Abstract
Objective:
The objective of this study was to assess the relationships among diabetes, diabetes treatment and thyroid cancer risk using a large prospective cohort, the Women's Health Initiative.
Methods:
A total of 147 934 women who were free of known cancer at baseline were followed prospectively. Diabetes status and diabetes treatment at baseline and during follow-up were ascertained. Incident cases of thyroid cancers were confirmed by physician review of central medical records and pathology reports. Time-dependent Cox proportional hazards regressions were used to estimate hazard ratios and 95% confidence intervals for thyroid cancer risk associated with diabetes status, diabetes treatment, and duration of diabetes.
Results:
With a median follow-up time of 15.9 years, 391 incident thyroid cancers were identified. We found no significant associations between thyroid cancer and diabetes (hazard ratio = 1.09; 95% confidence interval, 0.79–1.52), diabetes treatment, or duration of diabetes.
Conclusion:
Our findings do not support the hypothesis that diabetes, or treatment of diabetes is associated with risk of thyroid cancer among postmenopausal women. Studies to investigate the specific effects of hyperinsulinemia and insulin resistance on thyroid cancer risk may provide additional information.
Thyroid cancer is the most common endocrine malignancy. Although cancers of the thyroid are relatively uncommon, comprising about 3% of all cancers diagnosed in the United States, the incidence rate of thyroid cancer has been increasing annually by about 6% since the mid-1990s (1). Although this increase may be largely explained by improved detection of very small papillary tumors and changes in diagnostic criteria, changes in environmental risk factors may also play a role (2–4). Currently, little is known about the etiology of thyroid cancer. Ionizing radiation exposure, particularly in childhood, and family history, are the few established risk factors for thyroid cancer. Other consistently reported risk factors include previous benign thyroid disease and high iodine intake (5).
Recently, it has been proposed that the rising thyroid cancer incidence in the world might be related to insulin resistance (6). This hypothesis has been supported by epidemiological evidence that a higher body mass index (BMI) is associated with an increased risk of thyroid cancer (7, 8). Studies have also observed that patients with insulin resistance have larger thyroid volumes and higher risk for formation of thyroid nodules (9, 10). Another small cross-sectional study noted that increased prevalence of insulin resistance is present in patients with differentiated thyroid carcinoma (11). These findings suggest that the higher circulating levels of insulin may cause increased thyroid proliferation and thyroid nodules.
Insulin resistance is a key feature of type 2 diabetes mellitus. It is therefore possible that patients with type 2 diabetes have increased thyroid cancer risk. Autoimmune thyroid diseases are frequent in patients with type 1 diabetes (12). Studies have also observed that type 2 diabetes patients had a higher incidence of thyroid dysfunction (13), or higher prevalence of abnormal serum thyroid stimulating hormone concentration (14), which in some studies have been linked to an increase in thyroid cancer (15–17). However, epidemiological studies have directly examined the relationship between diabetes and thyroid cancer risk and findings have been inconclusive (18–20).
Experimental studies have associated metformin treatment with a decrease of cancer risk (21), although the clinical data outcomes remain inconclusive (22, 23). However, whether metformin use can reduce the risk of thyroid cancer in patients with type 2 diabetes remains to be confirmed. Evidence from experimental research has suggested that metformin may inhibit the growth of thyroid cancer cells (24, 25). However, to our knowledge, there is only one study examining the relationship that reported a protective effect of metformin on thyroid cancer risk (26).
In this proposed study, we conducted a comprehensive assessment of diabetes associated with the risk of thyroid cancer based on a large prospective study in the United States, the Women's Health Initiative (WHI), with more than 15 years of follow-up, and with detailed information on diabetes, diabetes treatment, potential confounders, and centrally adjudicated thyroid cancer cases (for a short list of WHI investigators, please see Supplemental Materials).
Materials and Methods
Women's Health Initiative
The WHI was designed to address the major causes of morbidity and mortality in postmenopausal women (27). Details of the scientific rationale, eligibility requirements, and baseline characteristics of the participants in the WHI have been published elsewhere (28–32). Briefly, a total of 161 808 women ages 50–79 were recruited at 40 clinical centers throughout the United States between September 1, 1993 and December 31, 1998, including both multicenter clinical trials (CTs) and an observational study (OS). The study was overseen by institutional review boards at all 40 clinical centers and at the coordinating center, as well as by a study-wide data and safety monitoring board. All participants in WHI gave informed signed consent and were followed prospectively.
The following participants were excluded from the original cohort of 161 808 for this analysis: 12 655 women who had a history of cancer (except nonmelanoma skin cancer) at baseline; 636 women who had no follow-up information; 221 women who were diagnosed with diabetes before age 20 and/or who were “ever hospitalized for diabetic coma” (these were deemed to have a probable type 1 diabetes diagnosis); and 362 women who had missing values of the main exposures (including diagnosis of diabetes, age at diagnosis, and diabetes treatment). After these exclusions, 147 934 women remained for final analysis.
