Thiazolidinediones and the risk of edema: A meta-analysis

www.elsevier.com/locate/diabres

Diabetes Research and Clinical Practice 76 (2007) 279–289

Thiazolidinediones and the risk of edema: A meta-analysis

Helen D. Berlie, James S. Kalus *, Linda A. Jaber

Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, United States

Received 26 June 2006; accepted 4 September 2006

Available online 18 October 2006

Abstract

The use of thiazolidinediones (TZDs) in the management of type 2 diabetes mellitus (T2DM) has been associated with an

increased risk of peripheral edema. A meta-analysis was performed to assess the overall risk for developing edema secondary to

TZD. A systematic literature search was conducted using five electronic databases. All prospective, randomized, either placebo-

controlled or comparative studies reporting the incidence of edema with TZD therapy were included. Odds ratios were generated by

pooling estimates across the studies. The analysis included 26 studies consisting of 15,332 patients with T2DM. The pooled odds

ratio for TZD induced edema was 2.26 (95% CI: 2.02–2.53). The results yielded a higher risk for developing edema with

rosiglitazone (3.75 [2.70–5.20]) compared to pioglitazone (2.42 [1.90–3.08]). Concordant results persisted with calculations of the

adjusted indirect estimate. This meta-analysis demonstrates at least a two-fold increase in the risk for developing edema with a TZD

agent. The risk appears to be greater with rosiglitazone than with pioglitazone. Further studies are needed to explore this difference.

# 2006 Elsevier Ireland Ltd. All rights reserved.

Keywords: Thiazolidinediones; Pioglitazone; Rosiglitazone; Edema

1. Introduction

The thiazolidinediones (TZDs), pioglitazone and

rosiglitazone, are insulin sensitizing agents that have

been used in the management of type 2 diabetes

mellitus (T2DM) either as monotherapy or in combina-

tion with other glucose-lowering drugs [1,2]. TZDs are

ligands of the transcription factor peroxisome pro-

liferator activated receptor-gamma (PPAR-g) nuclear

receptors, which are present in high concentrations in

adipocytes [3]. Their insulin sensitizing actions are

mediated largely by the activation of the PPAR-g in the

* Corresponding author at: Department of Pharmacy Practice,

Eugene Applebaum College of Pharmacy and Health Sciences, Wayne

State University, 259 Mack Avenue, Detroit, MI 48201-2417, United

States. Tel.: +1 313 916 7755; fax: +1 313 916 1302.

E-mail address: [email protected] (J.S. Kalus).

0168-8227/$ – see front matter # 2006 Elsevier Ireland Ltd. All rights re

doi:10.1016/j.diabres.2006.09.010

adipose tissues resulting in modulating the genes

responsible for the regulation of glucose and lipid

metabolism [4]. TZDs have been shown to produce

sustained lowering of hyperglycemia with an average

reduction in HbA1c (A1C) levels by 1–1.5% [3]. Aside

from their glucose lowering effects, a preponderance of

evidence indicates that these agents can potentially

modify the metabolic abnormalities commonly asso-

ciated with insulin resistance such as dyslipidemia,

hypertension, abnormal endothelial function, and

procoagulant abnormalities [5–7]. The recently pub-

lished PROactive study has confirmed that pioglitazone

therapy reduces the composite endpoint of all-cause

mortality, non-fatal myocardial infarction, and stroke

[8]. Given that cardiovascular disease (CVD) is

responsible for over 65% of all diabetes related deaths,

the benefits of TZDs apparently extend beyond

achieving glycemic control to the potential reduction

of CVD risks and events [9].

served.

mailto:[email protected]

http://dx.doi.org/10.1016/j.diabres.2006.09.010

H.D. Berlie et al. / Diabetes Research and Clinical Practice 76 (2007) 279–289280

Fig. 1. Study selection flowchart.

