At an initial glance, our synthesis of the available evidence suggests no association between metformin exposure and prostate cancer risk, a finding that is congruent in observational studies whether Western-based or Asian-based. A lower risk of prostate cancer with metformin exposure was evident in Asian-based studies, although statistically insignificant, and heavily influenced by a single, large study from Taiwan with an extreme risk estimate . Removing this study returns this association to the null, and removes substantial heterogeneity. Although based on its Newcastle-Ottawa score, this study was not more biased than other studies, had a high level of precision and had a large sample size. Thus it may inappropriate to exclude this study from the pooled estimates. In fact, this study may act as a reference point in the funnel plot that all other studies should be compared against. However, given its large sample size and subsequent influence on the pooled risk estimate, we felt it prudent to explore the effect of this study on the pooled risk estimate by excluding it from pooled risk estimate as a type of sensitivity analysis.
Only two clinical trials were identified thus insufficient data from a study design with a high level of methodological rigour are available. Furthermore, observational studies do not identify an association but contradict the study with the largest sample size. Moreover, the funnel plot contains points clustered around the null and does not resemble a funnel shape. This may indicate that there are unpublished or unidentified studies or that metformin exposure has disparate effects on disparate study characteristics such as age or utilization of metformin. Thus there is currently insufficient evidence to form strong conclusions regarding the association between ethnicity, metformin exposure and prostate cancer. However, the current evidence may suggest that there is no association between metformin exposure, ethnicity and prostate cancer incidence.
Previous systematic reviews on the topic have found similar results, with no statistically significant association between metformin exposure and prostate cancer risk. Gandini et al. associated metformin exposure with a 1.06 (0.80,1.41) relative risk and an I2 of 91% . However they could only pool 12 studies at the time. Franciosi et al. achieved a similar pooled estimate from observational studies, 0.96 (0.87, 1.05) with an I2 of 60% but pooled certain studies more than once . Noto et al. pooled 7 studies and found a risk estimate of 0.89 (0.66, 1.19) with an I2 of 66% . Similarly, Soranna et al. found a pooled estimate of 0.92 (0.73, 1.17) with an I2 of 78% . Wu et al. pooled 10 studies yielding an estimate of 0.92 (0.84, 1.03) with an I2 of 71% . However, Yu et al. and Deng et al. found a slight statistically significant reductions in prostate cancer risk associated with metformin use, of 9% and 12%, respectively, although with substantial (50-75%) heterogenetity [38, 39]. Thus, our results agree with most previous systematic reviews, which were also limited by significant heterogeneity, while including more recent studies. Moreover, our specific focus on the stratification by ethnicity has specifically addressed one potential source of heterogeneity.
Despite some strengths, the review possesses some limitations. The first and most significant limitation is the lack of individual patient data, thus we were relegated to stratifying by ethnicity based on the origin of the database. These databases may contain patients of several ethnicities and any potential ensuing misclassification may have biased our results. Furthermore, despite stratification by ethnicity, study design and risk of bias, significant heterogeneity was observed. Because analysis using crude values yielded I2 ranging from 74% to 98%, the observed heterogeneity may not be solely due to disparate methods of statistical adjustment. Instead it may be a result of different patient populations or methodological heterogeneity. Regardless, pooling may not be the most accurate depiction of the association between metformin exposure and prostate cancer risk. Furthermore, pooling two Western-based clinical trials likely does not provide reliable results, thus we are limited to reporting the pooled estimate from Western-based clinical trials on a narrative basis. Similarly, other analyses in our supplemental materials only included one or two studies which would not provide reliable estimates and are only provided for illustrative purposes.
What may also be considered a major limitation is the inconsistent drug exposure definitions used in each study, which may have also contributed to the observed heterogeneity. While some studies defined metformin exposure using an ever/never definition or metformin use/no use definitions, other studies compared metformin use against sulfonylurea use or diet. Ideally, the association between metformin exposure and cancer risk would account for time-varying and accumulated drug exposure . Van Staa et al., Azoulay et al., Preston et al. and Margel et al. evaluated the association between prostate cancer risk and cumulative metformin exposure [9, 18, 23, 26]. Among these studies, higher metformin doses were associated with increased, decreased and no association with any prostate cancer risk. Preston et al. did not associate higher doses of metformin exposure with any prostate cancer but with a reduced risk of localized prostate cancer . On the contrary, Margel et al. found no association between cumulative metformin exposure and low- or high-grade prostate cancer . This presents another potential factor in to our research questions, suggesting that definition, cumulative dose or duration of metformin exposure, as well as prostate cancer grade, may influence the association between metformin and prostate cancer risk.
Moreover, body mass index (BMI) has been associated with increased aggressive prostate cancer risk, which may be particularly important in our study . Non-Asian-Americans with normal BMIs possess lower mean prostate specific antigen levels than Asian-Americans with normal BMIs while non-Asian-Americans who are overweight or obese have higher levels than overweight or obese Asian-Americans. Thus BMI introduces an additional variable that may affect the potential association between metformin exposure, ethnicity and prostate cancer incidence. Further, most studies lacked adjustment for other prognostic clinical variables such as family history of cancer. Unfortunately, these could not be adequately explored in our review because not all studies adjusted for BMI or other clinical covariates and individual level data was not available.