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Cancer Incidence in Patients With Type 1 Diabetes Mellitus: A Population-Based Cohort Study in Sweden

Kazem Zendehdel, Olof Nyrén, Claes-Göran Östenson, Hans-Olov Adami, Anders Ekbom, Weimin Ye

Affiliations of authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (KZ, ON, HOA, AE, WY); Department of Molecular Medicine, Endocrine and Diabetes Unit, Karolinska Hospital, Stockholm (CGÖ); Endocrine and Metabolism Research Center and Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran (KZ); Department of Epidemiology, Harvard School of Public Health, Boston, MA (HOA).

Correspondence to: Weimin Ye, MD, MSc, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Box 281, SE 171 77, Stockholm, Sweden (e-mail: Weimin.Ye{at}meb.ki.se)


    ABSTRACT
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Although patients with type 2 diabetes have elevated risks of liver, pancreatic, kidney, and endometrial cancer, little is known about the risk of cancer for patients with type 1 diabetes. We conducted a cohort study to examine cancer incidence among 29 187 patients in Sweden who were hospitalized for type 1 diabetes from 1965 through 1999. Relative risks of cancer were estimated by age-, sex- and calendar year of follow-up–adjusted standardized incidence ratios (SIRs), using data for the entire Swedish population as a reference. After excluding cancers diagnosed during the first year after hospital discharge, we observed 355 incident cases of cancer, which corresponded to a 20% increase in overall cancer incidence among type 1 diabetes patients (SIR = 1.2, 95% confidence interval [CI] = 1.0 to 1.3). Patients with type 1 diabetes had elevated risks of cancers of the stomach (SIR = 2.3, 95% CI = 1.1 to 4.1), cervix (SIR = 1.6, 95% CI = 1.1 to 2.2), and endometrium (SIR = 2.7, 95% CI = 1.4 to 4.7). Type 1 diabetes is associated with a modest excess cancer risk overall and risks of specific cancers that differ from those associated with type 2 diabetes.


The two subtypes of diabetes mellitus have fundamentally different metabolic and hormonal characteristics. Type 2 diabetes is characterized by impaired insulin release and/or decreased hepatic and extrahepatic insulin sensitivities (1,2), whereas type 1 diabetes is characterized by the cessation of insulin biosynthesis due to the autoimmune destruction of insulin-producing pancreatic {beta} cells. Increased circulating levels of insulin precursors (i.e., proinsulin and related peptides) have been implicated as mediators of the elevated risks of cancer of the liver, pancreas, kidney, and endometrium among type 2 diabetes patients (36). If hyperinsulinemia acts as a critical link between the observed increased cancer risk and type 2 diabetes, one would predict that patients with type 1 diabetes would have a different cancer risk pattern than patients with type 2 diabetes because the former patients are exposed to lower levels of exogenously administered insulin. Our previous attempts to examine cancer risks associated with type 1 diabetes were limited by small sample sizes, short follow-ups, and a questionable algorithm for the identification of patients with type 1 diabetes (4,79). Another cohort study from Denmark also had these limitations (6). We therefore sought to obtain precise estimates of cancer risk in type 1 diabetes patients by performing a large population-based retrospective cohort study.

We used the Swedish Inpatient Register created by the National Board of Health and Welfare to identify the study cohort (10). Each record in this register includes the patient's national registration number and the discharge diagnoses coded throughout the study period according to the 7th through 10th revised versions of the International Classification of Diseases (ICD) (1114). The coding for diabetes in ICD versions 7 through 9 did not allow us to distinguish between patients with type 1 diabetes and those with type 2 diabetes because unique codes for insulin-dependent diabetes were not introduced until 1997, when the ICD-10 became effective. In addition, many elderly patients diagnosed with insulin-dependent diabetes after 1997 had previously been diagnosed with type 2 diabetes that had become insulin-dependent. Therefore, we defined patients with type 1 diabetes as those who were 30 years old or younger at first hospitalization for diabetes (15,16). We initially selected the records of 30 072 patients who were diagnosed with diabetes mellitus and were 30 years old or younger when discharged from the hospital. The records were then linked to the Swedish Cancer, Total Population, Migration, and Death Registers. We excluded 159 records with erroneous national registration numbers and records for 122 patients who were diagnosed with cancer before the first hospitalization for type 1 diabetes (index hospitalization), 18 patients who underwent a renal transplantation during or before the index hospitalization, and 22 patients hospitalized after 1996 with a diagnosis of non–insulin-dependent diabetes during the subsequent or previous hospitalization, and 564 records with other inconsistencies. We used the records of the remaining 29 187 patients, who were presumed to have type 1 diabetes, in our study.

The number of person-years at risk for each patient was calculated from the date of discharge from the index hospitalization until the date of the first malignant cancer diagnosis, renal transplantation, death, emigration, or December 31, 1999, whichever came first. Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs), adjusted for age, sex, and calendar year at follow-up, were calculated to estimate relative risks by using the entire population of Sweden as reference group (17). To minimize the impact of selection bias, we excluded person-time accrued and cancer events observed during the first year of follow-up. The Regional Research Ethics Committee at Karolinska Institutet approved this register-based study.

