Participants
We conducted a case-control study using PCBaSe 4.1 which is based on the National Prostate Cancer Register (NPCR) of Sweden, a nationwide population-based register starting in 1998 that includes more than 98% of the men registered with PCa in the National Cancer Register. NPCR contains detailed data on cancer characteristics including prostate-specific antigen (PSA) at the time of diagnosis, staging and Gleason Grade Groups [18]. Using the unique personal identity number given to all residents in Sweden, all participants have been subsequently linked to Swedish health care registers and demographic databases. These include the National Patient Register and Longitudinal integrated database for health insurance and labour market studies, to obtain data on co-morbidities, civil status and educational level in 2008[18]. Comorbidities were quantified using the Charlson Comorbidity Index (CCI), based on discharge diagnoses in the In-Patient Registry with different weights (1, 2, 3 and 6) to each ICD code[19, 20]. For the current study, diabetes was not included in the CCI.
For every case in PCBaSe, five PCa-free control men (n=154,812) were randomly selected from the general Swedish population by use of the personal identity number [21], matched on year of birth and county of residence. The National Diabetes Register was initiated in 1996 and data is record linked via the personal identity number to PCBaSe [1]. In 2013, approximately 92% of the prevalent cases of type 1 and type 2 diabetes mellitus were included in the National Diabetes Register. We also used data from the National Prescribed Drug Register. The National Prescribed Drug Register was established in July 2005 and contains all prescribed drugs dispensed at pharmacies in Sweden.
Identification of men with T2DM
To investigate the association between T2DM and PCa, we assessed data related to T2DM diagnosis and drug treatments available in the National Diabetes Register and National Prescribed Drug Register. We defined pre-existing T2DM as fulfilling at least one of following criteria:
1) a medical record of the year of T2DM onset in the National Diabetes Register
2) a registration date of T2DM in the National Diabetes Register
3) a prescription for antidiabetic drugs (at least two filled prescriptions records) in the National Prescribed Drug Register.
Exposure
The primary exposure was duration of T2DM. The duration of T2DM was calculated using the year of T2DM onset or the registration date of T2DM in the National Diabetes Register (94%), or the duration of antidiabetic medications in the National Prescribed Drug Register (6%).
In addition, we also used duration of antidiabetic medications, including insulin, metformin, and sulphonylurea (SU) as documented in the National Prescribed Drug Register up to 8.5 years prior to the date of PCa diagnosis (July 2005 – December 2016). As the Swedish drug reimbursement system is based on records of patients’ visiting to the pharmacies every 3 months, the 8.5-year period in the National Prescribe Drug Register was divided into 34 sub-periods, which were shown as 34 filled prescription records in the dataset of the study. Each filled prescription record equates to 3 months’ antidiabetic medication. Men with at least two filled prescription records of the same antidiabetic medication were assumed to be taking that antidiabetic drug as a treatment of T2DM. The duration of an antidiabetic drug can was defined by the number of the corresponding records found in the National Prescribed Drug Register.
Use of metformin was divided into high-dose and low-dose groups with a cut-off at 1g of metformin per day. We categorized duration into 3 groups: (i) ≥0.5 year - <3 years, (ii) ≥3 year - <5 years, and (iii) 5 year - ≤8.5 years. We calculated duration of insulin, metformin, and SU separately, even if some men received more than one antidiabetic drug. For example, if a man took high dose metformin and insulin, he contributed time to the duration of both high dose metformin and insulin.
Outcome
The primary outcome of the study was diagnosis of PCa, and we also obtained information on PCa risk categories from the NPCR. According to the modified version of the National Comprehensive Cancer Network (NCCN) guideline, men with PCa can be categorized into five risk categories: i) low-risk: T1 or T2a stage, PSA<10 ng/mL and Gleason score 6; ii) intermediate-risk: T2b or T2c stage, 10 ng/mL, PSA<20 ng/mL, or Gleason score 7; iii) high-risk: T3a or T4 stage, PSA≥20 ng/mL, or Gleason score ≥8; iv) regional metastases any T, N1 and M0 stage; v) distant metastases, any T or N and M1 stage [22]. In the main analysis, we included men with high-risk, regional metastases, and distant metastases into the high-risk category group to increase the power. We also conducted a subgroup analysis for each category.
Statistical analysis
Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for PCa risk. Models were adjusted for education levels (high, middle and low), civil status (married, not married, widowed and divorced), CCI and age at the year of PCa diagnosis.
All data management was performed with STATA 15.1. The study has been approved by The Research Ethics Board at Uppsala University, Sweden.