazone Last Diabetes Vision Vision Drug on off gestive Other (Focal, Laser Additional
Use Examination Age Duration (OD/ (OD/ Glitazone Drug Start Stop Drug Drug Heart Hyper- Medical Diffuse, (Focal, Diabetes
Patient Noted) Date (y) Sex (y) OS)* OS)* Drug(s) Date Date (lb) (lb) Failure tension History Both) PRP) Medication

1 4/00 (4/03) 5/03 71 M 4 20/150 100/150 Rosiglitazone 4/02 7/03 Negative 20 Negative Positive Respiratory Both OU F&P Glucovance
insufficiency
2 (6/03) 6/03 51 F 3 100/70 70/50 Pioglitazone 2001 NA Positive NA Negative Negative Hyper- Focal OD, Focal None
thyroidism diffuse OS
3 7/02 (5/03) 9/03 38 F 1 40/20 60/150 Pioglitazone 9/02 5/03 36 10 Negative Negative — Both OU F&P Glucovance,
insulin
4 8/01 (4/03) 5/03 67 M 5 25/150 30/70 Pioglitazone 6/02 NA Unknown NA Positive Negative — Diffuse OU Focal Glipizide
5 (4/03) 6/03 71 M 20 60/40 50/30 Pioglitazone 2001 NA Negative NA Negative Positive Myocardial Diffuse OU Focal Insulin,
infarct amaryl
6 4/98 (5/03) 8/03 70 F 9 200/200 400/400 Rosiglitazone 2001 4/03 50 18 Negative Positive — Both OU Focal Insulin
7 3/02 (8/03) 3/04 65 M 2 20/60 70/400 Rosiglitazone 2000 NA 15 NA Negative Negative — Both OU Focal None
OU
8 (9/03) 9/03 66 M 10 200/70 200/70 Rosiglitazone Unknown 9/03 Unknown NA Positive Positive Myocardial Both OU Focal —
infarct
9 9/02 (6/03) 8/03 74 F 8 800/30 400/40 Pioglitazone 8/02 6/03 Positive Negative Negative Positive Colon Both OU Focal Glyburide,
cancer glucophage
10 5/01 (1/02) 10/03 61 M 10 60/400 60/HM Rosiglitazone, Rosiglitazone, 1/02 30 30 Negative Positive Renal failure Diffuse OU F&P Insulin
pioglitazone 11 mo; OU
pioglitazone,
3 mo
DME WITH GLITAZONE USE

11 4/00 (9/01) 10/03 60 F 40 60/70 300/100 Rosiglitazone 9/99 9/01 15 0 Positive Positive High Both OU F&P Insulin
●

cholesterol OU
12 (9/01) 2/04 52 F 16 40/25 150/40 Rosiglitazone, Rosiglitazone, 9/01 30 30 Negative Positive — Both OU Focal Glucophage,
pioglitazone 2 mo; OU glyburide
pioglitazone,
3 mo
13 (11/99) 1/00 46 M 19 50/80 25/40 Rosiglitazone 8/99 11/99 24 24 Positive Positive — Diffuse OU Prior Glucophage,
PRP insulin
14 (9/02) 3/03 65 F 11 60/50 50/50 Pioglitazone Unknown 7/02 Positive 12 Negative Positive Asthma, Diffuse OU Focal Insulin,
RYAN JR ET AL

colon amaryl
cancer
15 10/02 (7/03) 7/03 61 M 12 25/25 20/20 Pioglitazone 2001 5/03 30 15 Negative Negative Neuropathy Diffuse OU Focal Glucophage,
insulin
16 9/01 (7/02) 7/02 55 M 2 60/40 60/70 Pioglitazone 2002 NA Positive Negative Negative Positive Nephropathy, Diffuse OU Focal Glucophage
neuropathy
17 (8/03) 11/03 72 M 4 60/40 40/30 Rosiglitazone 3/03 8/03 15 28 Negative Positive Neuropathy Diffuse OU Focal Amaryl
18 7/02 (9/03) 11/03 62 M 7 40/80 60/150 Pioglitazone Unknown NA Unknown Negative Negative Positive Nephropathy, Diffuse OU Focal, Oral agent,
neuropathy PRP unknown
19 (8/03) 8/03 56 F 12 150/20 150/20 Pioglitazone Unknown NA Positive NA Negative Negative — Diffuse OD Focal Insulin
Diffuse — — Mean, — — Mean Mean — — — Mean, Mean, — — — — — —
leakage 62 visual visual 23 19
acuity, acuity,
20/60 20/84
(Table continues)
563
 Table 1. (Continued)
564

