In our study, recurrence and progression rates were not significantly different between the DM and non-DM groups. Metformin and TZD use had no effect on recurrence rate. Nevertheless, in the subgroup analysis, patients who had HbA1C ≥ 7 had significantly higher risks of recurrence and worse RFS. Patients with DM who had proper glycemic control had similar RFS compared with patients without DM.
DM is associated with increasing incidence and poor prognosis of several cancers, including colorectal, breast, endometrial, liver, pancreatic, and bladder cancers [4, 5, 10,11,12,13]. Several studies have discussed the effect of DM on bladder cancer. Xu et al. conducted a meta-analysis including 21 cohort studies, which involved 13 million participants, and reported that DM is associated with a higher risk of bladder cancer or cancer mortality (relative risk: 1.23; 95% CI = 1.12–1.35) . Other studies also reported higher recurrence of NMIBC in patients with DM, with rates of 45–60% in patients with DM versus 30–40% in patients without DM [6,7,8].
Another interesting issue is whether glycemic control is associated with prognosis of bladder cancer. Hwang et al. found that patients who had serum HbA1C ≥ 7 have higher rates of tumor multiplicity and tumor grade, but the recurrence and progression rates are not significantly higher . Ahn et al. reported that poor glycemic control is associated with a higher progression rate and worse PFS . Tai et al. also reported that poor glycemic control is associated with a higher risk of bladder recurrence in patients with UTUC . However, the HbA1C levels for analyses in those studies were single data obtained during the study period rather than averages of all data in the study period.
Metformin has been discovered to suppress tumor by activating AMP-activated protein kinase and liver kinase B1 and downregulating mammalian target of rapamycin and insulin-like growth factor-1 . Tseng reported that cumulative dose and duration of metformin use are associated with decreased incidence of bladder cancer . Studies also found that metformin use appears to be associated with better RFS or cancer-specific survival in patients with bladder cancer [6, 18, 19]. However, the effect of metformin on reducing the incidence and recurrence of bladder cancer were challenged by other studies [8, 20, 21]. On the other hand, pioglitazone is associated with increased risk of bladder cancer [22, 23].
The mechanism of association between bladder cancer and DM remains unclear. Chronic inflammation and hyperinsulinemia induced by hyperglycemia may be the two major factors. Poor glycemic control results in direct cell damage by fluctuating serum glucose level and accumulation of advanced glycation end products (AGEs). The interaction between AGEs and their receptors leads to increased oxidative stress that results in DNA damage, upregulation of series of cell molecules, and inflammation process. Cell molecules including transcription factors (e.g., NF-κB, STAT3, HIF1α) and cytokines (e.g., IL-6, Cox-2, and TNF-α) coordinate together and lead to the amplification of inflammation and creation of a suitable environment for cancer growth [24,25,26]. Hyperinsulinemia in type 2 DM upregulates insulin-like growth factors (IGF) that act as stimulators of mitogenesis and cellular transformation. On the other hand, insulin-like growth factor-binding proteins (IGFBPs) serve as moderators of IGFs and regulate cell proliferation and apoptosis . Zhao et al. reported that patients with bladder cancer have higher plasma levels of IGF-1 and lower levels of IGFBP-3 than patients without bladder cancer . Studies have also reported that overexpression of IGFs and their binding proteins is associated with poor prognosis in bladder cancer [29, 30].
This study has several limitations. First, the DM group had fewer patients, and only 33 patients had HbA1C data. Due to a small sample size, there is a lack of multivariate analysis bias in the subgroup analysis. Second, demographic distributions in the DM and non-DM groups were not similar in terms of age, obesity, hypertension, and serum creatinine level, which may lead to potential biases.
On the other hand, several strengths of our study are noteworthy. First, for patients who had HbA1C data, we calculated the mean HbA1C levels from the time of diagnosis to the time of end points. To our knowledge, this study is the first to use mean HbA1C levels for evaluation, which is more representative because the follow-up period of cancer may be much longer than the half-life of HbA1C. Second, we included patients with a follow-up period of more than 2 years, in which more than 80% of recurrence occurred. Third, we performed Kaplan-Meier analysis for patients without DM, patients with DM and proper glycemic control, and patients with DM and poor glycemic control. The result shown in Fig. 1b illustrates the relationship between glycemic control and RFS. Finally, in our center, treatment and follow-up protocol for bladder cancer were strictly according to the current AUA or EAU guidelines. For patients with CIS, mapping biopsies were regularly performed. We believe that the detection of recurrence or progression can be early as possible.