Despite these advantages, the widespread use of

these novel agents has been limited by the propensity of

TZDs to promote peripheral edema and weight gain

thus increasing the risk of congestive heart failure

(CHF). These growing safety concerns have led to the

development of a combined consensus statement by the

American Heart Association and the American Dia-

betes Association aimed at increasing the awareness

and at providing guidelines as to the prevention and

management of these potentially serious side effects

[10]. Although edema is a recognized consequence of

TZD therapy, concrete evidence of its incidence or risk

factors remain elusive. The clinical trials evaluating

TZDs have reported varied rates for developing edema

ranging from 1.9 to 28% with pioglitazone [11,12] and 3

to 16.2% with rosiglitazone [13,14]. It is widely held

that edema is more likely to occur when TZDs are

combined with oral antihyperglycemic agents [10]. The

greatest risk is considered to be when TZDs are

combined with insulin [10,14,15]. Since edema appears

to occur in a relatively small fraction of patients with

T2DM, none of the individual studies have been

powered to define the rate of its occurrence or to detect

whether differences in the risk of edema exist between

pioglitazone and rosiglitazone. The objective of this

meta-analysis was to pool results across published

clinical studies to obtain a more precise estimate of the

odds for developing TZD induced edema. We also

explored whether differences in the risk for developing

edema exist between the two TZD drugs or the choice of

the glucose-lowering agent used in combination.

2. Methods

2.1. Data sources

A comprehensive literature search was conducted to iden-

tify all English language studies examining the safety and

efficacy of TZD therapy either as monotherapy or in combi-

nation with other glucose-lowering agents. The electronic

databases searched included: Medline (1966 through May

2006), CINHAL (1982 through May 2006), Cochrane Central

Register of Controlled Trials (up to the 1st quarter of 2006),

Cochrane Database of Systemic Reviews (up to the 1st quarter

of 2006), and EMBASE (1996–2005). The medical subject

heading (MeSH) ‘‘thiazolidinediones’’ was the primary search

term utilized (see flowchart; Fig. 1). Additionally, a manual

search for references of review articles and original manu-

scripts was completed. Scientific session abstracts (2003 to

present) presented at meetings of the American Diabetes

Association, American Heart Associations, and American

College of Cardiology were also reviewed. Finally, the man-

ufacturers of pioglitazone (Actos, Takeda, Lincolnshire, IL),

and rosiglitazone (Avandia, GlaxoSmithKline, Research Tri-

angle Park, NC), were contacted to obtain studies included in

their New Drug Applications.

2.2. Study selection and data extraction

Studies were included in the meta-analysis if they (1) were

prospective, randomized, active or placebo controlled, (2)

evaluated the effects of pioglitazone, or rosiglitazone as

monotherapy or in combination with other glucose-lowering

agents in patients with T2DM, and (3) had reported the rates of

edema in a manner that allowed data extraction. A study could

yield more than one data entry if such study had more than one

TZD arm and reported separate rates of edema for the various

arms.

Data extraction included the following variables: study

design, sample size, intervention, study duration, age, diabetes

duration, baseline and final body weight, and rates of edema.

Data extracted were examined for accuracy by an independent

reviewer.

2.3. Statistical analysis

The primary analysis evaluated the overall risk of edema

associated with the use of TZDs and included all the studies

meeting the inclusion criteria. Subgroup analyses were per-

formed in order to establish the impact of clinical hetero-

geneity on the meta-analysis results and to identify specific

patient groups at greatest risk of developing TZD-induced

H.D. Berlie et al. / Diabetes Research and Clinical Practice 76 (2007) 279–289 281

edema. These subgroup analyses examined whether differ-

ences in risk for developing edema exist relative to the specific

TZD chosen, the TZD dosages employed, the use of TZDs

alone or in combination, or the specific comparator agent

tested. The comparison of TZD induced edema between

pioglitazone and rosiglitazone was also examined using an

adjusted indirect comparison method [16]. Sensitivity ana-

lyses were conducted to determine the effects of including

open-label studies on the overall outcome and to compare the

fixed versus random effect model results for the primary

analysis.