Initial
Examination Study Weight Weight Macular
Date (Date Entry Present Gain Loss Con- Edema
Glitazone Last Diabetes Vision Vision Drug on off gestive Other (Focal, Laser Additional
Use Examination Age Duration (OD/ (OD/ Glitazone Drug Start Stop Drug Drug Heart Hyper- Medical Diffuse, (Focal, Diabetes
Patient Noted) Date (y) Sex (y) OS)* OS)* Drug(s) Date Date (lb) (lb) Failure tension History Both) PRP) Medication

20 3/01(7/03) 9/03 66 M 10 50/20 30/30 Rosiglitazone 4/03 7/03 Negative Negative Negative Positive Stroke Focal OD Focal Insulin,
glucophage
21 (8/02) 10/03 73 F 20 150/20 100/20 Pioglitazone 5/02 8/02 40 10 Negative Positive — Focal OU Focal Glyburide,
OU glucophage
22 (8/03) 8/03 74 M 18 30/50 30/50 Pioglitazone Unknown NA Unknown NA Positive Negative Myocardial Focal OU Focal Insulin
infarct
23 3/03(9/03) 9/03 52 M 4 20/20 40/20 Pioglitazone 5/03 NA 40 Unknown Negative Positive — Focal OU Focal Glucophage,
insulin,
metformin
24 (8/03) 9/03 69 M 5 20/20 20/20 Pioglitazone Unknown 9/03 Unknown 3 Negative Positive — Focal OU None Glyburide
25 1/02(7/03) 10/03 84 F 10 25/25 50/30 Rosiglitazone 6/03 7/03 Negative 11 Negative Positive Myocardial Focal OS None Glyburide
infarct,
nephropathy
26 12/01(7/02) 4/03 41 M 12 70/70 60/80 Pioglitazone 2001 NA Positive Negative Negative Positive Nephropathy, Focal OU Focal, Insulin
neuropathy, PRP
alcohol
abuse
27 (12/02) 12/02 64 F 23 50/50 50/50 Pioglitazone 6/01 NA Positive Negative Positive Positive Myocardial Focal OS None Insulin
infarct,
thyroid
cancer,
RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES

neuropathy
●

28 (8/03) 9/03 46 M 16 20/20 20/20 Rosiglitazone “Longtime” 8/03 100 Negative Negative Positive — Focal OS Focal Glucophage
29 (5/03) 8/03 49 M 15 20/25 20/30 Pioglitazone 4/03 NA 10 Negative Negative Positive Peripheral Focal OS Focal Glucophage,
2006

neuropathy amaryl
●

30 (3/03) 8/03 55 M 16 40/100 50/60 Rosiglitazone 3/02 3/03 Positive Positive Negative Positive Nephropathy, Focal OU Focal Insulin
neuropathy
Focal leakage† — — Mean, — — Mean Mean — — — — — — — — — — —
61 visual visual
acuity, acuity,
VOLUME 26

20/35 20/36
●

Overall† — — Mean, — — Mean Mean — — — — — — — — — — —

61 visual visual
acuity, acuity,
20/50 20/62
NUMBER 5

*Visual acuity shown as 20/(number) OD/20/(number) OS.

†Mean visual acuity shown as 20/(number) and includes both eyes.
PRP, panretinal photocoagulation; F&P, focal and peripheral; NA, not available; HM, hand motion.
 Table 2. Characteristics of 11 Patients Followed for ⬎3 Months After Cessation of Glitazones
Initial Study Macular Macular
Examination Entry Present Weight Weight Edema Macular Edema
Date (Date Months Vision Vision Gain on Loss off Congestive (Focal, Laser Edema Response to
Glitazone Followed Age Years of (OD/ (OD/ Glitazone Start Stop Drug Drug Heart Diffuse, (Focal, Response Drug
Patient Stopped) off Drug (y) Sex Diabetes OS)* OS)* Drug(s) Date Date (lb) (lb) Failure Hypertension Both) PRP) to Laser Discontinuation

