Lung cancer risk

OBJECTIVE--The incidence of some cancers has been reported to be higher in diabetic patients than in the general population. We estimated the incidence of lung cancer in diabetic patients and investigated the hypothesis that the rate of lung cancer is different in diabetic compared with nondiabetic patients.

RESEARCH DESIGN AND METHODS--Diabetic patients and age-, sex-, and general practice-matched nondiabetic control subjects were identified from U.K. computerized general practice records (General Practice Research Database), and these records searched for any incident lung cancer, demographic details, and smoking status. Primary lung cancer incidence was calculated and rates compared between diabetic patients and nondiabetic control subjects using multivariate Cox regression, adjusting for age, sex, and smoking. The comparison was repeated for incident diabetic patients followed from diagnosis and after stratifying by diabetic treatment.

RESULTS--The incidence of primary lung cancer in all 66,848 diabetic patients was 1.63 per 1,000 patient-years (95% CI 1.48-1.79) and 2.05 per 1,000 patient-years (1.76-2.38) among diabetic patients followed from diagnosis. When compared with nondiabetic control subjects, the hazard ratio was 0.88 (0.79-0.97) for all diabetic patients and 1.12 (0.95-1.34) for those followed from diagnosis. When observation was truncated to allow for shorter life expectancy, the hazard ratio for the total cohort was 0.98 (0.84-1.13), and no association was found with any treatment group.

CONCLUSIONS--No increased risk of lung cancer in diabetes was found. We hypothesize that the lower incidence may be partly due to shorter life expectancy.

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The incidence of lung cancer in subjects with diabetes might be different from that in the general population. Smoking is the major risk factor for lung cancer, and both insulin resistance (1) and type 2 diabetes (2,3) have been reported to be increased in smokers. Epidemiological studies have found positive associations between diabetes and cancer, including colorectal (4), breast (5), endometrial (6), and pancreatic (7) malignancies. Several biologically plausible mechanisms could explain this relationship. In particular, hyperinsulinemia, which occurs in patients with impaired fasting glucose and early type 2 diabetes, may affect the development of cancer directly or through insulin-like growth factor or stimulation of insulin-like growth factor receptors (8,9). Conversely, other studies of diabetes and cancer (10,11) have reported no or decreased risk (12,13), and reduced life expectancy as a result of diabetes itself may bring down the incidence of lung cancer that occurs more frequently in later life.

A comparative study (14) of lung cancer in diabetes, adjusting for smoking, reported a slight nonsignificant increased risk in women but not men. No incidence figures were given. Other studies (15-18) did not adjust for smoking, the major risk factor for lung cancer, and are therefore difficult to interpret. We estimated the incidence of lung cancer in a cohort of diabetic patients and investigated the hypothesis that the rate of lung cancer is different in diabetic compared with non-diabetic patients.

RESEARCH DESIGN AND METHODS--Diabetic patients and nondiabetic control subjects were identified from the General Practice Research Database (GPRD) (19,20), an observational database containing primary care records from throughout the U.K. Details of demographics, primary care diagnosis, and prescription treatment are routinely recorded against date in individual patient records. Information on referrals, secondary care diagnoses, and deaths are also captured because of the structure of the U.K. National Health Service, within which members of the general population are registered with a general practitioner and remain on the general practitioner's list while being treated by specialists or hospitalized. Major events from before computerization are added retrospectively. Medical events are automatically coded. Each patient within GPRD is assigned an up to standard (UTS) date when their records are considered to be of research standard.

The diabetes cohort included all patients on GPRD with a record of or a prescribed treatment (insulin or oral antidiabetic drug) for diabetes while permanently registered and with at least 1 year of computerized records after the UTS date. Potential control subjects had no record of diabetes or diabetic treatment on GPRD at any time and, at the diabetic patient's index date, were permanently registered, had at least 1 year of computerized records after the UTS date, and no history of lung cancer. These potential nondiabetic control subejcts were stratified by primary care practice, year of birth, and sex, and up to four control subjects were randomly selected from the appropriate stratum for each diabetic patient. When four control subjects were not available, the age band was widened by [+ or -] 1 year to a maximum of [+ or -] 5 years. Control subjects were only used once and had the same index date as that of the diabetic patient. Diabetic patients with no control subject, gestational diabetes, an incomplete index date, or a record of lung cancer on or before the index date were excluded. The observation period for each subject was from the index date to an end date. The primary end date allowed observation for the longest available period and was the first of the following: first record of lung cancer, death, transfer out of the practice, or the date of the final data collection. An additional end date was assigned to test the robustness of the results. The group end date was the earliest of the individual end dates for the four observations within each diabetic-control group and provided a censoring of observation to investigate the possibility that shorter life expectancy in diabetes may reduce the rate of lung cancer.

The diabetes cohort and nondiabetic control subjects were grouped into four smoking categories based on GPRD records in the 10 years before their end date: unknown (no record of smoking status), nonsmoker (non- or ex-smokers who had no record of being a smoker in the 10 years), smoker (a record of being a smoker but no record of being a non- or ex-smoker), or mixed status (records of being both a smoker and a nonsmoker). The proportion of current smokers on GPRD is consistent with the U.K. general household survey, but ex-smokers are underestimated, and it is presumed that ex-smokers have been classified for current medical purposes as nonsmokers (21). Smoking classification was based on the previous 10 years of records, as the risk of lung cancer falls after smoking cessation (22).

In addition, as biguanides are the only type 2 diabetes treatment that do not increase plasma insulin levels, the cohort was grouped by GPRD prescription record at anytime: no diabetic drug treatment, insulin only, biguanide only, other oral treatment only, biguanide plus another treatment, and insulin plus oral nonbiguanide. Separately, the diabetic patients were stratified into incident and nonincident diabetic cases. Incident cases had their first diabetes record (diagnosis or treatment) dated more than 1 year after the UTS date and provided a subgroup followed from diagnosis. The index date was the date of the first diabetes record for incident cases and the UTS date plus 1 year for others.

Diabetic patient and nondiabetic control records covering the observation period were searched for terms indicating lung cancer: tumors of the lung, trachea, pleura, bronchus, alveolar and respiratory tract, malignant pleural effusion and morphology, and procedures suggesting lung cancer. The general practitioner of each subject with one of these terms in their record was contacted and asked to send either copies of documentation related to the diagnosis or details that would allow the death certificate to be obtained. From this documentation, it was judged whether lung cancer had been diagnosed and if the tumor was primary or secondary metastatic to the lung. Primary tumors of the lung and bronchus were considered to be cases. Primary mediastinal tumors, mesothelioma, and sarcoma of the pleura were not considered to be cases. Retrieval of documents was through a third party to maintain confidentiality. From the documentation retrieved, each term was assigned a positive predictive value for lung cancer and where documentation was not available or was inconclusive, the cases were assigned as primary lung cancer or not based on the positive predictive value of the term used on GPRD.

Analysis