Measurement of exposures, outcome, and confounders
Exposures
Treated diabetes, types of diabetes treatment, and diabetes duration were considered as main exposures. Treated diabetes at enrollment was defined as whether or not the participant reported ever having been treated for diabetes with pills or insulin injections. Incidence of newly reported medically treated diabetes was determined during annual WHI follow-up. The definition of incident diabetes was a positive response to the question: “since the date given on this form has a doctor prescribed any of the following pills or treatments?,” with mention of any newly prescribed pills or insulin injections for treating diabetes. For consistency with earlier methods of reporting, we did not include self-reports of incident diabetes treated only with diet or exercise, because these response options were not added until 2006. Information on types of treatment for diabetes was also extracted from the WHI medication inventory collected at baseline, visit year 1, 3, 6, and 9. Diabetic patients were divided into 3 groups based on the type of drugs used at each visit (ie, insulin with or without oral antidiabetic drugs, metformin, or other drugs). The duration of diabetes was estimated as difference between age of participants when first diagnosed with diabetes and end of follow-up. Self-reported diabetes in WHI has been validated by medication inventories, laboratory data, and chart review as a reliable indicator of diagnosed diabetes (33, 34).
Follow-up and ascertainment of cases
Incident thyroid cancer cases were identified by self-administered questionnaires (administered every 6 mo in the CT through 2005, and annually in the CT after 2005 and in the OS), with all cases confirmed by medical record review. All primary thyroid cancer cases were then coded centrally in accordance with the Surveillance Epidemiology and End Results coding guidelines. All participants were followed from enrollment to first thyroid cancer diagnosis, date of death, loss to follow-up, or end of CT or OS follow-up (September 20, 2013), whichever occurred first.
Confounders
In the multivariable models, we considered potential confounders at baseline, including age at enrollment (<55, 55–59, 60–64, 65–69, 70–74, and ≥75), ethnicity (American Indian or Alaska Native, Asian or Pacific Islander, Black or African-American, Hispanic/Latino, non-Hispanic white, and other), education (high school or less, some college/technical training, college or some postcollege, and master or higher), BMI (<18.5, 18.5–24.9, 25.0–29.9, 30.0–34.9, 35.0–39.9, and ≥40), recreational physical activity (total metabolic equivalent tasks [METs] per wk: <5, 5–<10, 10–<20, 20–<30, and ≥30), smoking status (never, former, and current), alcohol intake (nondrinker, past drinker, <1 drink per mo, and current drinker, including frequency: <1 drink per mo, 1 drink/mo to <1 drink/wk, 1–< 7 drinks/wk, and ≥7 drinks/wk), history of hormone therapy (HT) use (none, estrogen alone, estrogen and progestin, mixed), family history of cancer (yes, no), and previous thyroid disease (yes, no). The previous thyroid disease was a positive response to the question “did a doctor ever say that you had a thyroid grand problem (not including thyroid cancer)?”
Statistical analysis
All exposures, including diabetes, type of diabetes treatment, and duration of diabetes, were considered as a time-dependent variables. Cox proportional hazards regression models with a time-dependent covariate were employed to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between diabetes and risk of thyroid cancer. In the time-dependent covariate Cox model, diabetes status was updated at the date that diabetes was reported. The proportionality assumption was satisfied for all exposure variables of interest and potential confounding variables based on graphs of scaled Schoenfeld residuals (35). In the multivariable models, we adjusted for potential confounders as described above. Different study cohorts (participation in OS or CTs, and different treatment assignments for all 3 CTs) were treated as strata in the model to take into account possible different baseline hazards in different subgroups and treatment effects. Because hyperinsulinia is a purported mechanism, adjusting for difference in BMI might make it less likely that an association would be detectable. Thus, we performed multivariable models with and without adjustment for BMI.
In addition, we also performed several sensitivity analyses, including considering diabetes status at baseline only, and restricting to papillary thyroid cancer. All statistical analyses were conducted using SAS (version 9.3; SAS Institute).
Results
Baseline characteristics by type 2 diabetes status at enrollment and during follow-up are shown in Table 1. Compared with women without diabetes, women with diabetes were more likely to be non-White (non-Hispanic), less educated, have higher BMI and higher waist to hip ratio, a current-smoker, and a nondrinker. They were less physically active, and less likely to report a family history of cancer, and report use of estrogen and progestin HT (all P < .05). Among 6224 (4.2%) diabetic women at baseline, 21.5% were receiving no pharmacologic treatment or unknown for diabetes, 14.8% used metformin, 41.1% used other oral medications, and 22.7% used insulin (Table 1).
Table 1.