17 (8/03) 3 72 M 4 60/40 40/30 Rosiglitazone 3/03 8/03 15 28 Positive Positive Both OU Focal OD Improved Improved
Diffuse
14 (9/02) 8 65 F 11 60/50 50/50 Pioglitazone Unknown 2002 Positive 12 Negative Positive OU Focal OU Improved Improved
Diffuse Slow
10 5/01 (1/02) 21 61 M 10 60/400 60/HM Both 11/01 2/02 30 30 Negative Positive OU F&P OU decrease Slow decrease
Slow
11 4/00 (9/01) 25 60 F 40 60/70 300/100 Rosiglitazone 12/99 12/01 15 0 Positive Positive Both OU F&P OU decrease Slow decrease
Decreased
21 (8/02) 14 73 F 20 150/20 100/20 Pioglitazone 3/02 8/02 40 27 Negative Positive Focal OU Focal OU edema Slow decrease
12 (9/01) 30 52 F 16 40/25 150/40 Both 11/01 4/02 30 30 Negative Positive Both OU Focal OU No effect Slow decrease
DME WITH GLITAZONE USE

Diffuse Prior PRP,

●

13 (11/99) 3 46 M 19 50/80 25/40 Rosiglitazone 8/99 11/99 24 24 Positive Positive OU no focal NA Resolved
25 1/02 (7/03) 3 84 F 10 25/25 50/30 Rosiglitazone 6/03 7/03 Negative 12 Negative Positive Focal OS None NA Resolved
Increased
6 4/98 (5/03) 3 70 F 9 200/200 400/400 Rosiglitazone 2001 4/03 50 18 Negative Positive Both OU Focal OU edema No change
Increased
3 7/02 (5/03) 4 38 F 1 40/20 60/150 Pioglitazone 9/02 5/03 36 10 Negative Negative Both OU F&P OU edema Unknown
Edema
30 (3/03) 5 55 M 16 40/100 60/50 Rosiglitazone 3/02 3/03 Positive Positive Negative Positive Focal OU No worse No effect
RYAN JR ET AL

6 F,
Average† — 10.6 61.5 5M 19 20/60 20/85 — — — 30 19 — — — — — —

*Visual acuity shown as 20/(number) OD/20/(number) OS.

†Mean visual acuity shown as 20/(number) and includes both eyes.
PRP, panretinal photocoagulation; HM, hand motion; F&P, focal and peripheral; NA, not available.
565
566 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES ● 2006 ● VOLUME 26 ● NUMBER 5

