Acta Diabetol DOI 10.1007/s00592-013-0504-8 ORIGINAL ARTICLE Thiazolidinediones and cancer: results of a meta-analysis of randomized clinical trials Matteo Monami • Ilaria Dicembrini Edoardo Mannucci • Received: 1 May 2012 / Accepted: 6 July 2013 Ó Springer-Verlag Italia 2013 Abstract Recent epidemiological data have contributed to the formulation of the hypothesis about the long-term safety of pioglitazone, a thiazolidinedione (TZD), with respect to malignancies, in particular bladder cancer. The primary aim of this meta-analysis of randomized clinical trials, not designed a priori to test this hypothesis, was to explore whether TZDs affect the risk of cancer. A metaanalysis was performed including published and unpublished randomized trials with a duration of at least 52 weeks, enrolling patients with or without diabetes, comparing TZDs with either placebo or other drug therapies on various different outcomes. We found 22 trials reporting at least one cancer and enrolling 13,197 patients to TZD (pioglitazone: n = 3,710 and rosiglitazone: n = 9,487) and 12,359 to placebo or active comparator groups. The mean follow-up was 26.1 months. Overall, those assigned at random to TZDs had a significant reduction (MH-OR 0.85 [0.73–0.98]; p = 0.027) in the incidence of malignancies, with no significant difference in Communicated by Antonio Secchi. Electronic supplementary material The online version of this article (doi:10.1007/s00592-013-0504-8) contains supplementary material, which is available to authorized users. M. Monami (&) Geriatric Cardiology, Careggi Teaching Hospital, Florence, Italy e-mail: [email protected] I. Dicembrini Obesity Agency, Careggi Teaching Hospital, Florence, Italy E. Mannucci Diabetes Agency, Careggi Teaching Hospital, Azienda Ospedaliero-Universitaria Careggi, Via delle Oblate 4, 50141 Florence, Italy e-mail: [email protected] effect between pioglitazone and rosiglitazone. Specifically, subgroup analyses showed a significant reduction for rosiglitazone (MH-OR 0.82 [0.69–0.98]; p = 0.029), but not for pioglitazone (MH-OR 0.66 [0.34–1.28]; p = 0.22). In further subgroup analyses of site-specific malignancies based on the data from four trials, the risk of bladder cancer with pioglitazone (MH-OR) was 2.05 [0.84–5.02]; p = 0.12. Further, rosiglitazone, but not pioglitazone, was associated with a significantly reduced risk of bowel cancer. In contrast, pioglitazone, but not rosiglitazone, was associated with a significant reduction in breast cancer. The present meta-analysis of trials, not designed a priori to test the hypothesis, provides reassuring evidence that TZDs are not associated with risk of overall malignancies. In fact, they are compatible with the possibility of a decreased risk of cancer. In site-specific subgroup analyses, for rosiglitazone, there was a significant decreased risk of bowel cancer. Subgroup analyses for pioglitazone did not allow to exclude an increased risk of bladder cancer, while the risk of breast cancer was significantly decreased. While these data are also useful to formulate not test hypotheses, they provide somewhat more cogent evidence than the previously published epidemiological data. Keywords Thiazolidinediones Cancer Type 2 diabetes Introduction Recent epidemiological data have raised concerns on the long-term safety of pioglitazone with respect to malignancies, showing an association with bladder cancer [1, 2]. These results, which were in line with reports from some large-scale randomized trials [3–6], prompted regulatory 123 Acta Diabetol authorities to modify the labels of pioglitazone-based products; in some countries (i.e., France), the drug was withdrawn from the market. Little systematic information is available on the effect of thiazolidinediones on other types of malignancies, different from bladder cancer. Many experimental studies had shown that thiazolidinediones, as a class, could inhibit proliferation of some types of cancer cells in vitro and in vivo [7, 8], although pilot studies with these drugs as anti-cancer therapy provided unsatisfactory results [9, 10]. Epidemiological studies failed to detect any association of thiazolidinedione use with the overall incidence of cancer [11]. We have previously shown that rosiglitazone was not associated with any increase in the overall incidence of cancer in randomized trials available as of December 1, 2007 [12]. Interpretation of epidemiological data on the relationship between treatments and adverse events is always problematic, because patients who receive any specific drug are different from