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Chinese Medical Journal 2012;125(23):4301-4306

Meta analysis
Risk of cardiovascular disease and all-cause mortality among
diabetic patients prescribed rosiglitazone or pioglitazone: a
meta-analysis of retrospective cohort studies
CHEN Xin, YANG Li and ZHAI Suo-di
Keywords: cardiovascular risk; meta-analysis; pioglitazone; rosiglitazone; cohort study
Background The difference of cardiovascular effects between rosiglitazone and pioglitazone treatment for diabetic
patients has not been thoroughly studied. We performed a meta-analysis to compare the risk of cardiovascular adverse
effects in patients with type 2 diabetes treated with rosiglitazone compared to pioglitazone.
Methods The Cochrane Library, PubMed, and Embase were searched to identify retrospective cohort studies
assessing cardiovascular outcomes with rosiglitazone and pioglitazone. Meta-analysis of retrospective cohort studies
was conducted using RevMan 5.0 software to calculate risk ratios.
Results Of the 74 references identified, eight studies involving 945 286 patients fit the inclusion criteria for the analysis.
The results of meta-analyses showed that, compared with pioglitazone, rosiglitazone therapy significantly increased the
risk of myocardial infarction (risk ratios (RR) 1.17, 95% confidence interval (CI) 1.04–1.32; P=0.01), the risk of heart
failure (RR 1.18, 95% CI 1.02–1.36; P=0.03), and total mortality (RR 1.13, 95% CI 1.08–1.20; P <0.000 01).
Conclusion Compared with pioglitazone, rosiglitazone was associated with an increased risk of myocardial infarction,
heart failure, and all-cause mortality in diabetic patients.
Chin Med J 2012;125(23):4301-4306

R

osiglitazone and pioglitazone, the only marketed
thiazolidinediones (TZDs), are oral hypoglycaemic
agents that have been shown to improve glycaemic
control and may act to slow the progression of beta cell
failure. In May 2007, a meta-analysis of data from 42
randomized controlled clinical trials found an increased
risk of myocardial infarction (MI) and death from
cardiovascular causes in relation to the use of
rosiglitazone.1 However, several meta-analyses did not
come to the same conclusion. Moreover, the results of the
Rosiglitazone Evaluated for Cardiac Outcomes and
Regulation of Glycemia in Diabetes (RECORD) trial,
which was once considered to be the strongest evidence
evaluating the cardiovascular safety of rosiglitazone,
showed no significant increase in these events with
rosiglitazone compared to metformin or sulfonylurea in
2009.2 On the other hand, a meta-analysis of 19
randomised controlled trials with pioglitazone found a
statistically significant reduction in the composite
outcome of nonfatal MI stroke, and all-cause mortality.3
Thus, the cardiovascular risk data for rosiglitazone and
benefits of pioglitazone are less than conclusive and an
intriguing disparity between the drugs has emerged,
suggesting an intraclass variation in TZD effects. The
debate about the TZDs effects on cardiovascular health of
has gone on for years; especially in the case of
rosiglitazone.4-8 This debate is set against a background of
a lack of sufficient data and uncertainty about the
cardiovascular safety differences between the two types
of TZDs, mainly due to limitations in the randomised,
controlled trials to date, such as short duration and small

sample size.9
In contrast, surveillance data routinely collected through
general practice are able to capture information on drugs
and events in a wide range of patients as they present for
clinical care. That is to say, cohort studies provide data on
real-life use, rare outcomes, and long-term effects that are
undetectable in randomised controlled trials.10 With large
healthcare utilisation databases being used more and
more frequently, active surveillance in the form of
retrospective cohort studies can provide evidence of risk
that is not necessarily provided by randomised controlled
trials.11 Therefore, the comparison of cardiovascular
events in diabetic patients treated with rosiglitazone and
pioglitazone in the same cohort study can illustrate the
differential cardiovascular outcomes of these two
medications, which may provide strong evidence in the
debate on TZD safety.
The cardiovascular risks of rosiglitazone and pioglitazone
have been compared with one another in several
observational studies. A meta-analysis of these cohort
studies in type 2 diabetic patients was conducted to
compare the risk of myocardial infarction, heart failure,
and all-cause mortality between rosiglitazone and
DOI: 10.3760/cma.j.issn.0366-6999.2012.23.025
Department of Pharmacy, Peking University Third Hospital,
Beijing 100191, China (Chen X, Yang L and Zhai SD)
Correspondence to: Prof. ZHAI Suo-di, Department of Pharmacy,
Peking University Third Hospital, Beijing 100191, China (Tel &
Fax: 86-10-82266686. Email: zhaisuodi@163.com)

