Metformin use and mortality in Asian, diabetic patients with prostate cancer on androgen deprivation therapy: A population‐based study

Abstract Background This study aims to examine the associations between metformin use concurrent with androgen deprivation therapy (ADT) and mortality risks in Asian, diabetic patients with prostate cancer (PCa). Methods This study identified diabetic adults with PCa receiving any ADT attending public hospitals in Hong Kong between December 1999 and March 2021 retrospectively, with follow‐up until September 2021. Patients with <6 months of medical castration without subsequent bilateral orchidectomy, <6 months of concurrent metformin use and ADT, or missing baseline HbA1c were excluded. Metformin users had ≥180 days of concurrent metformin use and ADT, while non‐users had no concurrent metformin use and ADT or never used metformin. The primary outcome was PCa‐related mortality. The secondary outcome was all‐cause mortality. The study used inverse probability treatment weighting to balance covariates. Results The analyzed cohort consisted of 1971 patients (1284 metformin users and 687 non‐users; mean age 76.2 ± 7.8 years). Over a mean follow‐up of 4.1 ± 3.2 years, metformin users had significantly lower risks of PCa‐related mortality (weighted hazard ratio [wHR]: 0.49 [95% confidence interval, CI: 0.39–0.61], p < 0.001) and all‐cause mortality (wHR 0.53 [0.46–0.61], p < 0.001), independent of diabetic control or status of chronic kidney disease. Such effects appeared stronger in patients with less advanced PCa, which is reflected by the absence of androgen receptor antagonist or chemotherapy use (p value for interaction: 0.017 for PCa‐related mortality; 0.048 for all‐cause mortality). Conclusions Metformin use concurrent with ADT was associated with lower risks of mortality in Asian, diabetic patients with PCa.


| INTRODUCTION
Globally, prostate cancer (PCa) was the second most common cancer and fifth major cause of cancer mortality among males in 2012. 1 Patients with PCa have a high rate of mortality, which could be partially attributed to the treatment they receive. Androgen deprivation therapy (ADT) has been the mainstay treatment of locally advanced and metastatic PCa. Despite the benefits associated with ADT, it can cause a range of side effects such as metabolic changes and greater risk of diabetes mellitus (DM) and cardiovascular diseases. 2,3 Metformin is used as first-line pharmacotherapy to treat people with DM. In addition, it could decrease some of the unfavorable metabolic consequences of ADT. Moreover, metformin could enhance the tumor-suppressive effect of ADT, 4 possibly because of its anticancer activity and interplay with the androgen receptor (AR) signaling axis. 5 It has been shown that metformin may decrease risk of biochemical recurrence 6 and improve survival in patients with PCa. 7,8 However, it is unclear whether the survival benefits associated with metformin use in PCa is applicable to ADT.

Research in this area is important, especially in Asian populations
where the incidence of PCa is increasing. 9 Therefore, this study examined the associations between metformin use concurrent with ADT and mortality risks among Asian, diabetic patients with PCa.

| Source of data
This retrospective cohort study was performed in accordance with the Declaration of Helsinki and the STROBE guideline 10  death records, from which mortality data may be obtained. Causes of mortality were encoded using either ICD-9 or ICD-10 codes, depending on the year of death. This system has been used extensively for research. 11-14

| Study design and population
Adult patients (18 years old or above) diagnosed with PCa and DM, who were receiving ADT in Hong Kong between December 1, 1999 and March 31, 2021 were included. Diagnosis of PCa was determined by ICD-9 codes (Supporting Information: Table 1), while that of DM was determined by the corresponding ICD-9 codes (Supporting Information: Table 1), any baseline use of antidiabetic medication, or hemoglobin A1c (HbA1c) level higher than 6.5% before the initiation of ADT. ADT included bilateral orchidectomy, gonadotrophin-releasing hormone agonists, and gonadotrophin-releasing hormone antagonists.
The following patients were excluded: (a) with less than 6 months of medical castration without subsequent bilateral orchidectomy, (b) with less than 6 months of concurrent metformin use and ADT, and (c) with missing baseline HbA1c value.
Metformin users were defined as patients who had at least 6 months of concurrent metformin use and ADT. Metformin nonusers were defined as patients without concurrent metformin use and ADT or without any metformin use.

| Follow-up and outcomes
All patients were followed-up from the day of ADT initiation (baseline date) until September 30, 2021. The primary outcome was PCarelated mortality. The secondary outcome was all-cause mortality.
The duration between ADT initiation and mortality was recorded. All causes of death were determined by ICD codes (Supporting Information: Table 1).