those who are prescribed alternative therapies. Although many confounders can be controlled and adjusted for in analysis, a complete elimination of this prescription bias is impossible. On the other hand, randomized trials, which do not suffer from this limitation, usually lack a sufficient sample size to verify the effects of diabetes treatments on the incidence of cancer. Thiazolidinediones are the class of anti-hyperglycemic drugs, which has been most widely studied, due to a relatively huge number of longer-term available trials (either with metabolic or with cardiovascular outcomes) [3, 13–15]. Incident malignancies reported as serious adverse events in those studies can be a valuable source of information on the effects of thiazolidinediones on cancer. Materials and methods approval process, were also searched for retrieval of unpublished trials. Study selection A meta-analysis was performed including all randomized clinical trials with a duration of at least 52 weeks, enrolling patients with or without diabetes, comparing thiazolidinediones with placebo or active drugs (oral hypoglycemic agents and/or insulin) different from other thiazolidinediones. Trials with a shorter duration were excluded, due to the fact that they could not yield relevant information on cancer incidence, which had been chosen as the principal outcome variable. No review protocol was published elsewhere. Data extraction and quality assessment Results of unpublished trials were retrieved, if available, on www.clinicaltrials.gov, www.clinicalstudyresults.org, FDA (http://www.accessdata.fda.gov/scripts/cder/drugsatfda), EMA (www.clinicaltrialsregister.eu), and GSK (http:// www.gsk-clinicalstudyregister.com) Web sites. All those sources were also used to complete information on results of published trials, when not reported in publications. A request for further information was addressed to Takeda for trials on pioglitazone with missing data, but the company declined. For all published trials, results reported in papers were used as the primary source of information, when available. The quality of trials was assessed using some of the parameters proposed by Jadad et al. [16]. In particular, adequate reporting of randomization, allocation, blinding, and patient flow, together with the description of intentionto-treat safety analysis, were independently assessed by two investigators (M.M. and I.D.); conflicts were resolved by a third investigator (E.M.). The score was not used as a criterion for the selection of trials, whereas some items were used only for descriptive purposes. Data sources and searches Data synthesis and analysis An extensive MEDLINE and Embase search for ‘‘pioglitazone,’’ ‘‘rosiglitazone,’’ ‘‘troglitazone,’’ ‘‘rivoglitazone,’’ and ‘‘balaglitazone’’ was performed, collecting all randomized clinical trials on humans up to August 1, 2011. The identification of relevant abstracts, the selection of studies based on the criteria described above, and the subsequent data extraction were performed independently by two of the authors (I.D. and M.M.), and conflicts resolved by the third investigator (E.M.). Completed but still unpublished trials were identified through a search of www.clinicaltrials.gov Web site. FDA (www.fda.gov) and European Medicines Agency (EMA, www.ema.europa.eu) reviews of approved drugs, as well as published information provided to FDA in response to queries during the 123 The principal outcome was the effect of thiazolidinediones, compared either with placebo or with active drugs, on the incidence of cancer. Secondary outcomes included allcause and non-cardiovascular mortality, and cancer-related mortality. Pre-defined separate analyses were performed for trials with different comparators and for site-specific malignancies. Heterogeneity was assessed by using I2 statistics. If a low heterogeneity was detected, both a random-effects model and a fixed-effects model were applied. We report the results of the random-effects models because the validity of tests of heterogeneity can be limited with a small number of component studies. To estimate possible Acta Diabetol Standard Error Fig. 1 Funnel plot of standard error by Mantel–Haenszel odds ratio with 95 % confidence interval (MH-OR, 95 % CI) MH-Log Odds Ratio publication/disclosure bias, we used funnel plots (Fig. 1) and the Begg-adjusted rank correlation test [17, 18], including published and unpublished, but disclosed, trials. However, because these tests have low statistical power when the number of trials is small [19], undetected bias may still be