Available data from randomized clinical trials, summarized in the present meta-analysis, do not support the recent hypothesis of an increased risk of cancer associated with rosiglitazone (2
). On the contrary, the incidence of malignancies in patients receiving rosiglitazone is not higher than that observed with comparators, although a possible protective effect of the drug, as suggested by previous observations, was not confirmed by the present data (1
). In consideration of the fact that metformin treatment is associated with reduced risk of cancer in epidemiological studies (18
), the hypothesis of a protective effect attributable to enhancement of insulin sensitivity and/or reduction of circulating insulin levels should be considered, along with other more direct, PPAR-γ–dependent or –independent effects of the drug (4
). However, the pooled rate ratio did not highlight any effect of rosiglitazone on the risk of cancer. This discrepancy could be due to the fact that the proportion of subjects receiving rosiglitazone and control treatments varies across trials enrolling patients with different characteristics, which may affect the incidence of cancer. It should also be considered that incidence densities and rate ratios reported in the present analysis were obtained on the basis of several problematic assumptions (i.e., that rates of loss at follow-up, mortality, and incidence of malignancies were constant throughout the duration of each trial); these results should therefore be considered with caution. A meta-analysis of rosiglitazone trials based on patient-level data should be performed to gather more reliable information on this issue.
The gold standard for the assessment of the effects of drug treatments on major outcomes is represented by specifically designed and appropriately sized randomized clinical trials. Unfortunately, in the case of hypoglycemic drugs, such trials are often unavailable. Therefore, meta-analyses of events occurring in randomized trials designed with different end points have been used as a surrogate source of information (15
). The limitations of this procedure should be clearly recognized; in particular, the classification of outcomes reported as adverse events and not as predefined end points can be problematic. Notably, most published trials do not report any information on incident malignancies; cases could be easily identified only in trials reported on the GSK Web site (11
), which contains a detailed description of all serious adverse events. Furthermore, the inclusion in a meta-analysis of many small trials with a very low number of events poses challenging problems in statistical analysis (12
). It should also be considered that clinical trials usually enroll relatively young patients with low comorbidity and high compliance, who can be considered to have a low risk for cancer.
On the other hand, a trial assessing the effect of a hypoglycemic drug on the incidence of malignancies would be hypothetically very difficult to realize because of the required sample size and duration of follow-up. For this reason, information on this end point can be obtained only through epidemiological studies or meta-analyses of trials designed for other purposes. The epidemiological approach provides the advantage of the possibility of collecting large samples with a long duration of follow-up; however, in observational studies multiple adjustments for confounders can never fully eliminate the prescription bias (i.e., the effect of differences in characteristics of patients on different therapeutic choices). Such a bias could be responsible for the discrepancy between our results and those of a recent cross-sectional survey (2
The number of events included in the present meta-analysis does not allow a reliable analysis on specific types of cancer. However, our data are consistent with the possibility of specific protection from lung cancer, which has been reported previously in a epidemiological study (1
). Considering that the pathogenesis of different forms of cancer is very heterogeneous, the drug could have divergent effects on different malignancies. Interestingly, no reduction of risk for cancer of the female genital tract was detected in rosiglitazone-treated patients, although the drug is used in the treatment of polycystic ovary syndrome (20
), which is a known risk factor for these malignancies (21
). Larger databases are needed to elucidate the risk profile for individual forms of cancer in rosiglitazone-treated patients.
In summary, the use of rosiglitazone appears to be safe with respect to risk of incident malignancies, whereas further studies are needed to confirm a possible protective effect. The incidence of cancer, which can probably be modified by hypoglycemic drugs, deserves to be considered among the relevant outcomes for the choice of treatment for type 2 diabetes.