Geriatric Cardiology, Careggi Teaching Hospital, Florence, Italy,
Acta Diabetol. 2014 Feb;51(1):91-101. doi: 10.1007/s00592-013-0504-8. Epub 2013 Jul 14.
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 A meta-analysis was performed including published and unpublished randomized trials with a duration of at least 52 weeks, enrolling patients with or without diabetes, comparing TZDs with either placebo or other drug therapies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 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.
最近的流行病学数据有助于提出关于吡格列酮（噻唑烷二酮[TZD]）长期安全性的假设，特别是膀胱癌的安全性。这项对随机临床试验的荟萃分析的主要目的是探索 TZD 是否会影响癌症风险。该荟萃分析包括已发表和未发表的至少 52 周的随机试验，招募了患有或不患有糖尿病的患者，比较了 TZD 与安慰剂或其他药物治疗在各种不同结果方面的差异。我们发现 22 项试验报告了至少一种癌症，并招募了 13197 名患者接受 TZD（吡格列酮：n = 3710 名和罗格列酮：n = 9487 名）和 12359 名患者接受安慰剂或活性对照组。平均随访时间为 26.1 个月。总体而言，随机分配到 TZD 的患者恶性肿瘤发病率显著降低（MH-OR 0.85 [0.73-0.98]；p = 0.027），吡格列酮和罗格列酮之间的效果无显著差异。具体而言，亚组分析显示罗格列酮显著降低（MH-OR 0.82 [0.69-0.98]；p = 0.029），但吡格列酮无显著降低（MH-OR 0.66 [0.34-1.28]；p = 0.22）。基于四项试验的数据，进一步对特定部位恶性肿瘤进行亚组分析，吡格列酮相关膀胱癌的风险（MH-OR）为 2.05 [0.84-5.02]；p = 0.12。此外，罗格列酮而不是吡格列酮与结直肠癌风险显著降低相关。相反，吡格列酮而非罗格列酮与乳腺癌风险显著降低相关。本项并非事先设计用于检验假设的临床试验荟萃分析提供了令人放心的证据，表明 TZD 与总体恶性肿瘤风险无关。事实上，它们与癌症风险降低的可能性一致。在特定部位的亚组分析中，罗格列酮结直肠癌的风险显著降低。吡格列酮的亚组分析不能排除膀胱癌风险增加的可能性，而乳腺癌的风险则显著降低。虽然这些数据也有助于制定而非检验假设，但它们提供的证据比之前发表的流行病学数据更有说服力。