The incidence of edema was treated as a dichotomous

variable and reported as an odds ratio (OR) with a 95%

confidence interval (CI). For each analysis, the chi-square

test was performed to assess the presence of statistical hetero-

geneity between studies. A p-value <0.1 indicated that sig-

nificant heterogeneity was present. When statistical

heterogeneity was not detected, a fixed-effect model using

Mantel–Haenszel methodology was applied to estimate odds

ratios [17]. When significant heterogeneity was present, a

random-effect model using DerSimonian and Laird metho-

dology was employed [17]. A funnel plot was examined to

assess for bias in the meta-analysis. Review Manager 4.2.8

software was used to calculate a pooled OR for the overall

analysis as well as the subgroup and sensitivity analyses [17].

3. Results

3.1. Studies and patients

Relevant characteristics of the studies included in the

meta-analysis are summarized in Table 1. A total of 26

prospective studies met the inclusion criteria for this

analysis; seven studies had open-label design, five

studies compared TZD monotherapy to placebo, and 20

compared a TZD to other glucose-lowering agents. The

duration of these studies ranged from 16 weeks to 34.5

months. In the TZD monotherapy-placebo trials, the

total daily dosing ranges were 7.5–45 mg for piogli-

tazone, and 4–8 mg for rosiglitazone. In the TZD

combination comparative trials, the daily dosages

ranged from 15 to 30 mg for pioglitazone and from 4

to 8 mg for rosiglitazone. All but seven studies excluded

patients with New York Heart Association (NYHA)

class III or IV heart failure [11,13,18–22]. Additionally,

a recent history of CVD was used as exclusion criteria in

8 of the 26 studies [15,18,23–28]. A recent history was

defined as less than 6 months, and CVD included all or a

combination of the following: unstable angina, myo-

cardial infarction, angioplasty, coronary artery bypass

graft, cerebrovascular accident, and stroke. In these

studies, information as to the proportion of participants

with any cardiac history was not provided. Similarly,

studies not listing any cardiac exclusion criteria did not

report whether any such patients were enrolled.

The 26 studies included a total of 15,332 patients

with T2DM. Of the patients included, 8586 received a

TZD and the remaining 6746 were either in the placebo

or the comparator groups. Individual study population

ranged from 62 to 5238 subjects. Across the included

studies, the average participant age ranged from 53.7 to

61.9 years and the average duration of diabetes ranged

from 5.6 months to 13.6 years. The mean baseline A1C

levels ranged from 7.5 to 10.2% with pioglitazone and

7.9 to 9.1% with rosiglitazone. The mean reduction in

A1C levels ranged from 0.56 to 2.3%. In the three

studies that reported heart failure, the incidence ranged

from 1.9 to 11% [8,14,18]. The range of weight gain

reported by the included studies was �0.59 to +3.86 kg

for pioglitazone (12 studies) and +1.2 to +5.0 kg for

rosiglitazone (six studies). Edema was reported

separately from weight gain. Of the 26 included

studies, only 2 reported the use of an objective scale

for assessing edema [12,31]. Edema was described as

‘‘mild’’ in three studies [15,19,35] and ‘‘moderate’’ in

one study [35]. One study [28] also described edema as

‘‘pitting.’’ Aside from these studies, most simply

reported edema as an adverse effect and described it

as ‘‘peripheral edema’’ or ‘‘edema’’ with no objective

evidence provided. None of the included studies

provided information about concomitant medications

that can precipitate edema, such as calcium channel

blockers or NSAIDs.

3.2. Overall risk of edema

The primary analysis reveals a two-fold increase in

the relative risk of edema secondary to TZD therapy

compared to placebo, oral antihyperglycemic agents, or

insulin. Fig. 2A presents the odds ratios and 95% CIs

graphically. Statistical heterogeneity was not present

( p = 0.14) in the primary analysis. The pooled odds

ratio was 2.26 (95% CI 2.02–2.53; p < 0.00001) as

estimated by the fixed-effect model. The sensitivity

analysis, in which a random-effect model was used,

yielded similar results (2.65 [2.19–3.20], p < 0.00001).