cally significant macular edema and systemic fluid determine the total number of diabetic patients seen
retention during glitazone use and to review the course versus the total number of patients taking glitazones
of both weight loss and DME status in patients fol- was performed. To calculate the number of patients
lowed for ⱖ3 months after cessation of glitazone use. taking glitazones who were likely to be seen over a
This retrospective study was not able to test whether 9-month period, we used the following formula:
glitazone causes worsening of macular edema; rather ([number of glitazone-using patient visits per week/2
it was intended to explore whether an association weeks] ⫻ [39 weeks/9 months]) ⫼ (average of 2 to 3
exists. visits/patient). We then divided this number by the
number of glitazone-using patients seen in 2003 who
Patients and Methods had macular edema, peripheral edema, and/or weight
gain.
This study was a noncontrolled, nonrandomized,
retrospective chart review. Institutional review board Results
exemption was obtained for this study. Thirty patients
with type 2 diabetes were identified who were using This study identified 30 patients seen in the period
pioglitazone or rosiglitazone and had the characteris- November 1999 through September 2003 who had
tics of identifiable lower extremity edema that in- clinically significant macular edema and peripheral
creased since starting the drugs and clinically signif- edema during glitazone use (Table 1). A subgroup of
icant macular edema. There were no controls. Patients 11 patients was observed at least 3 months after ces-
were not matched for age or sex. Patients were iden- sation of glitazones. Nineteen patients were male, and
tified by a computer search of patient correspondence 11 were female. The mean age of the patients was 61
for mention of “Actos” (pioglitazone) or “Avandia” years (range, 38 – 84 years). All patients had type 2
(rosiglitazone). Patients were included in the study if diabetes (average duration since diagnosis, 8.3 years).
they had the following characteristics: clinically sig- Hypertension was found in 23 patients, congestive
nificant macular edema in at least one eye and lower heart failure, in 6, and renal failure, in 1.
extremity edema thought to be associated with glita- The first patient with the possible association of
zone use. Patients who had glitazone use without glitazones, fluid retention, and macular edema was
macular edema and glitazone use with no history of seen in late 1999. Twelve patients were seen for the
peripheral edema were excluded. first time during January to September 2003, while
The setting was the clinical practice of a single another eight previously established patients were first
specialty multiphysician retina-only referral group. recognized to have peripheral edema in 2003. Seven-
Clinically significant macular edema was documented teen patients took pioglitazone, 11 took rosiglitazone,
by clinical examination and review of the color pho- and 2 took both drugs at different times. Two patients
tographs and fluorescein angiograms. Fluid retention took glitazones as monotherapy, 12 took other oral
and peripheral edema were noted to be present or agents in addition to glitazones, 7 took insulin alone
absent. Response to laser treatment was assessed by with glitazones, 7 took insulin plus other oral agents in
clinical examination. Response to cessation of glita- addition to glitazones, and 2 had no information avail-
zones was measured by reported weight loss, clinical able. Fluid retention and peripheral edema were
estimation of lower extremity edema, visual acuity present in 20 patients; they were categorized as severe
change, and change in macular edema. The use of in 10 patients (Fig. 1). Weight gain was quantified in
other glycemic control agents (insulin or oral) was 13 patients (mean, 33 lb; range, 10 –100 lb) and was
reported by the patients. Therapeutic ocular interven- present but not quantified in all but 4 others. Clinically
tions included focal laser treatment. significant macular edema was bilateral in 24 patients
Therapeutic systemic interventions included cessa- and was unilateral in 6. Twenty-six of 30 patients
tion of glitazones, diuresis, and dialysis (one case). (48/60 eyes) received macular laser photocoagulation
Adverse effects were assessed using visual acuity (ⱖ2 times in 22/60 eyes). Panretinal photocoagulation
measurements and macular edema grading. Weight was performed on 15 of 60 eyes. Mean visual acuity
gain or loss was reported by the patients. Clinical overall at the first visit was 20/50, and at the last visit,
outcome assessments were made by the authors. Pa- it was 20/62.
tient follow-up was as clinically dictated. Visual acu- Macular edema was judged by the examining phy-
ities were converted from Snellen readings to log- sician based on results of clinical evaluation and flu-
MAR for calculations of averages and then orescein angiography to be diffuse in at least 1 eye of
reconverted to Snellen readings. 19 of 30 patients, with 17 of 30 patients having
A 2-week inventory of our clinic population to bilateral diffuse edema. Because fluid overload from
 DME WITH GLITAZONE USE ● RYAN JR ET AL 567