| Statistical analyses
All patients' age and other comorbidities at baseline, as determined by ICD-9 codes (Supporting Information: Table 2), type of ADT received, use of other medications, use of other treatments of PCa (radiotherapy, radical prostatectomy, prior chemotherapy and chemotherapy concurrent with ADT), and HbA1c level at baseline were recorded. The list of medications used were summarized in Supporting Information: Table 3.
Continuous variables were expressed as mean ± SD. Inverse probability treatment weighting (IPTW) using the aforementioned covariates was used to balance the treatment groups. Standardized mean differences (SMDs) were calculated for each covariate to examine the balance of covariates between treatment groups, with values ≤0.1 being considered to represent good balance.
IPTW univariable Cox regression was used to assess the associations of metformin treatment with the risks of outcomes.
Weighted hazard ratios (wHR) with 95% confidence intervals (CI) were used as the summary statistics. Kaplan-Meier curves were used to visualize the cumulative freedom from the outcomes.

| Subgroup analyses
An a priori subgroup analysis was performed for the use of AR antagonists or chemotherapy, typical treatments of metastatic PCa, as surrogate markers of metastatic PCa. A second a priori subgroup analysis was performed for each type of ADT given to investigate whether the associations between metformin use and mortality risks remained significant for different types of ADT. Furthermore, to examine the interactions between metformin's associations with mortality risks and diabetic control, for which baseline insulin use and baseline HbA1c level were used as surrogate markers, two a priori subgroup analyses were performed for these two covariates, with corresponding p values for interaction generated.

| Sensitivity analyses
As chronic kidney disease (CKD) is a contraindication for metformin prescription, a sensitivity analysis that only included patients without CKD at baseline was performed. To investigate whether the observed results were affected by metformin use that was not concurrent with ADT, a second sensitivity analysis was performed where patients who had any metformin use at any timepoint were excluded from the metformin nonuser group, such that metformin users were compared only against patients who never used metformin. To further investigate whether metformin use at the time of ADT initiation had any effect on the observed results, a third sensitivity analysis was performed where patients who were not using metformin at the time of ADT initiation were excluded from the metformin user group, and patients who had any metformin use at any timepoint were excluded from the metformin nonuser group, such that only metformin users who had metformin use at the time of ADT initiation were compared against patients who never used metformin.
To investigate the association between the duration of concurrent metformin use and ADT (metformin use duration) and To account for erroneous estimation of hazards by conventional survival analyses brought by high mortality rate, competing risk analysis was performed with non-PCa-related mortality as the competing event using Fine-Gray subdistribution model. Univariable competing risk regression with IPTW was used to assess the association between metformin use and risk of PCa-related mortality. Subhazard ratios (SHRs) with 95% CI were used as summary statistics.

| Study cohort
In total, 2886 patients were eligible for inclusion. After applying the exclusion criteria, 1971 patients were included in the analysis ( Figure 1), of whom 1284 were metformin users and 687 were non-users. The mean age was 76.2 ± 7.8 years; the mean metformin duration was 10.0 ± 5.1 years; 652 patients (33.1%) received bilateral orchidectomy only, 1090 (55.3%) received medical castration only, and 229 (11.6%) received both. Among those who received medical castration only, the mean duration of treatment was 2.9 ± 2.3 years.
Baseline characteristics of included patients were summarized in Table 1, which also demonstrates good balance of all covariates by IPTW (SMD ≤ 0.1 for all). The comparison of baseline characteristics between patients included and excluded in the analysis is shown in Supporting Information: Table 4, with higher percentage for the use of baseline chemotherapy, chemotherapy concurrent with ADT, and AR antagonists among patients to be analyzed.

| Subgroup analyses
Among patients with or without AR antagonists or chemotherapy use (N = 876 and N = 1096, respectively), metformin users had significantly lower risks of PCa-related mortality and all-cause mortality, with stronger associations observed in patients without AR antagonist or chemotherapy use (p value for interaction = 0.017 and 0.048, respectively; Table 2). This may suggest that the survival benefits associated with metformin may be more pronounced among patients without metastatic PCa.  Table 7.
These suggested that baseline diabetic control did not affect the observed associations between metformin use and risks of outcomes.