The mean age of patients with type 1 diabetes upon index hospitalization was 17.1 years. Patients were followed for a mean of 14.4 years and accrued a total of 415 838 person-years at risk. More males than females were hospitalized for type 1 diabetes, and females were first hospitalized at an older age and were followed up for a longer period of time than males (Table 1).


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Table 1. Characteristics of 29 187 type 1 diabetes patients hospitalized in Sweden from 1965 through 1999*

 
Starting follow-up 1 year after index hospitalization, we observed 355 incident cases of cancer among the type 1 diabetes patients, which corresponded to a 20% increase in overall cancer incidence (SIR = 1.2, 95% CI = 1.0 to 1.3) compared with the cancer incidence in the general population of Sweden (Table 2). Patients hospitalized for type 1 diabetes had greater than twice the relative risk of stomach cancer than the general population in Sweden (SIR = 2.3, 95% CI = 1.1 to 4.1). Analysis by follow-up duration indicated that the risk elevation was confined to the period starting 15 years after index hospitalization (SIR = 3.3, 95% CI = 1.5 to 6.3). In addition, patients hospitalized for type 1 diabetes had increased risks of cancers of the cervix or endometrium compared with the general population in Sweden (SIR = 1.6, 95% CI = 1.1 to 2.2 and SIR = 2.7, 95% CI = 1.4 to 4.7, respectively). The increased risk of endometrial cancer was greater during years 1 through 14 of follow-up (SIR = 4.8, 95% CI = 1.3 to 12.3) than after 15 or more years of follow-up (SIR = 2.2, 95% CI = 0.9 to 4.3) (Table 2). Patients with type 1 diabetes did not have statistically significantly increased risks for breast, colorectal, pancreatic, or kidney cancer (Table 2). We observed only two cases of primary liver cancer among the patients in our cohort which, when compared with the number of liver cancers observed in the general population, corresponded to a relative risk of 1.5 (95% CI = 0.2 to 5.4). Because most of the observed person-time in our study cohort was in young ages, where cancer occurrence is very rare, we did a secondary analysis in which we excluded cancers that occurred in young ages (attained age at follow-up younger than 18 years). The results remained virtually unchanged in the secondary analysis (data not shown).


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Table 2. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for cancer occurrence in patients hospitalized for type 1 diabetes in Sweden, 1965–1999, stratified by duration of follow-up*

 
The hypothesized mechanism for the observed increased risk of pancreatic cancer among type 2 diabetes patients is through hyperinsulinemia (5). Hence, lower or no excess risk of pancreatic cancer was anticipated in type 1 diabetes patients because they are exposed only to normal or low levels of exogenous insulin. Our finding is consistent with this expectation and supports the insulin hypothesis underlying the association between type 2 diabetes and pancreatic cancer.

Although two Swedish studies (7,19) have reported that patients with type 1 diabetes have an increased risk of endometrial cancer, an Italian study (20) reported no such increased risk. However, all of those studies defined patients with type 1 diabetes by using a cutoff age that was higher than the one used in our study. Several mechanisms could underlie the association between type 1 diabetes and endometrial cancer observed in our study. First, obesity is a recognized risk factor for endometrial cancer (19). Long-term insulin therapy used to treat diabetes patients may be responsible both for the weight gain these patients experience and the deposition of abdominal fat that leads to insulin resistance in later stages of the disease (21). Our finding, that patients with type 1 diabetes had a greater risk of endometrial cancer during the early follow-up period than during the late follow-up period, however, seems inconsistent with this hypothesis. Second, results of several studies have suggested that, compared with women without type 1 diabetes, women with type 1 diabetes have higher incidence of nulliparity, irregular menstruation, and fertility disorders (22,23), which are probable risk factors for endometrial cancer (24) and conceivable effect modifiers of the positive association(s) between endometrial cancer and other risk factors.

An unexpected finding in this study was that the risk of stomach cancer among type 1 diabetes patients increased with follow-up time. This finding may be related to the high prevalence of Helicobacter pylori infection among patients with type 1 diabetes (25,26) or the high incidence of pernicious anemia, a condition associated with a high risk of stomach cancer, because parietal cell antibodies are more common in type 1 diabetes patients than in the general population (27,28).

Our study has several limitations. We cannot exclude the possibility that our results are chance findings due to multiple comparisons; thus, these results should be interpreted with caution. Additional limitations include the possibility that some type 2 diabetes patients were misclassified as type 1 diabetes patients, the lack of information about several potential confounding factors and, despite the large number of observed person-years, the modest number of observed cancers for each specific site.


    NOTES
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Supported by several grants from the Swedish Cancer Society. K. Zendehdel was partly supported by the International Cancer Technology Transfer fellowship from the International Union Against Cancer (UICC).


    REFERENCES
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Manuscript received April 30, 2003; revised September 22, 2003; accepted September 26, 2003.


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