Inclusion of only open-label studies (n = 7) in a

sensitivity analysis demonstrated a higher risk (6.74

[3.32–13.71], p < 0.00001) than when only blinded

studies (n = 19) were analyzed (2.17 [1.94–2.43],

p < 0.00001). The increased risk of edema was present

in both monotherapy and combination therapy studies

(Fig. 2B and C). Monotherapy studies compared a TZD

to either an active comparator or placebo, whereas in the

combination therapy studies, the TZD was combined


Table 1

Included studies

Study (reference) Study design Comparator Methods Incidence of edema

(cases/no. of treatment arm)

Pioglitazone studies

Aljabri et al. [22] PIO 30 mg titrated to 45 mg.

Combination therapy with

MET + SU

INS (NPH) RCT, open label,

16 weeks, N = 62

PIO: 9/30; INS: 0/28

Aronoff et al. [18] PIO randomized to 7.5, 15,

30 or 45 mg

PLA R, DB, PC, 26

weeks, N = 408

PIO: 12/329; PLA: 0/79

Charbonnel et al. [19] PIO forced titration to 45 mg SU

(gliclazide)

R, PG, DD, DB,

52 weeks, N = 1270

PIO: 54/620; SU: 28/622

Dormandy et al. [8] PIO 15 mg titrated to 45 mg.

Combination therapy with

various pre-study medications

PLA RCT, 150 weeks,

N = 5238

PIO: 562/2605; PLA:

341/2633

Einhorn et al. [23] PIO 30 mg. Combination

(MET + PIO vs. MET + PLA)

MET R, DB, PC, 16

weeks, N = 328

PIO + MET: 10/168;

PLA + MET: 4/160

Goke and German

Pioglitazone Study

Group [24]

PIO 45 mg AGI

(acarbose)

R, PG, MC, open

label, 26 weeks,

N = 265

PIO: 6/129; AGI: 0/136

Herz et al. [28] PIO randomized to 30 or 45 mg PLA R, PG, DB, PC, MC,

16 weeks, N = 297

PIO30: 14/99; PIO45:

16/99; PLA: 16/99

Jovanovic et al. [20] PIO 30 mg fixed dose throughout

study. (a) Monotherapy (PIO vs.

repaglinide); (b) combination

therapy with both agents

(PIO + repaglinide)

Non-SU

(repaglinide)

R, PG, MC, open

label, 24 weeks,

N = 246

PIO: 1/62; PIO + NonSU:

7/123; NonSU: 0/61

Kipnes et al. [25] PIO randomized to 15 or 30 mg.

Combination (SU + PIO15 vs.

SU + PIO30 vs. SU + PLA)

SU R, DB, PC, MC,

16 weeks, N = 560

PIO + SU: 28/373;

PLA + SU: 4/187

Mattoo et al. [29] PIO 30 mg. Combination therapy

(INS + PIO vs. INS + PLA)

INS R, DB, PC, MC,

26 weeks, N = 289

PIO + INS: 20/142;

PLA + INS: 5/147

Pavo et al. [30] PIO 30 mg titrated to 45 mg MET R, DB, MC, 32

weeks, N = 205

PIO: 13/105; MET: 4/100

Rosenblatt et al. [26] PIO 30 mg PLA R, DB, PC, MC,

23 weeks, N = 197

PIO: 5/101; PLA: 1/96

Rosenstock et al. [15] PIO randomized to 15 or 30 mg.

Combination (INS + PIO15 vs.

INS + PIO30 vs. INS + PLA)

INS R, DB, PC, MC,

16 week, N = 566

PIO15 + INS: 24/191;

PIO30 + INS: 33/188;

PLA + INS: 13/187

Schernthaner et al. [11] PIO titrated up to 45 mg MET R, PG, DB, MC,

52 weeks, N = 1199

PIO: 40/597; MET: 11/597

Tan et al. [31] PIO 30 mg increased to 45 mg SU

(glibenclamide)

R, MC, 52 weeks,

N = 200

PIO: 24/91; SU: 9/109

Tan et al. [12] PIO 15 mg increase to 45 mg SU

(glimepiride)

R, PG, DB, MC,

52 weeks, N = 244

PIO: 35/121; SU: 17/123

Yamanouchi et al. [27] PIO started on 30–45 mg/d.

