Metformin use and prostate cancer in Caucasian men: results from a population-based case–control study

In this population-based case–control study, we observed a borderline significant reduction in the relative risk of PCa in Caucasian men taking the antidiabetic drug metformin. These results are consistent with findings from earlier epidemiologic studies and with preclinical studies demonstrating antitumor activity of metformin.

Metformin is an oral anti-hyperglycemic medication used in the management of type II DM that functions primarily through improved insulin sensitivity and decreased hepatic gluconeogenesis [16]. It is the most common drug used for treatment of type II DM and has been available in the United States since 1995 [17]. Metformin has a number of additional cellular activities that have potential antineoplastic activity including AMP-kinase pathway activation [6, 7], p-53 activation [8], downregulation of cyclin D1 [7, 9], and suppression of HER2 oncoprotein expression [6].

Recently, a Scottish case–control study found a reduced risk of overall cancer in diabetic patients taking metformin [5]. In that study, a diabetic clinical information system was linked to a prescription database and those with any vs. no metformin exposure had a 23% lower OR for cancer of any type (OR = 0.77; 95% CI 0.64–0.92). The strongest risk reduction was observed in those with the longest durations of metformin use. An additional population-based study in Saskatchewan linked a prescription database with a cancer registry and vital statistics database [4]. Diabetic patients taking metformin or a sulfonylurea were identified and followed for cancer-specific mortality. Patients taking sulfonylureas had an increased risk of cancer-specific mortality compared to those taking metformin (hazard ratio = 1.3; 95% CI 1.1–1.6). Few studies have looked specifically at PCa risk and diabetes treatment. In a large Finnish population-based registry study, a decrease in PCa risk was observed for the use of any antidiabetic drug [18]. This study found that duration of treatment was inversely related to PCa risk, suggesting that it is diabetes rather than any specific medication that decreases the risk of PCa. However, the investigators were unable to adjust for BMI, family history of PCa or PSA screening history. Further, the Finnish population is 98% Caucasian, so the differences we observed in race cannot be compared. A multi-ethnic study found an association between PCa and DM in European-Americans (RR = 0.65, 95% CI 0.50–0.84, p = 0.001) but not in African-Americans (RR = 0.89, 95% CI 0.77–1.03, p = 0.13) [3]. This was especially true in those with higher Gleason scores >7 [European-Americans (RR = 0.68, 95% CI 0.43–1.07, p = 0.09) and African-Americans RR = 0.98, 95% CI 0.71–1.29, p = 0.76)]. These results are consistent with our findings of effect modification of metformin use by race. Why diabetes and/or treatment effects on PCa risk would differ by race is unknown. African-American men often have a delay in diagnosis of DM and worse glycemic control [19], which may partially explain these findings. These differences may also relate to underlying genetic or environmental exposures and deserve further investigation.

There are several reasons to suspect that metformin may have specific anticarcinogenic properties, as it has shown inhibitory effects in preclinical models of a number of different tumor types, including prostate [9, 13], breast [6, 10, 12], pancreatic [11], lung [14] and colon cancers [8, 13]. In fact, metformin has recently been associated with increased complete response rates in women with breast cancer receiving neoadjuvant chemotherapy [20] and work is underway for Phase III trials of metformin in early stage breast cancer [21]. PCa risk has been associated with hyperinsulinemia [22, 23] and unlike sulfonylureas and exogenous insulin, metformin does not increase insulin levels [16], which may be one mechanism whereby metformin exhibits antitumor activity. Additionally, in PCa cell lines (LnCaP, PC-3, DU145), metformin has been shown to inhibit cyclin D1 expression, blocking the cell cycle in G₀/G₁ [9]. Metformin has also been shown to activate AMP-activated protein kinase (AMPK) in PC-3 cell lines [13]. AMPK is activated in response to cellular stress leading to an increased AMP/ATP ratio [24]. AMPK has gained attention for its downstream effects of reduced cellular proliferation and protein synthesis [25] along with mTOR inhibition [6, 10]. The precise pathway(s) that may be involved with metformin and its potential antitumor activity has not been defined and may involve more than one mechanism. Although our study does not evaluate any of the specific pathways that may be involved, our results draw attention specifically to PCa risk based on exposure to metformin and support ongoing efforts to explore the link between metformin exposure and PCa.

There are limitations of our study. We cannot assess duration of use of metformin, nor can we distinguish type I from type II DM. However, early onset type I is rare, and only three participants (1 case; 2 controls) reported being diagnosed with DM prior to age 18; exclusion of these men did not change our results. Overall, 10.7% of our population-based controls reported DM, which is similar to the 11% prevalence in the general US population of men over the age of 20 years [26]. We also rely on participant-reported use of medications rather than pharmacy records. In a separate analysis of a subset of this study population that was designed to validate use of statin medications, there was 87% agreement between self-reported use and computerized pharmacy records [15]. There are data showing a reduced risk of PCa in diabetic men [2, 3], such that our findings of a reduced risk in men taking metformin may be due to an independent aspect of diabetes. Further, DM may be associated with lower PSA levels [27], which could introduce detection bias. Additionally, our finding may be due to chance and should be replicated in a larger study. Despite these limitations, these findings are in support of the growing evidence from preclinical and epidemiological data supporting the potential antitumor activity of metformin. These results indicate that additional studies are warranted to evaluate the potential metformin-PCa association.