Impact of Glycemic Control and Metformin Use on the Recurrence and Progression of Non-Muscle Invasive Bladder Cancer in Patients with Diabetes Mellitus

Bladder cancer is the 7th most common cancer in men and the 17th most common in women in the world (1). Up to 85% of patients with bladder cancer present with disease confined to the mucosa (stage Ta and Tis) or submucosa (stage T1) at the time of presentation. However, non-muscle invasive bladder cancer (NMIBC) is characterized by a high risk of recurrence after transurethral resection of an initial tumor. Of these, 15%–61% recur within 1 year, 31%–78% recur within 5 years and 5%–20% progress to muscle invasive disease (2). Therefore, for oncologists who manage NMIBC, individual patient risk assessment of tumor recurrence and progression may guide treatment decisions and surveillance monitoring.

Diabetes mellitus (DM) is thought to be a factor which affects the treatment outcome of malignancies. Epidemiologic evidence indicates that type 2 DM is a risk factor for several cancers like colorectal cancer, breast cancer, endometrial cancer, hepatocellular cancer, but results for bladder cancer have been difficult to interpret and have not been established (3). Several studies have proposed an epidemiologic association between DM and bladder cancer (4, 5, 6). Indeed, if DM and bladder cancer risk have an association, it can be hypothesized that DM may have an influence on the recurrence or progression of bladder cancer. Also, DM-related status, such as glycemic control, possibly has an important clinical significance with respect to bladder cancer characteristics.

There has been considerable interest in the antitumor properties of metformin. Lin et al. (7) reported that the magnitude of cancer risk reduction and prolonged cancer onset times produced by metformin in patients with type 2 diabetes depended on the dose of metformin. Therefore, we determined the potential association of a history of DM and glycemic control with tumor characteristics and recurrence-free survival (RFS) and progression-free survival (PFS) among patients who underwent transurethral resection (TUR) for NMIBC. Also, we determined whether metformin use had an impact on the characteristics of bladder cancer.

Recently, the prevalence of diabetes mellitus and cancer is increasing. It is not surprising that the incidence of concomitant occurrence of two diseases will increase. Diabetes was found to be common in some cancers, including breast, colorectal, endometrial, liver, and pancreatic cancers (3, 10, 11, 12, 13). Epidemiologic studies of diabetes and the risk of bladder cancer have reported inconsistent results. Several cohort studies have reported that diabetes is related to a significant 1.3 to 2.5-fold increased risk of bladder cancer (14, 15, 16). Conversely, others have failed to find any association between the two disease entities (17, 18, 19). A recent updated meta-analysis of 36 observational studies showed that DM was associated with an increased risk of bladder cancer (the summary RR, 1.35; 95% CI, 1.17-1.56; P < 0.001) (20). However, there are limited data regarding the relationship between glycemic control of DM and recurrence or progression of bladder cancer. Hence, the present study focused on DM and glycemic control and whether it affected the RFS and PFS.

The risks for both recurrence and progression in NMIBC are associated with multiple tumor-related factors, including histologic grade, depth of invasion, multiplicity, tumor size, tumor morphology, the presence or absence of vascular or lymphatic invasion, and the presence or absence of CIS. Although these tumor-related factors provide some prognostic information, they ultimately fail to clearly evaluate the malignant potential of individual tumors. Therefore, there is a need to determine other clinical factors to predict tumor recurrence or progression in patients with NMIBC. In a study of clinical risk factors, Joo et al. (21) reported that patients with NMIBC who had high serum creatinine levels (1.5 mg/dL) had more frequent recurrence, but not progression, than those with low serum creatinine levels. In addition, the authors suggested that DM may affect tumor recurrence (HR, 2.06; 95% CI, 0.89–4.72; P = 0.091). Our results for DM reinforce these findings (for recurrence, HR, 1.42; 95% CI, 1.1–1.9; P = 0.021; for progression, HR, 1.79; 95% CI, 1.1–2.8; P = 0.013); furthermore, results for high serum creatinine level (HR, 1.24; 95% CI, 1.0-1.5; P = 0.014) were consistent with those in the study by Joo et al. (21), with no significant association being found between serum creatinine and progression in the present study.

The possible mechanisms underlying the association of diabetes with bladder cancer risk are uncertain. In type 2 diabetes, insulin resistance leads to a state of hyperinsulinemia (22, 23). Insulin has mitogenic properties and could stimulate tumor growth by increasing bioactive IGF-I, which in turn stimulates cell proliferation and inhibits apoptosis (24). In the circulation, IGF-I binds mainly to the main IGF binding protein, IGFBP-3 (25). Several epidemiological studies have implicated IGF-I and IGFBP-3 in the development of prostate, breast and colorectal cancers (26). IGF-I and IGFBP-3 may also play a role in the development of bladder cancer. In a US case–control study, statistically significantly higher plasma IGF-I concentrations and a higher molar ratio of IGF-I to IGFBP-3 were observed in patients with bladder cancer compared with controls (27).