Subgroup analysis was performed to answer specific questions about particular patient groups or types of interventions.10). reliability of database researches used. Conflict between the reviewers was resolved through discussion. a random effects model was used for analysis. we screened the reference lists of selected researches and wrote to authors for further detailed data. of which 15 were relevant for our study.13 One study were excluded because the data of rosiglitazone and pioglitazone respectively were not available. while there was no relevant research from Cochrane Library.4302 Chin Med J 2012. otherwise. such as MI.14.19 Unpublished data from Pantalone’s study were added to our analysis.05 was considered statistically significant. METHODS Search strategy The search strategy was designed to identify observational cohort studies conducted in any country. P <0. database. Two studies were excluded from the analysis based on the criterion for case control cohort studies. Four studies were head-to-head cohorts of these two TZD drugs. one in Canada. Data extraction and quality assessment Each potentially eligible study was independently assessed by two qualified reviewers (Chen and Zhai) to determine whether it met the inclusion criteria and to assess its methodological quality. (2) studies that compared rosiglitazone to pioglitazone with or without other classes of oral antidiabetes drugs. fixed-effects models were used. comparability of population characteristics between rosiglitazone groups and pioglitazone groups. Copenhagen.0 (Cochrane Collaboration. including: methodology. China. a third reviewer (Yang) determined the outcome.14-17 Four studies excluded patients that received a prescription for insulin during TZD treatment. hence. two studies compared rosiglitazone and pioglitazone as monotherapy or in combination. or mortality. did not meet the three parameters mentioned above. The characteristics of each study were identified and extracted. and one in Taiwan.18 Only one study specifically narrowed its population to newly diagnosed diabetic patients. respectively. patients . risk ratios (RRs) were calculated.20 In all studies. and a clear definition of diabetes and outcomes. Although no language restrictions were applied. Statistical analysis RevMan version 5. Denmark) was used to combine results from more than two separate trials. Most cohort studies were performed in the USA. were not available as full papers. The literature search was conducted by Chen and Zhai independently. number of patients. The two reviewers independently extracted data from each included study using a standardised form. The most important quality criteria for studies included: prior cardiovascular outcome researches. Inclusion criteria All identified articles were reviewed according to inclusion criteria before proceeding with further analysis.14-21 Figure 1 shows search process and reasons for excluding studies. A computer-based literature search was conducted up to July 2010 using the Cochrane library. three authors provided further data for analysis. As showed in Figure 2. and they showed statistical heterogeneity across studies (Q-test P values=0. and if consensus could not be reached. After attempting to contact corresponding authors. eight studies remained eligible for inclusion (Table 1).14-16 Another study by Gerrits included patients older than 45 years. as well as “myocardial infraction” and “heart failure”. and “cardiovascular risk”.12. The other studies were excluded because the original data relating to numbers of events were unpublished. follow-up period. diagnostic criteria of diabetes and outcomes. Since the outcomes were dichotomous. Statistical heterogeneity among the studies was identified using the χ2 test (P=0. and Embase. or were case-controlled studies. heart failure. (3) parameters used to estimate cardiovascular risks. The inclusion criteria were: (1) retrospective cohort study in patients with diabetes mellitus.19 Data synthesis and sensitivity analysis Myocardial infraction A total of seven studies reported numbers of myocardial infraction. PubMed. Three of the studies involved patients older than 65 years.16-18 Moreover. and aimed to compare cardiovascular outcomes of both rosiglitazone and pioglitazone at the same time.17 while the patients of Tzoulaki’s study were between 35 and 90 years old. intervention. and the range of the RRs was expressed as a 95% confidence interval (CI). the search results produced studies published only in English. compared with patients given pioglitazone. a follow-up period of at least one year. MeSH terms used to identify articles included “rosiglitazone”. Additionally. the rosiglitazone arm was compared with the pioglitazone arm. number of events of each group. population characteristics.002). one in the UK. respectively.05). in people of any age. Study characteristics Table 2 shows the main characteristics of the studies. “pioglitazone”. RESULTS Study inclusion The search of PubMed and Embase revealed 18 and 54 researches. “cohort study”. Random-effects models were applied when heterogeneity was identified in a group of studies (P ≤0. The outcome data extracted were: number of patients treated with rosiglitazone as well as those treated with pioglitazone.125(23):4301-4306 pioglitazone. Finally. Studies were excluded if they were not original research.18.