present. The Duval and Tweedie’s trim and fill method was used for the estimation of results after correction for publication bias. Mantel–Haenszel odds ratio with 95 % confidence interval (MH-OR) was calculated for all the adverse events defined above, on an intention-totreat basis, excluding trials with zero events. A sensitivity analysis was performed, for the main analysis and for the predefined separate analyses, including also trials with zero events, using continuity correction. The meta-analysis was reported following the PRISMA checklist [20]. All analyses were performed using Comprehensive Meta-analysis version 2, Biostat, (Englewood, NJ, USA) and SPSS 18.1. This research was performed independently of any funding, as part of the institutional activity of the investigators. Results The trial flow summary is reported in Fig. 2. Of the 72 identified trials that fulfilled the inclusion criteria, information on cancer incidence was available in 46 studies. In particular, the number of cases of malignancies was disclosed in 28 out of 33 trials with rosiglitazone, 18 out of 36 trials with pioglitazone; none of the three trials with troglitazone was disclosed. The characteristics of the studies included in the analysis are summarized in Table 1. The majority of the retrieved trials showed an adequate quality for the parameters considered (Table 1). Among the studies actually retrieved, 24 reported zero events, and therefore, they were not included in the main analysis, but only in the confirmatory analysis with continuity correction. In the 46 trials reporting information on cancer, which enrolled 14,666 and 13,970 on thiazolidinediones and comparators, respectively, with a mean follow-up of 83.7 weeks, the number of incident cases was 342 and 457, respectively; therefore, the observed yearly incidence of cancer was 1.5 % with thiazolidinediones and 5.3 % with comparators. The 22 trials reporting at least one event enrolled 13,197 and 12,359 patients in thiazolidinedione (pioglitazone: n = 3,710 and rosiglitazone: n = 9,487) and control groups, respectively, with a mean follow-up of 26.1 months. Recorded cases of incident cancer were 342 and 457 in the thiazolidinedione and control groups, respectively, with an yearly incidence of 0.95 and 1.12 cases/patient*year for drug and comparators, respectively. I2 for all thiazolidinediones, rosiglitazone, and pioglitazone was 0.1, 0.1, and 28.4, respectively (all p [ 0.10). Overall, thiazolidinediones were associated with a significant reduction (MH-OR 0.85 [0.73–0.98]; p = 0.027) in the incidence of malignancies (Fig. 3); a separate analysis for rosiglitazone (17 trials) yielded similar results (MH-OR 0.82 [0.69–0.98]; p = 0.029), whereas results for pioglitazone were not statistically significant (MH-OR 0.66 [0.34–1.28]; p = 0.22), due to the smaller number of available disclosed trials (n = 5). Similar figures were obtained in the confirmatory analysis with continuity correction performed on 46 trials, including those with zero events (MH-OR 0.86 [0.74–0.99], p = 0.034; 0.83 [0.70–0.98], p = 0.034; 0.92 [0.71–1.19], p = 0.52, for all thiazolidinediones, rosiglitazone, and pioglitazone, respectively). Kendall’s tau was -0.34 (p = 0.026), suggesting the possibility of publication bias; this was confirmed by the visual analysis of funnel plot (Fig. 1). Using the Duval and Tweedie’s trim and fill method, which suggested the addition of 8 undisclosed trials, the estimated MH-OR was 0.88 [0.76–1.02]. When different comparators were analyzed separately, rosiglitazone was associated with a significantly lower 123 Acta Diabetol Fig. 2 Trial flow summary incidence of malignancies in comparison with placebo (9 trials; MH-OR 0.58 [0.35–0.96]; p = 0.036), whereas a nonsignificant trend toward reduction was observed in studies versus sulfonylureas (6 trials; 0.75 [0.55–1.02]; p = 0.068). A lower number of disclosed trials (2 versus placebo and 2 versus sulfonylureas) was available for pioglitazone, with no significant result (MH-OR 0.75 [0.31–1.81], p = 0.52 and 0.58 [0.15–2.24], p = 0.43, respectively). Similar results were obtained when performing the same analyses using continuity correction (data not shown). 