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ORIGINAL ARTICLE
Year : 2023 | Volume
: 34
| Issue : 3 | Page : 155-162
Metformin is associated with better survival rate of localized upper tract urothelial carcinoma patients with type 2 diabetes
Chung-Yu Lin1, Chien-Sheng Wang1, Jhen-Hao Jhan2, Hsiang-Ying Lee3, Yi-Hsin Yang4, Che-Wei Chang5, Hung-Lung Ke1, Ching-Chia Li1, Yung-Chin Lee1
1 Department of Urology, Kaohsiung Medical University Hospital; Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
2 Department of Urology, Kaohsiung Medical University Hospital; Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University; Department of Urology, Kaohsiung Municipal Siaogang Hospital, Kaohsiung, Taiwan
3 Department of Urology, Kaohsiung Medical University Hospital; Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University;Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
4 National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan
5 Department of Urology, Kaohsiung Medical University Hospital; Department of Urology, Kaohsiung Municipal Siaogang Hospital, Kaohsiung, Taiwan
Correspondence Address:
Chung-Yu Lin
No. 100, Tzyou 1st Road, Kaohsiung 807
Taiwan
Source of Support: None, Conflict of Interest: None
DOI: 10.4103/UROS.UROS_60_22
Purpose: Metformin, an antidiabetic drug, has been proposed to play a possible protective role in cancer recurrence and patient mortality. However, the exact mechanism and efficacy of metformin in urothelial cancer, especially upper tract urothelial carcinoma (UTUC), remain unknown. In this study, we conducted a population-based analysis to investigate whether metformin could improve the survival rate of patients with UTUC. Materials and Methods: Males ≥40 years diagnosed with UTUC were included in this retrospective population-based longitudinal cohort study. Data were collected from the registry of the Taiwan National Health Insurance database for patients with UTUC and type 2 diabetes mellitus (T2DM). Patients who had received at least two prescriptions of metformin were included in the study cohort as ever-users, and patients who had never used metformin were included in the control cohort as never-users. The hazard ratios (HRs) were calculated using Cox regression for ever-users and never-users. Results: Among the 781 enrolled patients, 439 and 342 patients were included as ever-users and never-users, respectively. The median survival time was 3.95 years in the never-user cohort compared to 6.90 years in the ever-user cohort, which remained statistically significant in both univariate and multivariate analyses (HR = 0.63 and 0.72, P = 0.0001 and 0.011, respectively). Furthermore, subgroup analysis showed that continuous usage of metformin before and after the diagnosis of UTUC was associated with a better survival in patients with UTUC (adjusted HR = 0.72, 95% confidence interval: 0.55–0.93). Conclusion: This study shows a relationship between metformin usage and better survival outcome in patients with localized UTUC. The result may contribute a favorable anticancer role of metformin in localized UTUC and suggests that continuous metformin usage improves all-cause mortality in patients with localized UTUC and T2DM.
Keywords: Diabetes, metformin, urothelial carcinoma
In the past two decades, type 2 diabetes mellitus (T2DM) has emerged as one of the most crucial medical problems because of its rapidly increasing prevalence globally. Furthermore, this trend indicates that the number of people with diabetes will continue to increase in the next decade. In 2019, the global prevalence of diabetes was 9.3%, and a predicted 463 million people worldwide were afflicted. By 2030 and 2045, this number is projected to reach 578 and 700 million due to an aging population.[1] T2DM accounts for more than 90% of diabetes cases and is characterized by relative insulin deficiency and insulin resistance. The insulin sensitizer metformin is recognized as one of the preferred first-line oral hypoglycemic agents for the treatment of T2DM, particularly in patients with normal liver and renal functions. In addition, owing to its efficient and tolerable negative effects, metformin is commonly used as an oral drug for T2DM.
