Impact of Metformin on Clinical Outcomes Among Men With Prostate Cancer

A Systematic Review and Meta-analysis

AD Raval; D Thakker; A Vyas; M Salkini; S Madhavan; U Sambamoorthi

Disclosures

Prostate Cancer Prostatic Dis. 2015;18(2):110-121. 

In This Article

Abstract and Introduction

Abstract

Background Conflicting evidence exists regarding the beneficial effects of metformin in prostate cancer. To determine the association between metformin and clinical outcomes in prostate cancer using systematic review and meta-analysis.

Methods Original articles published in English until third week of July, 2014 were searched in electronic databases (Medline-Ovid, Scopus, The Cochrane Library, Web of Science, ProQuest) for studies on metformin use in prostate cancer. The clinical outcomes assessed were: development of biochemical recurrence, metastases or castration-resistant metastatic cancer, all-cause and prostate cancer-specific mortality. Meta-analysis was performed to calculate the pooled hazard ratio (pHR) and their 95% confidence interval (95% CI). Heterogeneity between the studies was examined using I2 statistics. Sensitivity analysis was conducted to assess the robustness of findings and publication bias was assessed by the Egger's regression asymmetry test and contour plot.

Results Out of 230 retrieved citations, eight retrospective cohort studies and one nested-case-control study met the inclusion criteria. Metformin use was marginally associated with reduction in the risk of biochemical recurrence (pHR: 0.82, 95% CI: 0.67, 1.01, P-value=0.06, I2=25%, five studies). Metformin use was not significantly associated with metastases (pHR: 0.59, 95% 0.30–1.18, P-value=0.14, I2=74%, three studies), all-cause mortality (pHR: 0.86; 95% CI, 0.67, 1.10, P-value=0.23, I2: 73%, six studies) and prostate cancer-specific mortality (pHR: 0.76, 95% CI: 0.43, 1.33, P-value = 0.33, I2=60%, four studies). Pooled estimates for all outcomes varied in sensitivity analysis by diabetes status and primary treatment of prostate cancer. Systematic review revealed mixed findings on metformin use and the risk of CRPC.

Conclusions Metformin may reduce the risk of biochemical recurrence in prostate cancer. Given the potential of selection bias in the observational studies, randomized trials should be designed to assess the efficacy of metformin use in prostate cancer.

Introduction

Metformin, a biguanide, is the first-line of treatment for individuals with type 2 diabetes mellitus (T2DM).[1] Currently, there is a growing interest in examining role of the metformin for its anticancer properties in different cancers. A recent systematic review by Franciosi et al. of metformin and risk of cancer among individuals with T2DM found a reduction in the risk of development of any cancer due to metformin use (pooled adjusted odds ratio, (paOR): 0.73, 95% confidence interval, (CI): 0.61–0.88, 18 studies, 561 836 individuals). Furthermore, three systematic reviews assessed the effects of metformin among individuals with any type of cancer.[2–4] A meta-analysis of 20 studies of individuals with T2DM reported that metformin was associated with a 34% reduction in overall mortality (pooled hazard ratio, (pHR)=0.66; 95% CI: 0.55–0.79) and a 38% reduction in cancer-specific mortality (pHR=0.62; 95% CI: 0.46–0.84).[2] Two systematic reviews of the association of metformin with mortality conducted among individuals with any type of cancer with presence or absence of T2DM and came to similar conclusions.[2–4] However, there have been differences in the associations between types of cancers and mortality risk with the use of metformin.[2–4] For example, a systematic review by Zhang et al.[3] found that metformin was associated with the reduction in mortality in breast, colorectal, ovarian and endometrial cancer while was not associated with the reduction in mortality in lung, pancreas and prostate cancer. These differences in the association of metformin on mortality by types of cancers may be attributed to the differential prognostic and primary treatment-related factors associated with different types of cancers. Therefore, there is a vital need for studies evaluating prognosis and outcomes of metformin use in men with a specific cancer such as prostate cancer.[5]

Prostate cancer is the most common non-skin cancer in men in the United States.[6] Although prostate cancer is the second leading cause of death due to cancers in men, 5-year survival rates approach nearly 100% among men diagnosed with prostate cancer at the localized or regional stage.[6] Therefore, one of the key management strategies for prostate cancer is to delay progression of cancer by delaying the development of biochemical recurrence, metastases and castration-resistant prostate cancer. Metformin has been shown to inhibit progression in prostate cancer by modifying the expression of tumor suppressor genes and oncogenes in animal and in vitro studies.[7] It is believed to activate protease enzymes that are responsible for the development of cancer via insulin-dependent and insulin-independent mechanisms.[7–9] Furthermore, metformin reduces hyperinsulinemia[10] and hyperglycemia,[11] both of which are potential risk factors for mortality in prostate cancer.[1] Metformin downregulates the androgen-receptors levels which in turn maximizes the anticancer properties of androgen depriving therapy (ADT).[12] Therefore, it is reasonable to expect that metformin may have a potential role in delaying disease progression, and improving clinical outcomes in men with prostate cancer.

Although evidence about the anticancer properties of metformin in in vitro and animal studies exists, there have been contradictory findings about the association between metformin use and prostate cancer-specific and all-cause mortality, biochemical recurrence and metastases among individual studies.[13–15] Three systematic reviews conducted at various time periods (as of June 2012,[3] as of July 2013,[2] and as of December 2013[4]) found that metformin was not significantly associated with all-cause and prostate cancer-specific mortality among men with prostate cancer. However, there have new studies published since the search time of the three systematic reviews assessing outcomes of metformin in men with prostate cancer. Furthermore, these systematic reviews did not assess crucial measures of cancer progression such as biochemical recurrence, metastases or castration-resistant prostate cancer (CRPC). Therefore, the current systematic review and meta-analysis were conducted to examine the association between metformin use and clinical outcomes. We have selected biochemical recurrence as the primary outcome because one of the key management strategies for prostate cancer is to delay progression of cancer by delaying development of biochemical recurrence. In addition, the reduction in the risk of biochemical recurrence may improve clinical outcomes such as metastases and mortality. We considered metastases, CRPC, all-cause and prostate cancer-specific mortality as secondary outcomes.

Our primary hypothesis was that metformin use will be associated with a reduction in the risk of biochemical recurrence among men with prostate cancer. Our secondary hypotheses were the metformin use will be associated with improvement in clinical outcomes such as metastases, CRPC, all-cause and prostate cancer-specific mortality. Although metformin is commonly prescribed for diabetes management, in this meta-analysis, we included studies that focused on men with prostate cancer regardless of diabetes status.

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