123 Results on most frequent malignancies are summarized in Fig. 4. In trials with available information with this respect [3; see Electronic supplementary material for 26A, 27A, 34A], pioglitazone was associated with an increased risk of bladder cancer, which did not reach statistical significance; conversely, no apparent effect was detected for rosiglitazone. Rosiglitazone, but not pioglitazone, was associated with a significantly reduced risk of bowel cancer. Conversely, pioglitazone, but not rosiglitazone, was associated with a significant reduction in breast cancer. No other significant effect, either harmful or beneficial, was Acta Diabetol Table 1 Moderators and outcome variables in individual studies included in the meta-analysis Study (Reference)a Trial duration (weeks) Number of patients (ID/C) Age (years) Cancer mortality (n, ID/C) Malignancies (n, ID/C) Pioglitazone Versus placebo Non-diabetic patients Ramachandran (1A) 204/203 45 0/0 NR/NR Gavrila (2A) 52 7/7 48 0/0 0/0 Aithal (3A) 52 30/31 53 0/0 0/0 Han (4A) Geldmaker (5A) 52 78 40/43 14/15 39 71 0/0 0/0 0/0 0/0 96 Sanyal (6A) DeFronzo (7A) 156 80/83 46 0/0 NR/NR 125 303/299 52 2/0 3/8 156 2,605/2,633 62 NR/NR 97/99 Diabetic patients Dormandy (8A) Versus none Diabetic patients Jin (9A) 30/30 52 0/0 NR/NR 123 294/294 58 0/0 NR/NR Derosa (11A) 52 175/175 56 0/0 0/0 Derosa (12A) 108 175/175 56 0/0 NR/NR 52 15/15 57 0/0 0/0 Nakamura (13A)b 52 15/15 57 0/0 0/0 Heliovaara (14A) 52 29/30 57 0/0 NR/NR Tan (15A) 52 91/109 59 0/0 NR/NR Giles (16A) 52 151/149 64 0/0 NR/NR Jain (17A) 56 251/251 52 0/0 0/2 1,051/1,046 54 0/0 NR/NR Kaku (10A) 52 Versus acarbose Diabetic patients Versus voglibose Diabetic patients Nakamura (13A) Versus glibenclamide Diabetic patients Tolman (18A) 144 Versus gliclazide Diabetic patients Perriello (19A) 52 146/137 58 0/0 NR/NR Matthews (20A) 52 317/313 58 0/0 0/0 Yamanouchi (21A) Derosa (22A) 52 52 38/37 69/66 55 57 0/0 0/0 0/0 0/0 Tan 2004 (23A) 52 121/123 55 0/0 NR/NR Mazzone (24A) 72 230/228 59 1/0 NR/NR Nissen (25A) 78 270/273 60 0/0 3/4 Versus glimepiride Diabetic patients Versus metformin Diabetic patients Yamanouchi (26A) 52 38/39 55 0/0 0/0 Derosa (27A) 52 69/67 54 0/0 0/0 Versus others Diabetic patients 123 Acta Diabetol Table 1 continued Study (Reference)a Abe (28A) Trial duration (weeks) 96 Number of patients (ID/C) Age (years) Cancer mortality (n, ID/C) Malignancies (n, ID/C) 31/32 66 0/0 0/0 Versus vildagliptin Diabetic patients Bolli (29A) 52 281/295 57 0/0 0/5 67.4 4,446/4,606 56.1 3/0 103/118 Ratziu (30A) Esposito (31A) 52 52 32/31 50/50 53 45 0/0 0/0 0/0 0/0 049653/331 (32A) 52 706/325 45 0/1 1/2 Totals Rosiglitazone Versus placebo Non-diabetic patients AVA102672 (32A) 52 934/467 74,1 1/0 6/5 049653/330 (32A) 52 1,181/382 44 0/0 1/2 AVA102670 (32A) 54 966/483 73,2 3/0 9/5 52 22/44 47 0/0 0/0 Diabetic patients Rahman (33A) BRL-049563/351 (32A) 52 30/30 NR 0/1 0/0 Hwang (34A) 52 43/46 54 0/0 0/0 Bertrand (35A) 52 98/95 65 0/0 NR/NR Dargie (36A) 52 110/114 64 1/0 2/3 Hedblad (37A) 52 277/278 67 3/1 3/3 80 NCT00386100 (38A) 348/340 51 NR/NR 1/1 Berberoglu (39A) 104 26/23 60 0/0 0/0 49653/135 (32A) Gram (40A) 104 104 116/111 187/184 68 56 0/0 NR/NR 4/7 3/8 52 20/40 58 0/0 0/0 52 16/15 56 0/0 0/0 Versus life style Non-diabetic patients Oberbach (41A) Versus metformin Non-diabetic patients 49653/392 (32A) Diabetic patients NCT00679939 (38A) 114/11 64 0/0 0/0 1,103/1,122 59 NR/NR 70/81 52 384/203 60 0/0 3/0 49653/097 (32A) 148 122/120 56 0/0 1/4 49653/080 (32A) Versus gliclazide 156 104/99 56 0/0 1/3 144 43/41 58 0/0 0/2 52 50/49 53 0/0 0/0 78 333/339 61 NR/NR 1/4 Home (42A) 52 286 Versus glibenclamide Diabetic patients Hanefeld (43A) Diabetic patients NCT00367055 (38A) Versus glimepiride Diabetic patients Derosa (44A) Versus glipizide Diabetic patients Gerstein (45A) 123 Acta Diabetol Table 1 continued Study (Reference)a Trial duration (weeks) Number of patients (ID/C) Age (years) Cancer mortality (n, ID/C) Malignancies (n, ID/C) Versus sulfonylureas Diabetic patients Hamann (46A) 52 294/301 59 2/1 0/0 Home (42A)b 286 1,117/1,105 57 NR/NR 73/89 260 1,456/2,895 57 NR/NR 60/120 Versus metf. or glib. Diabetic patients Kahn (47A) Versus insulin Diabetic patients Ko (48A) Totals 52 56/56 58 0/0 0/0 94.1 10,220/9,364 57.6 10/4 239/339 104 49/81 40 0/0 NR/NR 104 142/134 52 0/0 NR/NR 104 291/215 46 0/0 NR/NR Troglitazone Versus placebo Non-diabetic patients Schuster (49A) Diabetic patients Hodis (50A) Totals ID/C interventional drug/comparator, CV cardiovascular, NR not reported a b See Electronic supplementary material Studies with multiple comparators observed for any other type of cancer, including hepatocellular carcinoma (Fig. 4). Information on cancer-related mortality was available in 57 trials, enrolling 10,768 and 8,652 patients on thiazolidinediones and comparators, respectively, with a mean follow-up of 68.5; yearly cancer-related mortality was 13 and 4 with thiazolidinediones and