Interestingly, previous observational studies have shown that metformin use in patients with T2DM decreased not only blood glucose levels but also reduced the risk of developing cancer.[2] Furthermore, metformin may also enhance the overall survival rate of patients with T2DM patients with malignancies. For instance, in patients with colorectal or prostate cancer patients, metformin may be used as an adjuvant agent.[3] In urothelial carcinoma, some studies have concentrated on the possible preventive and therapeutic advantages of metformin use. In an observational study, metformin use seems to reduce the incidence of bladder cancer in patients with T2DM.[4] In addition, a recent retrospective analysis discovered that metformin administration could enhance cancer-specific survival and recurrence-free survival in diabetic bladder cancer patients who underwent radical cystectomy. In contrast, the use of insulin or other oral hypoglycemic agents did not reveal the same oncologic benefit.[5] Furthermore, T2DM without metformin use was an independent risk factor for postoperative bladder recurrence in upper tract urothelial carcinoma (UTUC) patients who received radical nephroureterectomy (RNU).[6] These outcomes indicate a possible protective role of metformin in the oncologic outcomes of bladder urothelial carcinoma.
Although both UTUC and bladder urothelial carcinoma originate from the urothelium, they differ in etiology, epidemiology, staging, clinical management, and clinical results. The possible role of metformin in improving oncologic results in patients with UTUC is not as clear as that in bladder urothelial carcinoma. Taiwan is unique in terms of UTUC. For instance, the incidence of UTUC in Taiwan is noticeably higher than that in Western countries. UTUC accounts for more than 30% of all urothelial carcinomas in Taiwan, significantly higher than the 5% in Western countries.[7] As this problem has never been resolved in the Taiwanese population, we obtained data from the Taiwan National Health Insurance (NHI) database on a cohort of patients with UTUC to investigate the possible protective effects of metformin use.
Materials and MethodsDatabase
This was a retrospective population-based longitudinal cohort study performed in men aged ≥40 years with documentation of UTUC. Data were gathered from the registry of the Taiwan NHI database for patients with the illness. This health insurance program, established in 1995, offers health care to nearly all of Taiwan's population of 23.7 million, thereby making it one of the largest insurance databases globally. This database allows researchers to longitudinally trace the use of medical services for enrollees. A cohort of 1 million individuals was randomly sampled, and important registration files and medical records of patients in the NHI program who were identified with UTUC were collected. This research was approved by the Institutional Review Board of Kaohsiung Medical University Hospital (KMUHIRB-E(I)-20180214), as the database consisted of de-identified secondary data released to the public for study purposes. This study was performed following the Declaration of Helsinki. The requirement for informed consent was waived.
Patients
The current study included a study cohort and a control cohort with propensity score matching for comparison. Initially, records of patients who were diagnosed with UTUC (International Classification of Disease 9 Clinical Modification [ICD-9-CM] codes 1891 and 1892) in Taiwan from January 1, 2003, to December 31, 2011, were obtained. Patients with T2DM were then diagnosed in this UTUC population utilizing ICD-9-CM diagnostic codes 250.0–250.9. Patients were excluded from the study if they met any of the following requirements: (1) had undergone chemotherapy or had been identified with metastatic UTUC, (2) only had one prescription of metformin in the previous 6 months, or (3) incomplete demographic data. Two cohorts were created from the included population: a never-user cohort and an ever-user cohort (defined as never having received more than two prescriptions for metformin or products containing it within 6 months). Demographic data of patients, such as age and follow-up duration, were recorded. Several oral hypoglycemic medicines and related drugs, including sulfonylureas, Dipeptidyl peptidase 4 (DPP-4) inhibitors, glinides, thiazolidinediones, insulin, and statins, were used; this information was gathered. Several comorbidities that might affect our results were also analyzed, such as myocardial infarction (ICD-9-CM codes), congestive heart failure (ICD-9-CM codes), peripheral vascular disease (ICD-9-CM codes), cerebrovascular disease (ICD-9-CM codes 430–438), dementia (ICD-9-CM codes), chronic pulmonary disease (ICD-9-CM codes), rheumatologic disease (ICD-9-CM codes), peptic ulcer disease (ICD-9-CM codes), chronic kidney disease (ICD-9-CM codes 581, 582, 583, 585, 586, and 587), and moderate or severe liver disease (ICD-9-CM codes).
