Cancer Epidemiology 41 (2016) 80–87

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Cancer among patients with type 2 diabetes mellitus: A population-based cohort study in northeastern Italy Andrea Ginia,* , Ettore Bidolia , Loris Zanierb , Elena Clagnanb , Giorgio Zanettec , Michele Gobbatob , Paolo De Paolid, Diego Serrainoa a

Epidemiology and Biostatistics Unit, IRCCS CRO National Cancer Institute, Aviano, Italy Friuli Venezia Giulia Central Health Direction, Udine, Italy Diabetology Unit, Santa Maria degli Angeli Hospital, Pordenone, Italy d Scientific Directorate, IRCCS CRO National Cancer Institute, Aviano, Italy b c

A R T I C L E I N F O

A B S T R A C T

Article history: Received 13 October 2015 Received in revised form 8 January 2016 Accepted 21 January 2016 Available online xxx

Diabetes mellitus (DM) is associated with an elevated risk of cancer. The aim of this study was to assess cancer risk and survival in individuals with type 2 DM (T2DM) in Friuli Venezia Giulia, Italy. A retrospective population-based cohort study of 32,247 T2DM patients aged 40–84 years was conducted through a record linkage of local healthcare databases and cancer registry for the period 2002–2009. Standardized incidence ratios (SIRs) with 95% confidence intervals (95%CIs) and 5-year survival probabilities after T2DM and cancer diagnosis were computed. The SIRs for all cancers (n = 2069) was 1.28 (95%CI: 1.23–1.34). The highest SIRs were observed for cancers of the liver, female genital organs, small intestine, and pancreas. After 3 years from T2DM diagnosis, a reduced risk of prostate cancer (SIR = 0.73, 95%CI: 0.54–0.96) was found in men aged 65–74 years, and a higher risk for breast cancer (SIR = 1.24, 95% CI: 1.00–1.52) was found among T2DM female patients. The overall 5-year survival after T2DM was 88.7%. Furthermore, T2DM appeared to have a negative effect on survival of women with breast cancer. This population-based study confirmed that T2DM patients are at increased risk of several cancers, and of premature death in women with breast cancer. ã 2016 Elsevier Ltd. All rights reserved.

Keywords: Type 2 diabetes mellitus Cancer Population-based cohort study Survival Cancer risk Record linkage

1. Introduction Diabetes mellitus (DM) is one of the major challenges in public health worldwide, with more than 381 million people living with DM in 2013. The prevalence among adults aged 20–79 years was around 8.3%, including Italy (where 8% of the whole population is affected by DM) [1]. In high-income countries, type 2 diabetes mellitus (T2DM) accounts for 85–95% of all types of DM [1]. T2DM is associated with a poor quality of life and prognosis, especially because of increased risks of cardiovascular heart diseases [2] and cancer [3]. The relationship between T2DM and cancer has been extensively investigated, and many epidemiological studies have found a positive association between T2DM and several cancers [3–5] such as – among others – cancers of the pancreas [6,7], liver [8],colonrectum [9], breast [10], and bladder

[11]. Conversely, a number of studies have reported a negative association between T2DM and prostate cancer [12]. Few studies have investigated these associations in southern European countries using data from population-based cancer registries. Regarding the pathogenesis of cancer in patients affected by T2DM, several possible biological mechanisms have been proposed, such as insulin resistance, hyperinsulinemia, and hyperglycemia [13,14]. In this study, we took advantage of the existing populationbased administrative health-related databases of the Friuli Venezia Giulia (FVG), a region with nearly 1,200,000 inhabitants in northeastern Italy and a DM prevalence around 8.0% [15]. These databases include the DM registry, the cancer registry (CR), the death-certificate database, and the hospital-discharge database [15–17]. Through a record-linkage approach we aimed to investigate, at a population level, the cancer risk of patients with T2DM. 2. Materials and methods

* Corresponding author at: Unità di Epidemiologia e Biostatistica, IRCCS Centro di Riferimento Oncologico, Via Franco Gallini 2, 33081 Aviano, PN, Italy. Fax: +39 0434 659231. E-mail address: [email protected] (A. Gini). http://dx.doi.org/10.1016/j.canep.2016.01.011 1877-7821/ ã 2016 Elsevier Ltd. All rights reserved.

A retrospective, population-based, cohort study was conducted using information derived from the administrative health databases of the FVG region through a record linkage procedure [15].