comparators, respectively. MH-OR for cancer-related mortality (N = 9 trials with events) was 1.79 [0.68–4.69], p = 0.24 (3.90 [0.43–35.45], p = 0.23, and 1.48 [0.51–4.34], p = 0.47, for pioglitazone and rosiglitazone, respectively). Conclusions In type 2 diabetes, the choice among the many available drugs is often driven by their glucose-lowering efficacy and short-term adverse effects, such as weight gain and hypoglycemia. On the other hand, there is increasing evidence that long-term treatments for diabetes could affect the risk of other, more relevant health outcomes, such as major cardiovascular events [21], bone fractures [22, 23], or cancer [24]. Different agents have been reported either to increase or to reduce the incidence of cancer [24]. With respect to thiazolidinediones, available epidemiological studies provided discordant results, suggesting either a harmful, neutral, or beneficial effect [11, 12, 25–27]. In a previous meta-analysis performed on a smaller number of trials, we had previously failed to detect any significant effect of rosiglitazone on the incidence of cancer [12]. The results of the present meta-analysis, which was performed on all molecules of the class and includes more recent trials, seem to exclude any increase in the risk of malignancies with thiazolidinediones. Conversely, the incidence of cancer in thiazolidinedione-treated patients is actually lower than that observed in comparator groups. This result should be considered with caution, because the trials included in the meta-analysis were not specifically designed for the assessment of the effects of treatment on the incidence of malignancies. Therefore, cases of cancer were only reported as treatment-emergent serious adverse events, with no formal adjudication. Furthermore, in the large majority of trials, no specific follow-up was planned after the end of the treatment period; this means that cases of cancer that developed during the trial, but were diagnosed later on, could have been overlooked. Another major limitation is that cases of cancer detected early after the initiation of treatment, which probably preexisted to drug exposure, were included in the analysis. These biases could have 123 Acta Diabetol Fig. 3 Mantel–Haenszel odds ratio with 95 % confidence interval (MH-OR, 95 % CI) for incident cancer for each individual trial MH odds ratio and 95% CI Statistics for each study First Author (Ref.) Bolli (29A) DeFronzo (7A) Dormandy (8A) Jain (17A) Nissen (25A) PIOGLITAZONE 04965/3310 (32A) 04965/331 (32A) 04965/080 (32A) 04965/097 (32A) 04965/135 (32A) AVA 102670 (32A) AVA 102672 (32A) Dargie (36A) Gerstein (45A) Gram (40A) Hanefeld (43A) Hedblad (37A) Home (42A) Home (42A)# Kahn (47A) NCT00367055 (38A) NCT00386100 (38A) ROSIGLITAZONE OVERALL MH odds Lower Upper ratio limit limit Z-Value p-Value 0,094 0,364 0,990 0,198 0,756 0,659 0,161 0,229 0,311 0,240 0,531 0,899 0,597 0,685 0,252 0,359 3,734 1,004 0,798 0,871 0,994 0,182 0,977 0,825 0,849 0,005 1,704 0,096 1,385 0,744 1,317 0,009 4,154 0,168 3,409 0,338 1,283 0,015 1,781 0,021 2,535 0,032 3,038 0,026 2,176 0,151 1,865 0,300 2,697 0,181 1,968 0,112 4,181 0,028 2,269 0,094 1,374 0,192 72,641 0,201 5,016 0,579 1,101 0,625 1,213 0,724 1,364 0,008 3,900 0,061 15,682 0,694 0,980 0,733 0,982 -1,600 -1,483 -0,069 -1,042 -0,365 -1,227 -1,489 -1,201 -1,005 -1,269 -0,988 -0,190 -0,847 -0,410 -1,229 -1,496 0,870 0,004 -1,375 -0,818 -0,038 -1,090 -0,016 -2,184 -2,206 0,110 0,138 0,945 0,297 0,715 0,220 0,136 0,230 0,315 0,204 0,323 0,849 0,397 0,682 0,219 0,135 0,384 0,996 0,169 0,413 0,970 0,276 0,987 0,029 0,027 0,1 0,2 0,5 Favours TZDs produced a background noise, determining an underestimation of actual differences between groups. Another major limitation is represented by incomplete disclosure of data. In fact, a complete description of serious adverse events was available for most trials with rosiglitazone, but not pioglitazone, even after a formal request to Takeda. The higher number of trials available for analysis could be responsible for the fact that rosiglitazone resulted to be significantly associated with a reduced risk of malignancies, whereas pioglitazone missed the threshold for statistical significance, despite a MH-OR lower than that of rosiglitazone. On the other hand, the possibility of selective reporting of favorable results for pioglitazone cannot be excluded. In fact, the distribution of results from disclosed trials suggests a selective reporting bias, which produces an overestimation of the benefits of thiazolidinedione therapy. Some of the drugs to which