Impact of oral hypoglycemic agents on mortality among diabetic patients with non-muscle-invasive bladder cancer: A populationbased analysis

摘要

IntroductionNon-muscle-invasive bladder cancer (NMIBC) accounts for 75–85% of all urothelial bladder cancers (UBC). Many UBC patients are also afflicted by diabetes mellitus (DM). It has been postulated that several oral hypoglycemic agents could impact disease-specific survival (DSS), but the data are sparse among NMIBC patients. Our primary objective was to evaluate the impact of metformin on DSS and overall survival (OS) in NMIBC patients.MethodsThis is a retrospective, population-based study that used linked administrative databases to identify diabetic patients ≥66 years who were subsequently diagnosed with NMIBC in Ontario between 1992 and 2012. Cumulative use of metformin and other hypoglycemic agent were calculated before and after NMIBC diagnosis. DSS and OS were estimated using multivariable competing risk and Cox proportional hazards models, respectively.ResultsA total of 1742 subjects were included in the study. After a median followup of 5.2 years, 1122 (64%) had died, including 247 (15%) deaths as a result of UBC. On multivariable analysis, cumulative duration of metformin use after NMIBC diagnosis did not appear to impact DSS (hazard ratio [HR] 1.1; 95% confidence interval [CI] 0.92–1.2), whereas glyburide use appeared to have a detrimental effect (HR 1.17; 95% CI 1.02–1.3). None of the other hypoglycemic agents had an impact on OS.ConclusionsIn this large, population-based study, we have provided further evidence that metformin use does not significantly impact DSS among diabetic patients diagnosed with NMIBC. However, our findings demonstrate that glyburide use inversely affects DSS. The detrimental effect of glyburide on DSS will require further validation.IntroductionUrothelial bladder cancer (UBC) is the fifth most common solid organ cancer in North America, with over 74 000 new cases diagnosed every year in the U.S. alone.1 UBC is especially prevalent among the elderly, with an average age at diagnosis of 73 years.1 Fortunately, approximately 75% of cases are non-muscle-invasive bladder cancer (NMIBC).2 Although associated with high recurrence rates, these cancers have lower progression and metastatic rates than muscle-invasive tumours (MIBC).3,4Many NMIBC patients are also afflicted by diabetes mellitus (DM), which affects over 25% of individuals aged 65 and older.5 Metformin, a member of the biguanide medication class, is considered to be the first-line therapy in the management of DM.6 Interestingly, metformin has recently gained interest for its antineoplastic properties against a number of non-genitourinary and genitourinary cancers.7–9 More specifically, there have been in vitro and animals studies demonstrating putative antineoplastic effects of metformin on UBC.10 However, there are limited clinical data evaluating the role of metformin in UBC patients and results, thus far, have been equivocal.11–13 Furthermore, many of these studies were underpowered and only one of them assessed NMIBC.12 It has also been proposed that other oral hypoglycemic agents may have a potential impact on cancer outcome.14,15Our primary objective was to assess the impact of cumulative use (after NMIBC diagnosis) of metformin on the disease-specific survival (DSS) and the overall survival (OS). The secondary objectives were to assess the impact of metformin (before NMIBC diagnosis) and other hypoglycemic agents (before and after NMBIC diagnosis) on both the DSS and OS. We hypothesized that metformin after NMIBC diagnosis is associated with improved DSS and OS, while the other studied hypoglycemic agents have no impact.MethodsStudy populationThis was an institutional review board-approved, population-based, retrospective study. Individuals diagnosed with incident UBC in Ontario and concomitant DM between January 1, 1992 and December 31, 2012 were identified using administrative databases. Individuals with other concomitant neoplasms (other than non-melanoma skin cancer) were excluded. The cohort was also restricted to subjects ≥66 years of age at the time of DM and UBC diagnosis. Since staging and pathological data were unavailable or incompletely captured with the available administrative databases, NMIBC patients were identified as individuals with UBC who had not undergone a cystectomy and/or radiotherapy and/or systemic chemotherapy treatments (i.e., radical or systemic therapy) within six months of the diagnosis of UBC, as these treatments are usually reserved for MIBC and/or advanced UBC (Supplementary Table 1). Similarly, individuals who were lost to followup or who died within six months of diagnosis were excluded, as the anti-diabetic medications were unlikely to have affected their outcomes and because those who died of UBC during that period were more likely to have been diagnosed with M