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The diagnosis of DM was assessed from the first date when DM was mentioned in one of the following health databases: (1) hospital discharge with diagnosis code 250.xx (International Classification of Disease ninth edition, ICD-9); (2) exemption from medical charges because of DM (regional codes ‘P200 or ‘013’); or (3) prescription of at least three packages of medications with Anatomical Therapeutic Chemical (ATC) codes A10Axx or A10Bxx in 365 consecutive days [15]. Classification of DM into type 1 (T1DM) or type 2 (T2DM) was carried out according to the available information on drug prescriptions and drug therapies used in hospitals. Patients with predominant lifetime use of insulin (ATC code: A10Axx) were considered T1DM patients. Conversely, patients with predominant lifetime use of anti-diabetic oral drugs – such as metformin, sulfonylurea, alpha-glucosidase inhibitors, thiazolidinediones, dipeptidyl peptidase 4 inhibitors (ATC code: A10Bxx) – were considered T2DM patients. Fig. 1 shows the flowchart of the selection procedure used to identify the T2DM study population. Briefly, inclusion criteria were new-onset T2DM during 2002–2009 and age between 40 and 84 years at diagnosis. Excluding criteria were: (1) less than 5 years of residence in FVG as of December 31st 2001; (2) a cancer diagnosed before December 31st 2001; (3) a DM diagnosis prior to December 31st 2001; (4) a cancer diagnosis at autopsy during the period 2002–2009; (5) duration of follow-up of less than 90 days; (6) a cancer diagnosis preceding the diagnosis of DM; and (7) a T1DM diagnosis. According to these criteria, 1,018,518 individuals without DM were identified prior to December 31st 2009, and 32,247 persons aged 40–84 years with new-onset of T2DM were identified during the period 2002–2009. Information on antidiabetic prescriptions was assessed for each T2DM patient. We classified the anti-diabetic drugs in the following classes: insulin and insulin analogs, metformin, sulfonylurea and other antidiabetic drugs. We defined ever exposure to each class by having at least one prescription of the corresponding anti-diabetic drug

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during the follow-up. Data on vital status (up to December 31st 2014) and underlying cause of death were retrieved from the regional mortality registry. The FVG cancer registry covers the whole population residing in the FVG region (north-eastern Italy), and a region-wide cancer registration began in 1995 as part of the North East Cancer Surveillance Network. Automated registration techniques take advantage of electronic records of diagnoses, hospital records, admission records, and population archives. Manual techniques are also used for analysis of some electronic records and ascertainment of prevalent cases, as well as for quality control. Data from the cancer registry are published in the volumes “Cancer Incidence in Five Continents” by the International Association of Cancer Registries (IACR) according to IACR rules [18]. Cancer diagnoses were coded according to the ICD, tenth edition (ICD-10). 2.1. Statistical analysis Person-years (PYs) at risk of cancer were computed from 90 days following T2DM diagnosis to the first of the following dates: primary diagnosis of any type of cancer (excluding skin nonmelanoma—C44); death; last follow-up; or end of study period (December 31st 2009). The potential reverse causation issue was controlled by taking into consideration several criteria: (1) exclusion of any cancer diagnosed at least 7 years before T2DM diagnosis; (2) follow-up time (equivalent to the latency period) of 90 days after T2DM diagnosis; and (3) follow-up time 3 years. Standardized incidence ratios (SIRs) were calculated as the ratio between the observed and the expected number of cancer cases [19]. The expected number of cases was calculated according to the age-, sex-, and calendar-year-specific incidence rates computed among the 1,018,518 individuals without diabetes and with residence in the FVG region on January 1st 2002. SIRs were standardized by sex, 5-year age group, and two calendar periods

Fig. 1. Flow chart for selection of patients aged 40–84 years with new-onset type 2 diabetes during 2002–2009.

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(2002–2005 and 2006–2009); 95% confidence intervals (95%CIs) were calculated assuming a Poisson distribution. Furthermore, SIRs were estimated by strata of age at cancer diagnosis (40–64, 65–74) and sex. In addition, to assess the risk for female breast cancer, the SIRs were further computed by strata of age according to menopausal status (

Cancer among patients with type 2 diabetes mellitus: A population-based cohort study in northeastern Italy.

Diabetes mellitus (DM) is associated with an elevated risk of cancer. The aim of this study was to assess cancer risk and survival in individuals with...
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