Elsevier

European Journal of Cancer

Volume 50, Issue 16, November 2014, Pages 2831-2837
European Journal of Cancer

Original Research
Metformin significantly reduces incident prostate cancer risk in Taiwanese men with type 2 diabetes mellitus

https://doi.org/10.1016/j.ejca.2014.08.007Get rights and content

Abstract

Background

Whether metformin therapy affects incident prostate cancer risk in Asian patients with type 2 diabetes mellitus (T2DM) has not been investigated.

Methods

The National Health Insurance reimbursement database of Taiwanese male patients with new-onset T2DM between 1998 and 2002 and aged ⩾40 years (n = 395,481) were retrieved to follow up prostate cancer incidence until the end of 2009. Metformin was treated as a time-dependent variable. Of the patients studied, 209,269 were never-users and 186,212 were ever-users. A time-dependent approach was used to calculate prostate cancer incidence and estimate hazard ratios using Cox regression for ever-users, never-users and subgroups of metformin exposure (tertiles of cumulative duration and cumulative dose). Sensitivity analyses were conducted in various subgroups, using time-dependent and non-time-dependent approaches.

Results

During the follow-up, 2776 metformin ever-users and 9642 never-users developed prostate cancer, representing an incidence of 239.42 and 737.10 per 100,000 person-years, respectively. The hazard ratio (95% confidence intervals) after adjustment for propensity score (PS) for ever- versus never-users was 0.467 (0.446–0.488). The PS-adjusted hazard ratios for the first, second and third tertiles of cumulative duration of metformin therapy were 0.741 (0.698–0.786), 0.474 (0.441–0.508) and 0.231 (0.212–0.253), respectively (P-trend < 0.001); and were 0.742 (0.700–0.786), 0.436 (0.406–0.468) and 0.228 (0.208–0.251) for the respective cumulative dose (P-trend < 0.001). Sensitivity analyses consistently supported a protective effect of metformin on incident prostate cancer.

Conclusions

Metformin use is associated with a decreased risk of incident prostate cancer in Taiwanese male patients with T2DM.

Introduction

The incidence of prostate cancer varies by 25-fold among different countries [1]. In general, developed countries in Europe and North America have a higher incidence than less developed countries in Asia and Africa [1]. In contrast to the decreasing incidence in well-developed countries, the incidence in Asian populations is increasing [1]. In Taiwan, the age-standardised incidence of [2] and mortality from [3] prostate cancer are both increasing in the general population.

Metformin is a commonly used oral antidiabetic drug in patients with type 2 diabetes mellitus (T2DM), and may exert anticancer effects [4]. However, whether metformin can affect the risk of incident prostate cancer is still a matter of debate. While some studies suggested a null association [5], [6], [7], [8], [9], a potential beneficial effect was observed in others [10], [11]. One study even suggested a significantly higher risk for patients having >36 metformin prescriptions [12]. A recent meta-analysis including four studies [2], [6], [12], [13] showed a null association with a pooled hazard ratio of 0.92 (95% confidence interval: 0.73–1.17) [14].

Because the association between metformin and incident prostate cancer is controversial and studies conducted in Asian populations are still sparse, the present study aimed to evaluate whether metformin use could be associated with the risk of incident prostate cancer in Taiwanese male patients with T2DM using the National Health Insurance (NHI) database. A new-user design and a time-dependent approach for metformin use in data analyses were applied in order to minimise the potential confounding factors and biases commonly seen in studies using an administrative database.

Section snippets

Materials and methods

This population-based retrospective cohort study was approved by the ethics review board of the National Health Research Institutes (approval number 99274). The study used the NHI database and included all patients with a diagnosis of diabetes mellitus during the period from 1996 (the earliest database available) to 2009. A detailed description of the NHI database can be seen elsewhere [2], [15]. Diabetes mellitus was coded 250.1–250.9 and prostate cancer, 185, based on the International

Results

Fig. 1 shows the flowchart for the procedures followed in creating the cohort of male patients with new-onset T2DM and aged ⩾40 years at entry during 1998–2002. At first, 411,783 male patients were recruited. After further excluding patients with type 1 diabetes (n = 1232), those with a diagnosis of prostate cancer before diabetes diagnosis (n = 2641), those with a duplicated identification number (n = 39), unclear information on date of birth or sex (n = 7404) and a follow-up duration of <180 days (n = 

Discussion

The findings suggested that metformin use in male patients with T2DM was significantly associated with a lower risk of incident prostate cancer, which was dose–responsive, independent of potential confounders and consistent in various sensitivity analyses (Table 2, Table 3, Table 4).

Findings from previous observational studies in humans are conflicting. The population-based case–control (1001 cases and 942 controls) study by Wright and Stanford from the United States of America (USA) showed an

Conflict of interest statement

None declared.

Acknowledgement

The author thanks the National Science Council (NSC102-2314-B-002-067) of Taiwan for continuous support on epidemiological studies on diabetes and arsenic-related health issues.

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