Diabetes, Glucose Control, Glucose Lowering Medications, and Cancer Risk: A 10-year Population-based Historical Cohort
Condition: Diabetes; Cancer
MeSH terms: Diabetes Mellitus
Study type: Observational [Patient Registry]

Summary: 
      This is a large nationwide population study, with 10 year follow-up, of the effect of
      diabetes, metabolic control and a large number of glucose-lowering medications, on total and
      site-specific cancer incidence and survival.

      The study is based on electronic medical records from the largest Israeli health maintenance
      organization in Israel, Clalit Health Services. 2,301,990 insurees age 21 years old or above
      at study entry, January 2002 will be included. Four study groups will be established
      according to the prevalence of diabetes and/or cancer on that date: neither diabetes nor
      cancer; prevalent diabetes but not cancer; prevalent cancer but not diabetes; both diabetes
      and cancer prevalence. Subjects free of diabetes at study entry will be followed for diabetes
      incidence, and all four groups will be followed until December 2012 for study outcomes. The
      cohort data file will be linked to the Israel National Cancer Registry for cancer morbidity.

      We will compare, after adjustment, all and site-specific cancer rates between individuals
      with and without diabetes; and investigate if metabolic control, as indicated by HbA1c and
      blood glucose levels, is related to cancer risk. Using time-dependent Cox proportionate
      hazard models, we will then evaluate differences in outcomes that associate with the use of
      one or a combination of glucose-lowering treatments, while stratifying by those who were
      already diagnosed with diabetes at study entry, and those diagnosed during follow-up. Data
      for a large number of potential confounding variables, including BMI, plasma glucose, HbA1c,
      hormone replacement therapy and comorbidities will help mitigate allocation bias. The
      accessibility and uniformity of the healthcare provided by Clalit Health Services, as well as
      data on cancer screening tests, will minimize the risk of surveillance bias.
    

Detailed description: 
      The study was based on electronic records from the largest health maintenance organization in
      Israel, Clalit Health Services, which insures and provides healthcare to 55% (3.9 million) of
      the nation's population. All persons between 21 and 90 years and registered with Clalit on
      January 1, 2002 (the date of study entry), without a previous history of cancer, were
      included in a closed cohort that was followed until December 31 2012.

      All individuals were followed for cancer incidence, which was ascertained by record linkage
      to the Israel National Cancer Registry, established in 1960. The registry has benefited since
      1982 from a national law mandating registration of cancer, and has greater than 95% coverage
      of solid tumors, and approximately 85% coverage of hematologic cancers [34].

      Definitions of diabetes: Incident diabetes was defined as fulfillment of at least one of the
      following six criteria during 2002-12: (1) diabetes recorded in the Clalit Chronic Disease
      Registry; (2) a physician's diagnosis of diabetes, and one plasma glucose test > 125 mg/dL
      within 12 months; (3) one HbA1c measurement > 6.5%; (4) 2-hour plasma glucose level during an
      oral glucose tolerance test ≥ 200 mg/dL; (5) 3 or more purchases of glucose-lowering
      medication within 12 months; (6) 2 plasma glucose measurements > 125 mg/dL within 12 months.
      The date of the earliest defining criterion was considered the date of diagnosis.

      Prevalent diabetes was defined as being recorded with diabetes in the Clalit Chronic Disease
      Registry on study entry, or fulfilling criterion #5 above (information on medication use was
      available from 1998) before study entry.

      Types of cancer: The following cancers were investigated: liver (ICD-O-3 codes C22.0 and
      C22.1), pancreas (C25.0-C25.9), gallbladder (C23.9-C24.9), endometrium (C54.0-C54.9, C55.9),
      stomach (C16.0-C16.9), kidney (C64.9, C65.9, C66.9., C68.0-C68.9), benign brain and central
      nervous system (C70.0-C72.9 with behavior code 0), malignant brain (C70.0-C72.9 with behavior
      code 3), multiple myeloma (C42.1 with relevant morphology codes), colorectum (C18.0-C21.8),
      non-Hodgkin lymphoma (C02.4, C09.8. C09.9, C11.1, C14.2, C37.9, C42.2, C77 and all other
      sites for extra-nodal Non Hodgkin's lymphoma), lung (all: C34.0-C34.9), adenocarcinoma,
      squamous cell), leukemia (C42.0, C42.1, C42.2 with relevant morphology codes), ovary (C56.9),
      bladder (C67.0-C67.9), breast (C50.0-C50.9), thyroid (C73.9) and prostate (C61.9). Apart from
      benign brain tumors, all cancers included in the analysis were coded as invasive (behavior
      code = 3).
    

Observational model: Cohort
Time perspective: Other
Sampling method: Non-Probability Sample
Study population: 
        The cohort will include all individuals who were aged 21 years or older at study entry,
        January 1, 2002, and who were insured by Clalit Health Services, from one year prior to
        study entry, until the end of the study period, December 31, 2012, or until death, for
        those who did not survive until the end of follow-up.
      
Keywords: Cohort; Historical; Prospective; Medications; Observational; Glucose; Control