| Sensitivity analyses
Sensitivity analysis performed for patients without CKD (N = 1828) showed that metformin use remained significantly associated with lower risks of all outcomes (p < 0.001 for all; Supporting Information: Table 8). Additionally, metformin use remained significantly associated with lower risks of all outcomes when metformin users were compared only against patients who never used metformin (N = 1630; p < 0.001 for all; Supporting Information: Table 9

| DISCUSSION
This retrospective cohort study showed that, over a mean follow-up duration of more than 4 years, concurrent metformin use and ADT in Asian, diabetic patients with PCa was associated with significantly lower risks of PCa-related mortality and all-cause mortality. Such associations were independent of diabetic control and metformin use nonconcurrent with ADT and appeared to be stronger in those without concurrent use of AR antagonist or chemotherapy. To the best of the authors' knowledge, this was one of the first studies F I G U R E 1 Study flow chart. ADT, androgen deprivation therapy. BO, bilateral orchidectomy. HbA1c, hemoglobin A1c.
demonstrating survival benefits associated with metformin use concurrent with ADT among patients with PCa in Asia.

| Underlying mechanisms
Metformin's anticancer activity may be related to AMP-activated protein kinase (AMPK) activation. Generally, AMPK can cause cell cycle arrest by inhibiting the protein kinase B/mammalian target of rapamycin signaling pathway 15 and p70S6 kinase, a downstream target. 16 Nonetheless, the role of AMPK in PCa is not fully understood. It is hypothesized that each unique AMPK complex regulates downstream processes that can be tumor suppressive or oncogenic, and their weighted net function then determines AMPK's final output, influenced by additional prostate-specific signaling. 17 Furthermore, how metformin inhibits cancer growth is controversial.
T A B L E 1 Baseline characteristics with standardized mean differences (SMD) before and after inverse probability treatment weighting (IPTW)  20 Metformin's anticancer activity can also be AMPK-independent. For instance, it may be attributed to its interaction with pathways specific for PCa cell lines.
AR signaling is involved in the development of PCa irrespective of castration 21 by disrupting cell cycle regulation 22 and activating the erythroblast transformation specific (ETS) oncogene family through ERG. 23,24 While ADT suppresses AR signaling, ectopic expression of the c-Myc oncogene could attenuate such effects, 25 leading to castration-resistant prostate cancer (CRPC). 26 In PCa cells treated by metformin, c-Myc protein levels are reduced and AR signaling could be suppressed. 27 Additionally, metformin could inhibit androgen-dependent upregulation of insulin-like growth factor receptor type I 28 responsible for promoting the survival, development, and proliferation of PCa cells. 29

| Prior studies and future directions
The association between metformin use and mortality risks in patients with PCa is unclear. While some studies suggested an association between metformin use and improved survival in diabetic patients with PCa, 7,8 others did not observe any significant associations. 30,31 Donata et al. 31 found null association in a nondiabetic population, but their study was limited by a small (N = 254) and largely heterogeneous population. Kaushik et al. 30 also showed null association, but their study was limited to patients with PCa who had undergone radical prostatectomy. Furthermore, PCa-related mortality was not explored.
Their incidence of all-cause mortality (7.8%) was also much lower than in our study (62.4%), suggesting that our study may be better powered to examine the associations between metformin use and mortality risks. Our results were consistent with metformin's potential role in delaying the development of CRPC. Patients receiving long-term ADT have higher risks of developing CRPC. 34 We observed stronger associations between metformin use and mortality risks among patients who never received AR antagonists or chemotherapy, which are typical treatments for metastatic PCa. 35 The survival benefits associated with metformin use appeared stronger in those without metastatic PCa as they are less likely to had already developed CRPC. 36 The anticancer activity of metformin was previously demonstrated in patients with localized PCa. 37

| Strengths and limitations
This study used a representative population-based database with long follow-up duration. Our results are thus likely to be widely generalizable and reflect real-world practice. Sensitivity analyses using different approaches showed consistent results, indicating robustness. However, several limitations should be noted. First, as an observational study, residual confounding cannot be excluded.
Second, since all diagnoses were identified using ICD-9 codes as recorded by CDARS, the data could not be adjudicated individually.
Nonetheless, the data input was performed by the treating physicians, and none of the authors had influence over these inputs. In addition, the coding accuracy of the system was well demonstrated in other studies. 11,13 Third, cancer staging details were unavailable due to the nature of the data. We addressed this limitation by using antiandrogens or chemotherapy as surrogates for metastatic PCa.

| CONCLUSIONS
Metformin use concurrent with ADT in Asian, diabetic patients with PCa was associated with significantly lower risks of PCa-related and all-cause mortality. Such associations appeared stronger in patients without AR antagonist or chemotherapy use and were independent of diabetic control and metformin use nonconcurrent with ADT.
Further validation in other Asian cohorts is warranted to explore whether the suggested benefits may be further generalizable.

AUTHOR CONTRIBUTIONS
All authors contributed to the study conception and design. Material T A B L E 2 Weighted comparisons of outcomes by metformin usage with subgroups for androgen receptor antagonist or chemotherapy usage. Hazard ratios were referenced against metformin non-users.