Monotherapy (MET vs. SU

vs. PIO)

MET SU RCT, open label,

52 weeks, N = 114

PIO: 4/38, MET: 0/39;

SU: 0/37

Rosiglitazone studies

Baksi [32] ROSI 4 mg bid. Combination

(SU + ROSI vs. SU + placebo)

SU

(gliclazide)

R, PG, DB, PC, MC,

26 weeks, N = 473

ROSI + SU: 25/225;

SU: 7/241

Dailey et al. [21] ROSI 4 mg/d titrated to 4 mg bid.

Combination (MET + SU + ROSI

vs. MET + SU + PLA)

MET SU

(glyburide)

R, PC, open label,

24 weeks, N = 365

ROSI + MET + SU:

14/181; PLA + MET +

SU: 4/184

Fonseca et al. [33] ROSI randomized to 4 or 8 mg/d.

Combination (MET + ROSI4 vs.

MET + ROSI8 vs. MET + PLA)

MET R, DB, PC, MC,

26 weeks, N = 348

ROSI4 + MET: 3/119;

ROSI8 + MET: 4/113;

PLA + MET: 1/116

Kerenyi et al. [34] ROSI 4 mg bid. Combination

(SU + ROSI vs. SU + PLA)

SU

(glibenclamide)

R, PG, DB, PC, MC,

26 weeks, N = 340

ROSI + SU: 16/165;

PLA + SU: 5/170


Table 1 (Continued )

Study (reference) Study design Comparator Methods Incidence of edema

(cases/no. of treatment arm)

Lebovitz et al. [35] ROSI randomized to 2 or 4 mg

bid

PLA R, PC, DB, MC,

26 weeks, N = 493

ROSI2bid: 10/166;

ROSI4bid: 18/169;

PLA: 3/158

Phillips et al. [36] ROSI randomized to 2 mg bid,

4 mg qd, 4 mg bid, or 8 mg qd

PLA R, DB, PC, MC,

26 weeks, N = 959

ROSI2bid: 8/186 R4:

10/181; R4bid: 13/187

R8: 8/181; PLA: 3/173

Raskin et al. [14] ROSI randomized to 2 mg bid

or 4 mg bid. Combination therapy

(INS + ROSI2 vs. INS + ROSI4

vs. INS + PLA)

INS R, DB, PC, MC,

26 weeks, N = 319

ROSI4 + INS: 14/106;

ROSI8 + INS: 17/103;

PLA + INS: 5/104

Raskin et al. [13] ROSI 2 mg bid, option to double to

4 mg bid. (a) Monotherpay (ROSI

vs. repaglinide); (b) combination

therapy (ROSI + repaglinide)

Non-SU

(repaglinide)

R, PG, MC, open

label, 24 weeks,

N = 252

ROSI: 2/62; ROSI +

NonSU: 5/127;

NonSU: 0/63

St John Sutton

et al. [37]

ROSI 4 mg bid SU

(glyburide)

RCT, open label,

52 weeks, N = 203

ROSI: 7/104; SU: 1/99

PIO: pioglitazone; ROSI: rosiglitazone; PLA: placebo; MET: metfromin; SU: sulfonylurea; NonSU: non-sulfonylurea secretagogue; AGI: alpha-

glucosidase inhibitor; INS: insulin; R: randomised; PC: placebo controlled; CT: controlled trial; DB: double blind; MC: multi-centre.

with the active comparator versus the active comparator

alone. The funnel plot for studies included in the

primary analysis was asymmetrical (figure not shown),

indicating that the presence of bias cannot be ruled out.

3.3. Pioglitazone and rosiglitazone

To explore the differences in the risk for developing

edema between the two TZD agents, 17 pioglitazone

studies with 21 data entries were compared to 9

rosiglitazone studies with 16 data entries (Fig. 3A). In

this secondary analysis, rosiglitazone was associated

with a more pronounced risk for edema than

pioglitazone. The calculated adjusted indirect compar-

ison of rosiglitazone to pioglitazone based on all

included studies, yielded an approximate three fold

higher risk of edema with rosiglitazone (2.74 [2.33–

3.14]).