thiazolidinediones have been compared in clinical trials, most notably insulin [28] and sulfonylureas [13, 14, 29–31], have been associated with an increased risk of cancer; however, the apparent protection from malignancies conferred by rosiglitazone was still clearly detectable (and statistically significant) when the analysis was restricted to placebo-controlled trials. This finding suggests that the difference between thiazolidinediones and comparators is due, at least partly, to a beneficial effect of these drugs, and not only to the detrimental action of comparators. Such an effect is not surprising, considering the amount of experimental evidence suggesting an inhibitory action of thiazolidinediones on cancer cell growth [32, 33]. 123 1 2 5 10 Favours Comparator The increased risk of bladder malignancies with pioglitazone, suggested by some epidemiological studies [1, 2, 6], but not confirmed by others [34], is not statistically significant in the present meta-analysis. However, our results are compatible with those reported by the European Medicinal Agency (EMA), which provided a (statistically significant) OR estimate of 2.14 [6]. Details on the methods of the EMA analysis, which was probably performed on patient-level data, are not available. However, we should be aware that our meta-analysis is affected by incomplete disclosure, with missing information on some relatively large trials [14, 35, 36]. In fact, the present risk estimate is based on the results of only four disclosed trials; the limited size of samples (and the small number of cases) in disclosed studies accounts for the large confidence intervals, ranging from a 16 % protection to a fivefold increase in risk. The higher risk of bladder cancer with pioglitazone is consistent with the results of some experimental studies [37, 38], although other authors had reported a protective effect in vitro [39]. Quite interestingly, no increase in risk of bladder cancer was observed with rosiglitazone, suggesting that the detrimental effect of pioglitazone, if confirmed, could be due to a PPAR-c-independent mechanism. On the other hand, thiazolidinediones could be protective for other types of cancer. In this meta-analysis, rosiglitazone was associated with a reduced risk of bowel cancer, and pioglitazone appeared to confer protection from breast cancer. These results are in line with some previous studies in vitro [32, 33]. However, the limited number of reported cases for each type of malignancy Acta Diabetol Fig. 4 Subgroup analyses of Mantel–Haenszel odds ratio with 95 % confidence interval (MH-OR, 95 % CI) for most frequent malignancies suggests caution in interpreting data. On the other hand, the previously described reduction in risk of hepatocellular carcinoma [40–43] was not confirmed, although this could depend on the small number of cases, with some large trials (including PROACTIVE) not reporting this specific result. The few cancer-related deaths reported in trials were more frequent in thiazolidinedione-treated patients, although the between-group difference was far from reaching statistical significance. It should be considered that, in the majority of cases, deaths from cancer occurred during the trials were probably determined by malignancies which preexisted to the initiation of treatment; on the other hand, most of the deaths determined by cases of cancer, which emerged during the active treatment phase probably occurred after the termination of follow-up, and were therefore missed in the present analysis. In conclusion, available data from disclosed clinical trials do not allow to exclude an association between pioglitazone exposure and bladder cancer, which is not present for other molecules of the class, such as rosiglitazone. On the other hand, thiazolidinediones could reduce the overall incidence of cancer, mostly because of a reduced risk of bowel and breast malignancies. The possible negative effects of each molecule on specific cancer types should be carefully considered when prescribing a long-term drug treatment; in fact, the indication of regulatory bodies to avoid pioglitazone therapy in patients at high risk for bladder cancer appears to be fully justified. However, a correct choice among available treatment options should be based on a comprehensive assessment of the risk–benefit ratio, which should include other adverse events (i.e., in the case of pioglitazone, bone fractures, and heart failure) together with possible favorable outcomes on different hard end points, such as myocardial infarction, and, possibly, reduced overall cancer risk. Conflict of interest Matteo Monami has received speaking fees from Bristol Myers Squibb, Merck, Novartis, Novo Nordisk, and Takeda. Ilaria Dicembrini has received speaking fees from Novo Nordisk. Edoardo Mannucci has received consultancy fees from Merck and Novartis, speaking fees from Astra Zeneca, Bristol Myers Squibb, Merck, and Novartis, and research grants from Merck, Novartis, and Takeda. 