In the head-to-head studies. 2009 Pantalone. 411.4 14 101 76. Basic characteristics of included studies References Graham. Follow-up (years) 3 7 5 8 Study period 2006–2009 2000–2006 2001–2005 1998–2006 7.32. P=0.3 1508 3816 ICD-9 READ CODE 22 785 72 52.15. exclusion of this study from the analysis gave an RR of 1.7 1879 Mono: 61. For the studies that excluded patients treated with insulin. above 65 years old The Ingenix Research Database 29 911 T2DM CV: cardiovascular. I2=84%) that reported the number of heart failure events.4 Multi: 52.XX ICD-9 READ CODE AMI: ICD-10codeI20,I21,I22 CHF: ICD-10codesI50 NA AMI: ICD-9code410 Figure 2. 2010 Brownstein. 2008 Gerrit. Comparison myocardial infarction.2 No.0 Multi: 53.8 48.010).6 64.XX CHF: ICD-9codes428. Multi: combination therapy. 2009 Winkelmayer.01.040). 402.08 (95% CI 1.3 2000–2005 2003–2006 given rosiglitazone had an increased risk of MI (RR 1. 2009 Winkelmayer.4 Mono: 65. P=0.2 15 104 Male (%) 58 58. above 65 years old ambulatory care reporting system database Medicare Beneficiaries 28 361 DM.0 51. 404. 2009 64. 2009 Juurlink. 2009 Tzoulake. DM: diabetes mellitus. of patients Population Medicare Database 227 571 T2DM. 404x3. Search process showing reasons for excluding studies.7 Multi: 64.XX Mono: monotherapy. 35–90 years old Ontario Public Drug Benefit Program.030). national 39 736 T2DM.8 14 807 ICD-9code250.11). 2009 Juurlink.0 14 260 NA 57.5 Mono: 50.2–1. 2007 Age (years) 74.5 Multi: 53.4 39.3 58 Pantalone.2 Multi: 55.17. Patient characteristics of included studies Rosiglitazone References Pioglitazone Age (years) Male (%) Graham. P=0.8 Multi: 54. 2010 74. the analysis used a random effects model.01–1.125(23):4301-4306 Table 1.01–1.4 Diagnostic criteria of diabetes Diagnostic criteria of cardiovascular events NA AMI: ICD-9code410 CHF: ICD-9codes402x1.11,402. P=0. Considering that the follow-up period of Gerrits’ study was shorter than others.7 52.1 16 951 NA 26.32. Table 2.3 26. 2009 Tzoulake. 2007 Country USA USA China USA UK Canada USA USA Database No. of .XX. 404.4 806 ICD-9code250.04–1.4 Mono: 53.XX,402.5 No.98–1.01.6 53. The risk of heart failure was increased in the Figure 1.6 Mono: 52.3 54. the RR was 1.XX 1079 18 082 61. 404.11. of patients 67 593 Brownstein.6 61.91. 2008 Gerrit.15 (95% CI 1. 95% CI 1.4303 Chinese Medical Journal 2012. T2DM: type 2 diabetes mellitus.XX 49 624 Mono: 60.2 12 010 ICD-9code250.1 76. AMI: ICD-9code410.20. the RR was 1. Heart failure Since there was significant heterogeneity among the five studies (P <0.0001. 2010 Hsiao.5 72 45. 2010 Hsiao. above 65 years old Partners Healthcare System 34 253 DM Taiwan’s National Health Insurance 473 483 Newly diagnosed T2DM Electronic health record derived clinical data at the 20 450 T2DM.1 3 1990–2005 2002–2008 5 1. no CV history Cleveland Clinic UK general practice research database 91 521 T2DM. of patients 159 978 63.428 AMI: ICD-9code410 40.09 (95% CI 0.