Statistical analysis
The average duration of overall survival in the metformin ever-user and never-user cohorts is expressed as the mean ± standard deviation of years. Pearson's Chi-squared and Fisher's exact tests were performed to compare the baseline features between the metformin ever-user and never-user cohorts. Overall survival curves were generated using Kaplan–Meier estimates to examine differences in overall survival between the cohorts. In univariate and multivariate analyses, P < 0.05 is the criteria for the stepwise selection algorithm, and the results for any-cause mortality are summarized in [Table 1], [Table 2], [Table 3]. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) calculated from univariate and multivariate Cox regression models were utilized to analyze the relationship between metformin use and overall survival. All analyses were performed using the SAS statistical software version 9.3.1 (SAS Institute Inc., Cary, NC, USA). A two-sided P < 0.05 was considered statistically significant.
Table 1: Univariate cox regression analyses of any-cause mortality in 781 upper tract urothelial carcinoma patients with type 2 diabetes mellitus about metformin usage
Table 2: Multivariate cox regression analyses of any-cause mortality in 781 upper tract urothelial carcinoma patients with type 2 diabetes mellitus about metformin usage
Table 3: Multivariable cox regression analyses of any-cause mortality in 781 upper tract urothelial carcinoma patients with type 2 diabetes mellitus Results Between January 1, 2003, and December 31, 2011, a total of 4418 patients were diagnosed with UTUC. Patients who had undergone chemotherapy and had been identified with metastatic UTUC, or whose demographic data were incomplete were excluded from the study. Ultimately, 828 patients diagnosed with T2DM and localized UTUC were selected from this population. We further excluded 47 patients because they only had one prescription of metformin in the previous 6 months. Among the 781 registered patients, 439 patients who had received at least two prescriptions of metformin were included in the study cohort (ever-users), and 342 patients who had never used metformin were included in the control cohort (never-users). The bifurcation of patient disposition by the inclusion and exclusion criteria is depicted in [Figure 1].
Figure 1: The bifurcation of patient disposition by inclusion and exclusion criteria. ICD: International Classification of Disease, UTUC: Upper tract urothelial carcinoma, T2DM: Type 2 diabetes mellitusThe baseline characteristics of the metformin never-user and metformin ever-user cohorts are revealed in [Table 4]. There were 307 men and 474 women among the 781 patients who were enrolled. Patients in the never-user cohort of metformin were 73.4 years old on average, compared to 71.8 years for the ever-user cohort. Univariate Cox regression and multivariate analyses were adjusted for variables, including age, sex, comorbidities, and medications, and were performed in the enrolled UTUC patients with T2DM [Table 1], [Table 2], [Table 3]. The median survival times of the metformin ever-user and never-user cohorts were 6.90 and 3.95 years, respectively [HR = 0.72, P = 0.011, [Figure 2]]. Both metformin uses before and after the diagnosis of UTUC decreased the all-cause mortality when compared with never-users in univariate Cox regression analysis (HR = 0.68 and 0.66, respectively). After multivariate analysis, the data on metformin use following the diagnosis were still statistically significant (HR = 0.71, 95% CI: 0.56–0.90). Subgroup analysis revealed that only continuous metformin administration before and after the diagnosis of UTUC obtained a survival benefit (adjusted HR = 0.72, 95% CI: 0.55–0.93). Regarding other parameters, age more than 60 years old (HR = 2.16, 95% CI: 1.29–3.60), comorbidities including dementia (HR = 1.684, 95% CI: 1.03–2.74), and moderate or severe liver disease (HR = 11.885, 95% CI: 1.37–103.479) revealed increased all-cause mortality considerably in multivariate analysis.