An additional purpose of the present study was to evaluate tumor characteristics according to HbA1c. Poor glycemic control was associated with progression, even though more patients with poor glycemic control received intravesical treatment than patients with good glycemic control. Also, baseline HbA1c (≥ 7%) (P = 0.033) and post-operative HbA1c (≥ 7%) (P = 0.032) were related to shorter PFS. Notably, poor glycemic control was not associated with tumor characteristics and recurrence. The finding of no significant difference in the recurrence can be explained as that the baseline HbA1c (≥ 7%) group received more intravesical treatment, although there was no difference in tumor characteristics between controlled and uncontrolled diabetic patients. As known, intravesical treatment could decrease the recurrence rate in patients with NMIBC. In spite of intravesical treatment, the HbA1c (≥ 7%) group had a higher progression rate. Therefore, early active treatment and good postoperative glycemic control might be necessary in the HbA1c (≥ 7%) group.

The importance of glycemic control has been highlighted in other types of cancer. Siddiqui et al. (28) reported that poor glycemic control, as judged by the HbA1c level, independently predicted the early onset of colorectal cancer, a more advanced stage at the time of presentation, and poorer 5-year survival. Tai et al. (29) reported that poorly controlled diabetic patients (HbA1c ≥ 7.0%) with upper urinary tract urothelial carcinoma exhibited a shorter duration of RFS in bladder cancer as compared to those with good glycemic controlled DM and without DM (log-rank test, P < 0.001 and < 0.001, respectively).

Metformin has been demonstrated to exert anticancer effects in several types of cancer, including those affecting the liver, colon, breast, pancreas, and prostate (7). However, the utility of metformin in the prevention and treatment of bladder cancer has not been specifically investigated. Rieken et al. (30) reported that patients with DM who did not take metformin had a greater risk of disease recurrence (HR 1.45, 95% CI 1.09–1.94, P = 0.01) and progression (HR 2.38, 95% CI 1.40-4.06, P = 0.001). DM with metformin use was independently associated with a lower risk of disease recurrence (HR: 0.50, 95% CI 0.27–0.94, P = 0.03). However, our results regarding metformin use are inconsistent with those in the study by Rieken et al. (30), with no significant association being found between metformin use and recurrence or progression. This difference might be explained by the previous study not including data about serum creatinine, BMI and DM control (HgbA1c). Metformin is generally recommended as the 1^st choice drug in patients with early DM, but is not recommended in patients with renal insufficiency because of fears about lactic acid accumulation (33). In this study, renal insufficiency and poor DM control were related with poor prognosis of patients with NMIBC. So the effect of metformin in the previous study could be influenced by DM control or other parameters including BMI and creatinine clearance. In this study, use of metformin had no impact on the recurrence and progression of bladder cancer when there was no difference about DM control, serum creatinine, and BMI between metformin ever-users and metformin never-users.

In previous studies showing that metformin affected the outcome of cancer, they have provided the following biochemical basis. First, the mechanisms may involve AMP-activated protein kinase (AMPK)-dependent and AMPK-independent pathways (31, 32). The activation of AMPK is indirect and appears to act via inhibition of mitochondrial complex I in the respiratory chain resulting in an increase in the AMP:ATP ratio (31). Metformin may inhibit cell cycle progression and cell proliferation through down-regulating cyclin D1 as an AMPK-dependent effect in breast cancer cells, or activating the HIF target gene REDD1 leading to the inhibition of the mammalian target of rapamycin (mTOR) pathway and cell cycle arrest in prostate cancer cells (31). Second, metformin inhibits hepatic glucose output and improves insulin sensitivity with lowering of circulating levels of insulin and glucose, reduces insulin-like growth factors (IGFs), decreases Akt phosphorylation, and inhibits the crosstalk between receptors of insulin/IGF1 and G protein-coupled receptor signaling pathways (31). Although it is reasonable to speculate that metformin may prevent the development of bladder cancer through these molecular mechanisms, clearly, more basic in vitro and in vivo studies are warranted.

The present study has several limitations. First, we did not consider the potential impact of biochemical data such as levels of glucose, insulin, C-peptide, and IGFs. Second, we did not assess the duration of DM, which may have been affected by recall bias or a period of undetected DM. Third, our results might have been affected by a selection bias because of the possibility of undiagnosed DM among patients who were classified as not having DM (Group I). Fourth, the baseline HbA1c (≥ 7%) group received more intravesical treatment, because patients with HbA1c ≥ 7.0% exhibited trends of higher rate of multiplicity, tumor grade and T1 stage. This might explain the finding that DM control was not related with shorter RFS of patients with NMIBC.

However, this study presented two significant facts. First, the blood sugar level might be controlled before and after TUR-BT in DM patients with NMIBC to expect a good result for the tumor. Second, the urologic clinician must consider controlling the blood sugar level after TUR-BT in DM patients and more aggressive care and follow-up are needed in DM patients with poor DM control.

DM patients with NMIBC showed decreased RFS and PFS. Poor baseline DM control and post-operative DM control were related with shorter PFS of patients with NMIBC. Use of metformin had no impact on the recurrence and progression. Therefore, tight glycemic control and close follow-up for bladder tumor may be beneficial in patients with poor glycemic control.