tive heart failure. Reduction in macular edema oc-

curred in ⬍3 months in only 4 of 11 patients, but it
was ultimately seen in both eyes of 8 of 11 patients
over a 1- to 2-year period. The three patients who had
no decrease in macular edema had been off glitazones
for ⬍6 months. The average visual acuity at the initial
visit was 20/60, and at the final visit, it was 20/85.
Although most patients had a progressive decrease in
macular edema over time, visual improvement did not
necessarily follow. Three patients developed renal
failure and recurrent fluid retention months after drug
cessation. One patient began dialysis and had rapid
resolution of macular edema. The other two patients
developed recurrent worsening of macular edema after
having had a transient decrease after stopping glitazone.
Most patients had several macular laser treatments,
and some were believed by the examiners to have
edema that was quite refractory to treatment (Fig. 3).
Several patients had retinal pigment epithelium atro-
phy or gliosis from chronic macular edema contribut-
ing to visual loss. Three patients (four eyes) did have
resolution of diffuse macular edema with improved vi-
sion after cessation of glitazones without laser treatment.
We identified 12 patients with peripheral edema
and/or weight gain and macular edema who were seen
Fig. 1. A 65-year-old man with a 40-lb weight gain and moderate
pitting edema while taking pioglitazone. for the first time in the first 9 months of 2003. Eight
other established patients were first noted to have this
association during this period. To calculate an esti-
other causes often leads to diffuse macular edema, we mate of the percentage of patients who were at risk for
thought that fluid retention associated with glitazone macular edema in association with glitazone-related
use might be provoking macular edema in these pa- fluid retention, we conducted an inventory of patients
tients. Patients with diffuse edema tended to have the with diabetes seen in our office over a 2-week period
most severe vision loss (Fig. 2). This group of patients and recorded the number of patients taking rosiglita-
had mean initial visual acuity of 20/60 and mean final zone or pioglitazone; 334 such patients were seen, and
visual acuity of 20/84, compared with 20/35 and 20/ 61 were taking glitazones. Because 20 patients had
36, respectively, for the patients with focal edema been identified with macular edema, weight gain, and
only. The average weight gain on drug was 23 lb, and peripheral edema associated with glitazone use during
the average weight loss off drug was 19 lb. Two a 9-month period, we estimated the risk of this to be
patients used glitazones as monotherapy, 7 took other 3.4% to 5% for patients taking glitazones: ([61 glita-
oral agents in addition to glitazones, 5 took insulin zone-using patient visits/2 weeks] ⫻ [39 weeks/9
alone with glitazones, 4 took insulin plus other oral months]) ⫼ (average of 2 to 3 visits/patient/9 months)
agents in addition to glitazones, and 1 had no infor- ⫽ 559 to 839 glitazone-using patients, divided by 20
mation available. Macular laser treatment was per- at-risk patients ⫽ 3.4% to 5%.
formed on 31 eyes of 18 patients (⬎1 time in 16 eyes).
Of the 11 patients followed for ⬎3 months after Discussion
cessation of glitazones, 10 had weight loss after drug
cessation, and decreased lower extremity edema oc- Fluid overload is reported to contribute to worsen-
curred in all 11. Weight loss was generally quite rapid, ing of DME, and laser treatment can be relatively
as was resolution of peripheral edema, and both were ineffective until the fluid overload is adequately treat-
mostly complete by 2 months. Weight gain on drug in ed.7–9 Congestive heart failure and renal disease are
this group averaged 30 lb (range, 15–50 lb), and two common causes of this. In patients seen early in
weight loss averaged 19 lb (range, 0 –30 lb) (Table 2). this study, these two entities were first suspected as
Of the 11 patients, 10 were hypertensive, 3 developed the cause of macular edema associated with peripheral
renal failure while being followed, and 3 had conges- edema, and consultation with the primary physician
568 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES ● 2006 ● VOLUME 26 ● NUMBER 5

Fig. 2. A 61-year-old man

taking pioglitazone who had a
30-lb weight gain and pro-
nounced lower extremity
edema. A, Color photograph
of right eye; vision 20/200
and diffuse edema. B, Color
photograph of left eye; vision
2/200 and severe diffuse
edema. C, Transient-phase
fluorescein angiogram of
right eye showing telangiecta-
sia and early leakage. D,
Late-phase fluorescein angio-
gram of left eye showing se-
vere diffuse leakage.

was obtained. After congestive heart failure and renal For patients in this study who were followed for ⱖ3
disease were ruled out, fluid retention due to glitazone months after discontinuation of glitazones, two prom-
use was recognized as a possible cause after review of inent patterns developed. First, weight loss and reduc-
product information.4,5 Once we became aware of this tion or resolution of peripheral edema occurred rap-
possible association, we identified many more cases, idly in nearly all cases. Several patients said that they
in part by paying more careful attention to lower felt better and had less difficulty breathing. In our
extremity edema. We think that the much larger num- patients, the resolution of macular edema was often
ber of cases recognized in 2003 (20/30 patients) rep- very slow after drug stoppage and reversal of fluid
resents more likely better surveillance due to dissem- retention, for reasons unknown. In 3 of 11 patients (4
ination of information regarding glitazones and fluid eyes), macular edema also resolved substantially and
retention than a greater frequency of occurrence. promptly, without laser treatment, and with visual
Worsening of congestive heart failure, as well as improvement. In the other cases, macular edema re-
pulmonary edema, is described in some patients using solved slowly, requiring laser treatments. In some of
glitazones.6,11 Functional improvement (increased ex- these cases, visual acuity remained poor due to mac-
ercise tolerance) is seen when the fluid overload is ular scarring from chronic edema. It is unclear why
corrected, shortly after glitazones are discontinued. the peripheral edema cleared rapidly and the macular
Fluid overload rather than a direct toxic effect on the edema cleared slowly in so many cases. It is possible
heart is implicated as the cause.12 Some evidence that some diabetic patients who are prone to the vas-
suggests that glitazone-associated fluid retention is cular leakage that would cause diffuse macular edema
related to increased endothelial cell permeability.3 are likewise prone to peripheral edema associated with
Glitazones also increase plasma concentrations of vas- glitazone use and that discontinuation of the drug
cular endothelial growth factor,13 which could also lessens the fluid overload but does not affect the
lead to increased vascular permeability. Fluid accu- preexisting tendency for macular leakage.
mulation in the retina might be caused by several Patients with worsening of DME associated with
mechanisms leading to both increase in plasma vol- fluid overload have diffuse edema.7 In the study group
ume and increased permeability. as a whole, 19 (63%) of 30 patients had diffuse
 DME WITH GLITAZONE USE ● RYAN JR ET AL 569