heart failure and all cause mortality—were higher in the rosiglitazone group than in the pioglitazone group.98–1. which may have very important consequences in clinical practice. P <0.24.19. P=0.125(23):4301-4306 Figure 3. 95% CI 1. The risk of all three outcomes—MI. Furthermore. the risk of mortality remained significant in the rosiglitazone group for the whole analysis (RR 1. which can be far more useful to drug safety assessment activities than generally acknowledged.14. Comparison of risk of heart failure. we had strict inclusion criteria. three .02–1.13 (95% CI 1. P <0. Our study assessed the difference in cardiovascular outcomes between rosiglitazone and pioglitazone through a meta-analysis of retrospective cohort studies.99) All-cause mortality All-cause mortality was reported in four studies. We excluded case-control studies because these will bring more heterogeneity to the analysis.31.00001). among the six studies. of all of the corresponding authors of the included studies. P <0. In recent years both FDA and EMA consider observational researches as more appropriate vehicle of exploring drug safety issues. the population of rosiglitazone’s RCTs are often younger than the patients who are treated with it. they are not necessarily so for drug safety because of their inadequate power to detect either multiple or rare adverse events. One of the strengths of this study was that we combined the results of cohort studies that reflected the differential effects of cardiovascular outcomes between rosiglitazone and pioglitazone during real-life use.08–1.36. the FDA restricted rosiglitazone to a narrowed population. while the EMA has suspended it.16. Figure 4.03) (Figure 3). When unpublished data for Pantalone’s study were included.00–1. 95% CI 1. however.00001) (Figure 4). Our findings suggest clear evidence for the cardiovascular harm of rosiglitazone. The RR was 1.00. the results of the main analysis involving the whole population was significant. the cardiovascular safety issue has not been fully researched. Recently.00001). though part of the analysis did not show significant differences.4304 Chin Med J 2012. especially rosiglitazone or pioglitazone as first-line treatment.18. After including data provided by the author of one study. Moreover.08–1. 95% CI 0. it should also be used with caution.13. To guard against heterogeneity.20. Analysis of the four studies that excluded patients on insulin combination therapy found no difference between the two TZDs (RR 1. Our study suggests that pioglitazone does not present as high a risk as rosiglitazone. and the results did not change with inclusion of the unpublished data from one study or sensitivity analysis of studies that did not involve insulin treatment. DISCUSSION This meta-analysis compared the cardiovascular risks of rosiglitazone and pioglitazone based on a total of eight retrospective cohort studies. 95% CI 1. Thus observational studies are increasing in uptake because they reflect the real-life utility of drugs. The results of our study provide further evidence to support the decision.77–1. Comparison of risk of all-cause mortality rosiglitazone group compared to the pioglitazone group (RR 1. including that all the researches should be designed to study the cardiovascular outcomes of patients treated with anti-diabetic drugs. Sensitivity analysis of studies that did not involve insulin treatment showed more risk with rosiglitazone (RR 1. P=0. the conditions under which drugs are approved for market use are often different from the settings in actual use. Take rosiglitazone for example. Though randomized controlled trials (RCTs) are the golden standard for efficiency assessment of drugs. Moreover. P=0.08). the difference between rosiglitazone and pioglitazone was not significant (RR 1.32. As far as pioglitazone is concerned. 95% CI 0.

Our results are consistent with a previously suggested. patients’ characteristic. Effects of the thiazolidinedione medications on micro. 22: 233-240. The differences of research characteristic reminded us that cohort studies were less homogeneous without control mechanism. 4. Beck-Nielsen H. Thus. 3. The progression of diabetes increases sudden cardiac death. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre. Meta-analysis of rare events: an update and sensitivity analysis of cardiovascular events in randomized trials of rosiglitazone. one author provided further unpublished data. 54–65 years). evidence for the absolute risk of any outcome for either rosiglitazone or pioglitazone. Yusuf S. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. Although our study was not able to provide 8. probably because the number of patients included in this study was relatively small. rosiglitazone was associated with an increased risk of MI. By the addition of data from Pantalone’s study. McGuire DK. our results indeed showed that. Since diabetes mellitus is complicated by cardiovascular diseases. REFERENCES 1. 2. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. Nissen SE. so the result did not have much effect in the analysis. along with aging. Loke YK. previous studies that reported an insignificantly increased risk of MI with rosiglitazone were conducted in younger populations (mean age. 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