When only placebo controlled studies of pioglita-

zone (1.18 [0.61–2.28], p < 0.063) and rosiglitazone

(3.58 [2.11–6.10], p < 0.00001) were considered

(Fig. 3B), the risk was still greater with rosiglitazone.

The calculated adjusted indirect comparison of rosigli-

tazone to pioglitazone using only placebo controlled

trials was 3.03 (2.15–3.91). The omission of all open

label trials also pointed towards an increased risk with

rosiglitazone (3.64 [2.56–5.17], p < 0.00001) over

piogltiazone (2.18 [1.72–2.75], p < 0.00001). Further

analyses were performed to examine whether the

increase in risk for edema with rosiglitazone is related

to differences in total daily dosages used. For this ana-

lysis, only studies with titrations to the recommended

maximum daily dosages of either agent (8 mg/day for

rosiglitazone and 45 mg/day for pioglitazone) were

included. Here too, there was a trend for higher risk of

edema with rosiglitazone (Fig. 3C). The analysis was

repeated with the removal of those studies indicating

less than 90% of subjects were maintained on maximal

doses by the end of the study period. This analysis

yielded similar trends in edema risk for pioglitazone

(2.02 [0.91–4.47], p = 0.08) and rosiglitazone (4.13

[2.70–6.30], p < 0.00001).

3.4. Antihyperglycemic combination therapy

There were a total of four studies in which patients

were treated with insulin. Three of these studies

combined TZD therapy with insulin and one compared

TZD versus insulin therapy in addition to oral

antihyperglycemic agents. A total of eight studies

combined a TZD with other oral antihyperglycemic

agents and used the combined antihyperglycemic agent

as a comparator. There were also two placebo controlled

studies that allowed patients to continue the use of pre-

study oral antihyperglycemic agents. The odds ratios for

TZD monotherapy placebo controlled trials versus TZD

combination therapy appeared similar (Fig. 4A and B).

4. Discussion

The present meta-analysis reveals an overall

doubling of the risk of edema secondary to TZD

therapy in patients with T2DM. Sensitivity analyses

demonstrated a higher risk for edema in open-label


Fig. 2. (A) Primary analysis, (B) monotherapy and (C) combination therapy.


Fig. 3. Pioglitazone vs. rosiglitazone.


Fig. 4. Monotherapy and combination therapy.

compared to double-blinded studies. The analysis with

only the blinded studies yielded an odds ratio similar to

the cumulative analysis suggesting that the inclusion of

these open-label studies had little influence on the

overall results. The finding of higher risk in open-label

studies is not unexpected since patients and clinicians

are more likely to monitor for edema in such settings.

This observation may, in part, explain the inconsis-

tencies in the rates of edema reported in different

clinical studies included in this analysis. However,

factors such as the presence of hypertension, left

ventricular hypertrophy or coronary artery disease may

lead to higher rates of TZD induced edema reported in

this study [10]. These conditions are commonly seen in

patients with long-term or advanced diabetes and are

more likely to be started on a TZD agent. The majority

of subjects in this analysis, were over the age of 53 years

and had diabetes for an average of 7 years which could

have contributed to the increased risk of edema

displayed by the results.

Furthermore, the present analysis suggests that

rosiglitazone and pioglitazone may differ with regard

to the risk of edema. Concordant results were seen in the

analyses performed with the placebo only studies and in

the maximal dose comparison of the two agents. Of the

seven open-label studies included in the cumulative

analysis, three were rosiglitazone studies and four were

pioglitazone studies. When the analysis was run without

the inclusion of these open label trials, the trend towards

a higher risk with rosiglitazone persisted. In the only

published head-to-head comparison clinical trial, there

were no differences in adverse effects, including edema


[5]. However, the actual rates of edema were not

reported and the study was not designed to detect

differences in the incidence of edema between these two

agents.