Table 4: Baseline characteristics of 781 upper tract urothelial carcinoma patients with type 2 diabetes mellitus
Figure 2: The Kaplan–Meier's overall survival curves for the metformin ever-user and ever-user Discussion Metformin is frequently employed as a first-line oral antidiabetic drug, and various studies have found that metformin may play a possible protective role against cancer recurrence and mortality. In a retrospective study of 1502 patients with bladder cancer treated with radical cystectomy and pelvic lymphadenectomy, patients with DM and metformin use were related to decreased bladder cancer recurrence and cancer-specific mortality.[8] Similarly, Nayan et al. found that metformin use among diabetic patients was related to considerably higher bladder cancer-specific survival and recurrence-free survival.[5] Although several theories have been suggested, the exact mechanism of metformin in urothelial cancer remains unclear. First, insulin was associated with bladder cancer cell growth through the phosphatidylinositol 3-kinase-independent activation of the Akt pathway.[9] Advanced bladder cancer and a poor prognosis were also linked to the activation and overexpression of the insulin like growth factor 1 receptor (IGF IR).[10] Metformin can decrease insulin levels and prevent the activation of IGF-IR by lowering the expression of IGF-1.[11] Second, metformin reduces the production of cancer-related proteins by blocking mTOR through AMP-activated protein kinase (AMPK).[12] Third, in human epidermal growth factor receptor, 2 (HER2)-positive cancers such as gastric and breast cancers, the mechanism of metformin use on the oncologic outcomes is likely to be associated with its effect on the suppression of cell proliferation (Ki-67). HER2 overexpression has also been found in bladder cancer.[13] Rieken et al. also reported the potential protective effect of metformin in bladder urothelial carcinoma.[8] Furthermore, a recent study utilizing immunohistochemically stained samples from 320 cases of UTUC verified that low Ki-67 levels were more sensitive to intravesical instillations regarding bladder recurrence prevention after RNU.[14] Fourth, metformin also improves apoptosis induction in p53-deficient cancer cell lines by stimulating AMPK and by causing cancer cell cycle arrest through the suppression of the mitosis-related genes such as cyclin D1 protein.[15] These preclinical studies demonstrated the potential mechanisms of anticancer activity of metformin and confirmed the findings reported by Zhang et al., who showed metformin-induced bladder cancer cell cycle arrest in an in vitro model. Furthermore, an in vivo study involving bladder cancer-engrafted mice also demonstrated that metformin significantly decreased tumor volumes.[16]
In our research, we discovered that, among patients with both UTUC and DM, metformin use markedly reduced all-cause mortality by 2.95 years when compared with nonusers. The results remained significant after adjusting for the effects of standard clinicopathologic characteristics and comorbidities. Moreover, subgroup analysis revealed that only continuous use of metformin before and after the diagnosis of UTUC was related to an improved survival benefit. Our data supported the results of a previous retrospective study on 2492 patients with UTUC, which discovered that patients with diabetes using metformin had better cancer-specific survival and recurrence-free survival.[17]
The strengths of this study were its population-based design, the objective method used to define metformin usage, and its detailed prescription history. However, this study had some drawbacks. First, in our study, metformin exposure was classified as receiving two prescriptions for metformin or metformin-containing products within 6 months to ensure the impact of metformin; the actual dose and duration of metformin use in our groups were not recorded. Second, the Taiwan NHI database does not record a few fundamental participant features, such as a history of smoking or other substance use and body mass index. The strength of the NHI database analysis is big data involving more UTUC patients in Taiwan; however, the weakness is that no pathological data information in this database such as cancer Tumor, node and metastasis (TNM) stage, lymphovascular invasion, or positive surgical margin could not be included in the Taiwan NHI database. The subgroups of different prognoses could not be described more specifically in our study. Third, this was a retrospective nonrandomized examination of UTUC patients enrolled in the NHI database. Because a propensity-matching strategy was not used in the cohorts, selection bias may occur. Fourth, we excluded the patients with metastatic UTUC and chemotherapy due to shorter life expectancy in these patients. We suppose that the short survival duration may be difficult to reveal the benefit of metformin. The results of our study only could demonstrate the impact of metformin in localized UTUC.
ConclusionThis study demonstrated a relationship between metformin usage and better survival outcome in patients with localized UTUC. The outcome may contribute to the favorable anticancer role of metformin in localized UTUC. Metformin use is associated with improved all-cause mortality. Although several hypotheses have been suggested, the exact mechanisms underlying the protective effects of metformin against urothelial cancer remain unclear and need to be clarified. Further studies are warranted to assess the possible therapeutic effects of metformin in patients with localized UTUC patients.
Acknowledgments
The authors thank the help from the Division of Medical Statistics and Bioinformatics, Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Financial support and sponsorship
Nil.
Conflicts of interest
Dr. Hsiang-Ying Lee, an editorial board member at Urological Science, had no role in the peer review process of or decision to publish this article. The other authors declared no conflicts of interest in writing this paper.
References
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