123 Acta Diabetol References 1. Lewis JD, Ferrara A, Peng T, Hedderson M, Bilker WB, Quesenberry CP Jr, Vaughn DJ, Nessel L, Selby J, Strom BL (2011) Risk of bladder cancer among diabetic patients treated with pioglitazone: interim report of a longitudinal cohort study. Diabetes Care 34:916–922 2. Piccinni C, Motola D, Marchesini G, Poluzzi E (2011) Assessing the association of pioglitazone use and bladder cancer through drug adverse event reporting. Diabetes Care 34:1369–1371 3. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, MassiBenedetti M, Moules IK, Skene AM, Tan MH, Lefebvre PJ, Murray GD, Standl E, Wilcox RG, Wilhelmsen L, Betteridge J, Birkeland K, Golay A, Heine RJ, Koranyi L, Laakso M, Mokan M, Norkus A, Pirags V, Podar T, Scheen A, Scherbaum W, Schernthaner G, Schmitz O, Skrha J, Smith U, Taton J (2005) Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 366:1279–1289 4. Dormandy J, Bhattacharya M, de Bruyn ART (2009) Safety and tolerability of pioglitazone in high-risk patients with type 2 diabetes: an overview of data from PROactive. Drug Saf 32:187–202 5. Food and Drug Administration (2010) FDA drug safety communication: ongoing safety review of actos (pioglitazone) and potential increased risk of bladder cancer after two years exposure [Internet]. U.S. Food and Drug Administration, Silver Spring, MD. Available from http://www.fda.gov/Drugs/Drug Safety/ucm226214.htm. Accessed 21 Oct 2010 6. European Medicines Agency (2010) European Medicines Agency update on ongoing benefit-risk review of Avandia, Avandamet and Avaglim [Internet]. European Medicines Agency, London. Available from http://www.ema.europa.eu/docs/en_GB/docu ment_library/Press_release/2010/07/WC500094981.pdf. Accessed 25 Oct 2010 7. Wei S, Yang J, Lee SL, Kulp SK, Chen CS (2009) PPARgammaindependent antitumor effects of thiazolidinediones. Cancer Lett 276:119–124 8. Okumura T (2010) Mechanisms by which thiazolidinediones induce anti-cancer effects in cancers in digestive organs. J Gastroenterol 45:1097–1102 9. Yee AJ, Akens M, Yang BL, Finkelstein J, Zheng PS, Deng Z, Yang B (2007) The effect of versican G3 domain on local breast cancer invasiveness and bony metastasis. Breast Cancer Res 9:R47 10. Smith MR, Manola J, Kaufman DS, George D, Oh WK, Mueller E, Slovin S, Spiegelman B, Small E, Kantoff PW (2004) Rosiglitazone versus placebo for men with prostate carcinoma and a rising serum prostate-specific antigen level after radical prostatectomy and/or radiation therapy. Cancer 101:1569–1574 11. Koro C, Barrett S, Qizilbash N (2007) Cancer risks in thiazolidinedione users compared to other anti-diabetic agents. Pharmacoepidemiol Drug Saf 16:485–492 12. Monami M, Lamanna C, Marchionni N, Mannucci E (2008) Rosiglitazone and risk of cancer: a meta-analysis of randomized clinical trials. Diabetes Care 31:1455–1460 13. Home PD, Pocock SJ, Beck-Nielsen H, Curtis PS, Gomis R, Hanefeld M, Jones NP, Komajda M, McMurray JJ (2009) Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet 373:2125–2135 14. Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, Dinccag N, Hanefeld M, Hoogwerf B, Laakso M, Mohan V, Shaw J, Zinman B, Holman RR (2006) Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired 123 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. fasting glucose: a randomised controlled trial. Lancet 368: 1096–1105 Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, Lachin JM, O’Neill MC, Zinman B, Viberti G (2006) Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 355:2427–2443 Jadad AR, Moore RA, Carroll D et al (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17:1–12 Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50: 1088–1101 Egger M, Davey SG, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315: 629–634 Sterne JA, Gavaghan D, Egger M (2000) Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. J Clin Epidemiol 53:1119–1129 Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 151:264–269 Hemmingsen B, Lund SS, Wetterslev J, Vaag A (2009) Oral hypoglycaemic agents, insulin resistance and cardiovascular disease in patients with type 2 diabetes. Eur J Endocrinol 161:1–9 Vestergaard P, Rejnmark