The finding of increased risk for developing edema

with rosiglitazone is intriguing. Although the exact

mechanism for TZD induced-edema is not fully

understood, several mechanisms including increased

plasma volume, reflex sympathetic activation, altered

intestinal ion transport, and increased production of

vascular endothelial growth factor have been postulated

[38]. Additionally, an association between the activa-

tion of the PPARg receptors, which are present in the

nephron, and the risk of edema secondary to TZD has

been demonstrated in rodents [39,40]. The activation of

these receptors in the collecting duct leads to the

upregulation of sodium transporters, increased sodium

retention and in turn edema. Consequently, a plausible

explanation for greater tendency for edema with

rosiglitazone is the drug’s higher affinity for these

receptors in the nephron [41].

This analysis is not in agreement with the previous

observation of higher frequency of edema when TZDs

are used in combination with other glucose-lowering

agents compared to TZD monotherapy. It is likely that

there may be a varying risk of edema depending on the

glucose-lowering agent used, some agents having

additive effects and others having protective effects.

However, this meta-analysis is not the ideal study

design to address this issue.

The weight gain associated with the use of TZDs

noted in the included studies is consistent with the

adverse effect profiles of these agents [1,2]. It has been

demonstrated that improved glycemic control is often

accompanied by weight gain, which may be linked

with edema [10]. Improved glycemic control was

achieved in the studies which reported weight gain,

which is evident by the reported decreases in A1C. It is

also important to note that the weight gain associated

with the use of TZDs is a cosmetic concern rather than

a cardiovascular risk factor. The reason that increased

weight is not associated with increased cardiovascular

risks with these agents is because they result in a

decrease in visceral fat and a subsequent increase in

subcutaneous adipose tissue, which is partly respon-

sible for the improvement in insulin resistance seen in

TZD treated patients. Furthermore, few studies

reported the incidence of heart failure occurring as

an adverse effect secondary to TZD therapy. Con-

sistent with previous findings, although the risk of

heart failure is of concern, it is not a common side

effect of these agents [10]. It should be noted,

however, that NYHA Class III and IV heart failure was

used as exclusion criteria in the majority of studies,

and some studies also excluded patients with coronary

artery disease, therefore excluding patients who would

be at increased risk for developing heart failure. There

are a number of risk factors which may contribute to

the risk of developing heart failure while being treated

with a TZD. Some of these risk factors include age

greater than 70 years, duration of diabetes for greater

than 10 years, and history of heart failure [10]. The

majority of subjects from the included studies were

less than 70 years of age and had diabetes for less than

10 years.

Several important limitations of this analysis should

be considered. First, our search was confined to

English-language published studies. Also, this meta-

analysis compared multiple intervention groups from a

given study (when data was present). According to the

Cochrane Handbook, data from trials containing

multiple intervention groups should be treated with

care [42]. However, other meta-analyses have used the

same methodology employed in this paper [43].

Edema itself is a subjective finding, and there was

no consistent definition of edema among the included

studies. Only two studies used objective methods for

evaluating for the presence of edema and the severity

of edema was only noted in three studies. Addition-

ally, little is known regarding the use of concomitant

medications that can contribute to the occurrence of

edema in the included studies. This meta-analysis

excluded studies examining the use of TZDs in other

insulin-resistant conditions such as polycystic ovary

syndrome, pre-diabetes, and lipodystrophies. Patients

with T2DM, commonly have co-morbidities which

put them at an increased risk for developing fluid

retention and edema. However, the inclusion of

studies in non-diabetic populations would have

increased clinical heterogeneity and detracted from

the clinical relevance of this analysis. Publication bias

may have been present. However, the impact of

publication bias on the overall results of a meta-

analysis has been questioned [44]. Finally, a meta-

analysis is not a substitute for a randomized controlled

trial and should instead be regarded as hypothesis

generating.

This meta-analysis provides evidence that TZD

therapy is associated with at least a two-fold increase

in the risk of peripheral edema in patients with

T2DM. The increased risk of edema appears to be

greater with rosiglitazone. Future research is needed

to identify those at the greatest risk for developing

TZD induced-edema.


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