Fig. 3. Progression of dia-

betic macular edema in a 60-
year-old woman taking ros-
iglitazone. A, October 19,
2000; vision 20/60. B, Febru-
ary 8, 2001, vision 20/80. C,
May 23, 2001; vision 20/100.
D, September 20, 2001; vi-
sion 20/200 and rosiglitazone
discontinued. E, April 18,
2002; vision 20/300. F, Au-
gust 7, 2003; edema resolved
with subfoveal glial scarring
and vision 20/150.

macular edema in at least one eye. We think that the to missed cases, but it could be high due to the referral
fluid overload due to glitazone use likely contributed nature of our practice and would be less accurate than
to this. These patients had poorer vision than the an estimate obtained prospectively.
group as a whole (initial visual acuity, 20/60; final There are a number of problems inherent in this
visual acuity, 20/84; compared with 20/35 and 20/36, study due to its retrospective nature. A retrospective
respectively). In the three eyes of two patients with study cannot prove whether glitazone use–related fluid
rapid resolution of both peripheral and macular edema retention worsens DME. This study can only survey
once off the drug, we thought that there was a direct the incidence of glitazone-related fluid retention and
cause-and-effect relationship. Because our estimate of macular edema. A prospective study would be nec-
the risk of macular and peripheral edema associated essary to test causality, and optical coherence to-
with glitazone use is 2.4% to 3.6% and 63% of these mography could be used to quantify macular edema.
patients had diffuse edema, we think that the inci- This study can only suggest a possible association
dence of worsening of macular edema due to glitazone between fluid retention from glitazone use and
use is ⬇1.5% to 2.6%. This estimate may be low due worsening of DME.
570 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES ● 2006 ● VOLUME 26 ● NUMBER 5

We did not think it was ethical to rechallenge pa- Key words: diabetes mellitus, diabetic retinopathy,
tients with glitazones to see if peripheral and macular fluid retention, glitazones, macular edema, pioglita-
edema worsened again. We did not review in detail zone, rosiglitazone, thiazolidinediones.
the charts of glitazone-using patients who had no
reported weight gain or macular edema. Because these
subjects were referral patients, we did not have the References
opportunity to check visual acuity or evaluate for 1. Stumvoll M, Hfaring HU. Glitazones: clinical effects and
macular edema before the start of glitazone adminis- molecular mechanisms. Ann Med 2002;34:217–224.
tration; therefore, we are presuming that they devel- 2. Graham DJ, Green L, Senior JR, Nourjah P. Troglitazone-
oped worsening of edema after starting the drugs. induced liver failure: a case study. Am J Med 2003;114:299–
Other difficulties include dependence on patient 306.
3. Niemeyer NV, Janney LM. Thiazolidinedione-induced
reporting for weight gain and loss and drug start and edema. Pharmacotherapy 2002;22:924–929.
stop dates. In most cases, however, patients were very 4. Avandia Package Insert (see adverse reactions section).
certain about weight gain and loss recollection. In http://us.gsk.com/products/assets/us_avandia.pdf.
addition, many of the study patients had coexisting 5. Actos Package Insert (see adverse reactions section). http://
medical problems such as congestive heart failure, www.fda.gov/medwatch/SAFETY/2003/03Jan_labels/
Actos_PI.pdf.
which can worsen fluid retention. In addition, most of
6. Wang CH, Weisel RD, Liu PP, Fedak PW, Verma S. Glitazones
the patients underwent laser photocoagulation as part and heart failure: critical appraisal for the clinician. Circulation
of their treatment; therefore, the relative contribution 2003;107:1350.
of drug cessation versus laser treatment on fluid res- 7. Bresnick GH. Diabetic macular edema. A review. Ophthal-
olution is hard to discern. mology 1986;93:989–997.
8. Tokuyama T, Ikeda T, Sato K. Effects of haemodialysis on
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