L, Mosekilde L (2005) Relative fracture risk in patients with diabetes mellitus, and the impact of insulin and oral antidiabetic medication on relative fracture risk. Diabetologia 48:1292–1299 Monami M, Cresci B, Colombini A, Pala L, Balzi D, Gori F, Chiasserini V, Marchionni N, Rotella CM, Mannucci E (2008) Bone fractures and hypoglycemic treatment in type 2 diabetic patients: a case-control study. Diabetes Care 31:199–203 Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, Pollak M, Regensteiner JG, Yee D (2010) Diabetes and cancer: a consensus report. Diabetes Care 33: 1674–1685 Govindarajan R, Ratnasinghe L, Simmons DL, Siegel ER, Midathada MV, Kim L, Kim PJ, Owens RJ, Lang NP (2007) Thiazolidinediones and the risk of lung, prostate, and colon cancer in patients with diabetes. J Clin Oncol 25:1476–1481 Ramos-Nino ME, MacLean CD, Littenberg B (2007) Association between cancer prevalence and use of thiazolidinediones: results from the Vermont Diabetes Information System. BMC Med 5:17 Ferrara A, Lewis JD, Quesenberry CP Jr, Peng T, Strom BL, Van Den Eeden SK, Ehrlich SF, Habel LA (2011) Cohort study of pioglitazone and cancer incidence in patients with diabetes. Diabetes Care 34:923–929 Ko GT, Tsang PC, Wai HP, Kan EC, Chan HC (2006) Rosiglitazone versus bedtime insulin in the treatment of patients with conventional oral antidiabetic drug failure: a 1-year randomized clinical trial. Adv Ther 23:799–808 Jain R, Osei K, Kupfer S, Perez AT, Zhang J (2006) Long-term safety of pioglitazone versus glyburide in patients with recently diagnosed type 2 diabetes mellitus. Pharmacotherapy 26: 1388–1395 Hanefeld M, Patwardhan R, Jones NP (2007) A one-year study comparing the efficacy and safety of rosiglitazone and glibenclamide in the treatment of type 2 diabetes. Nutr Metab Cardiovasc Dis 17:13–23 Nissen SE, Nicholls SJ, Wolski K, Nesto R, Kupfer S, Perez A, Jure H, De Larochelliere R, Staniloae CS, Mavromatis K, Saw J, Hu B, Lincoff AM, Tuzcu EM (2008) Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA 299:1561–1573 Acta Diabetol 32. Kumar SR, Scehnet JS, Ley EJ, Singh J, Krasnoperov V, Liu R, Manchanda PK, Ladner RD, Hawes D, Weaver FA, Beart RW, Singh G, Nguyen C, Kahn M, Gill PS (2009) Preferential induction of EphB4 over EphB2 and its implication in colorectal cancer progression. Cancer Res 69:3736–3745 33. Voutsadakis IA (2007) Peroxisome proliferator-activated receptor gamma (PPARgamma) and colorectal carcinogenesis. J Cancer Res Clin Oncol 133:917–928 34. Tseng CH (2012) Pioglitazone and bladder cancer: a populationbased study of Taiwanese. Diabetes Care 35:278–280 35. Tolman KG, Freston JW, Kupfer S, Perez A (2009) Liver safety in patients with type 2 diabetes treated with pioglitazone: results from a 3-year, randomized, comparator-controlled study in the US. Drug Saf 32:787–800 36. Charbonnel BH, Matthews DR, Schernthaner G, Hanefeld M, Brunetti P (2005) A long-term comparison of pioglitazone and gliclazide in patients with Type 2 diabetes mellitus: a randomized, double-blind, parallel-group comparison trial. Diabet Med 22:399–405 37. Suzuki S, Arnold LL, Pennington KL, Kakiuchi-Kiyota S, Wei M, Wanibuchi H, Cohen SM (2010) Effects of pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, on the urine and urothelium of the rat. Toxicol Sci 113:349–357 38. Sato K, Awasaki Y, Kandori H, Tanakamaru ZY, Nagai H, Baron D, Yamamoto M (2011) Suppressive effects of acid-forming diet against the tumorigenic potential of pioglitazone hydrochloride in the urinary bladder of male rats. Toxicol Appl Pharmacol 251:234–244 39. Chaffer CL, Thomas DM, Thompson EW, Williams ED (2006) PPARgamma-independent induction of growth arrest and apoptosis in prostate and bladder carcinoma. BMC Cancer 6:53 40. Hassan MM, Curley SA, Li D, Kaseb A, Davila M, Abdalla EK, Javle M, Moghazy DM, Lozano RD, Abbruzzese JL, Vauthey JN (2010) Association of diabetes duration and diabetes treatment with the risk of hepatocellular carcinoma. Cancer 116:1938–1946 41. Chang CH, Lin JW, Wu LC, Lai MS, Chuang LM, Chan KA (2011) Association of thiazolidinediones with liver cancer and colorectal cancer in type 2 diabetes mellitus. Hepatology [Epub ahead of print]. doi:10.1002/hep.25509 42. Perseghin G, Calori G, Lattuada G, Ragogna F, Dugnani E, Garancini MP, Crosignani P, Villa M, Bosi E, Ruotolo G, Piemonti L (2012) Insulin resistance/hyperinsulinemia and cancer mortality: the Cremona study at the 15th year of follow-up. Acta Diabetol [Epub ahead of print] 43. Nicolucci A (2010) Epidemiological aspects of neoplasms in diabetes. Acta Diabetol 47:87–95 123