Baseline Characteristics of Participants by Diabetes Status at Baseline and During Follow-Up Among 147 934 Women at WHI Enrollment
| Variable | No Diabetes | Diabetes | P Value |
|---|---|---|---|
| Total number of women | 124 606 (84.2) | 23 328 (15.8) | |
| Age at baseline (mean; y) | 63.2 | 63.0 | .007 |
| White, non-Hispanic ethnicity (%) | 105 189 (84.4) | 16 989 (72.8) | <.0001 |
| College graduate or above education (%) | 50 577 (40.6) | 7617 (32.7) | <.0001 |
| BMI (mean, kg/m2) | 27.3 | 31.2 | <.0001 |
| Waist to hip ratio | 0.81 | 0.85 | <.0001 |
| Smoking status | .03 | ||
| Never smokers | 63 028 (50.6) | 11 841 (50.8) | |
| Former smokers | 51 560 (41.4) | 9502 (40.7) | |
| Current smokers | 8400 (6.7) | 1684 (7.2) | |
| Alcohol intake | <.0001 | ||
| Nondrinker | 12 866 (10.3) | 3263 (14.0) | |
| Past drinker | 20 805 (16.7) | 6319 (27.1) | |
| Current drinker | 90 011 (72.2) | 13 553 (58.1) | |
| Physical activity (mean, METs per wk) | 12.9 | 9.9 | <.0001 |
| Family history of cancer (%) | 79 151 (63.5) | 14 348 (61.5) | <.0001 |
| History of HT use | <.0001 | ||
| None | 52 666 (42.3) | 11 441 (49.0) | |
| Estrogen alone | 37 031 (29.7) | 7074 (30.3) | |
| Estrogen and progestin | 27 689 (22.2) | 3783 (16.2) | |
| Mixed | 7220 (5.8) | 1030 (4.4) | |
| Previous thyroid disease (yes, %) | 29 027 (23.3) | 5816 (24.9) | <.0001 |
| Type of diabetic drugs in medication inventory at baselinea | |||
| Untreated/drugs unknown | 1335 (21.5) | ||
| Metformin alone | NA | 921 (14.8) | |
| Other oral medication alone | NA | 2555 (41.1) | |
| Insulin (alone or with oral medication) | NA | 1413 (22.7) |
For women with treated diabetes at baseline only.
Over a median of 15.9 years of follow-up, we observed 391 thyroid cancers. There was no increased risk of thyroid cancer associated with diabetes (HR = 1.09; 95% CI, 0.79–1.52), regardless of type of treatment or duration of diabetes (Table 2). We also compared thyroid cancer risk in metformin users and all nonmetformin users in analyses restricted to diabetic women and found no association between metformin use and thyroid cancer risk (HR = 1.07; 95% CI, 0.44 2.56). Further, we did sensitivity analyses by modeling diabetes status at baseline, and restricting to papillary thyroid cancer (the most common type of thyroid cancer), and found no significant association for papillary thyroid cancer associated with diabetes.
Table 2.
HRs and 95% CIs for Thyroid Cancer Incidence Associated With Time-Dependent Diabetes Status (Including Diabetes at Baseline and Diabetes Diagnosed During Follow-Up)
| Exposure | Thyroid Cancer Cases | Person- Years | Incidence Rate (per 10 000) | Age-Adjusted HR (95% CI) | Multiple- Adjusted HR (95% CI)a | Multiple- Adjusted HR (95% CI)b |
|---|---|---|---|---|---|---|
| Treated diabetes | ||||||
| No | 347 | 1 852 366 | 1.87 | Reference | Reference | Reference |
| Yes | 44 | 184 843 | 2.38 | 1.17 (0.85–1.60) | 1.14 (0.83–1.58 | 1.09 (0.79–1.52) |
| Self-reported type of diabetic treatment | ||||||
| On oral medications only | 29 | 127 383 | 2.28 | 1.15 (0.75–1.76) | 1.13 (0.74–1.73) | 1.08 (0.70–1.67) |
| Receiving insulin (alone or with oral medications) | 15 | 57 460 | 2.61 | 1.19 (0.76–1.84) | 1.15 (0.74–1.81) | 1.11 (0.71–1.75) |
| Type of diabetic drugs in medication inventory | ||||||
| Insulin (alone or with oral medication) | 6 | 19 805 | 3.03 | 1.64 (0.73–3.67) | 1.61 (0.71–3.63) | 1.57 (0.69–3.55) |
| Metformin | 9 | 36 055 | 2.50 | 1.24 (0.64–2.41) | 1.21 (0.62–2.37) | 1.15 (0.59–2.26) |
| Other drugs | 9 | 40 698 | 2.21 | 1.20 (0.62–2.33) | 1.18 (0.61–2.30) | 1.13 (0.58–2.22) |
| Untreated/drugs unknown | 20 | 83 500 | 2.40 | 1.08 (0.68–1.70) | 1.06 (0.67–1.68) | 1.02 (0.65–1.62) |
| Duration of diabetes | ||||||
| <6 y | 19 | 87 820 | 2.16 | 1.06 (0.67–1.69) | 1.04 (0.66–1.66) | 1.00 (0.63–1.60) |
| ≥6 y | 25 | 97 023 | 2.58 | 1.26 (0.84–1.90) | 1.23 (0.81–1.87) | 1.18 (0.77–1.80) |
Adjusted for age at enrollment (<55, 55–59, 60–64, 65–69, 70–74, and >75), ethnicity (American Indian or Alaska Native, Asian or Pacific Islander, Black or African-American, Hispanic/Latino, non-Hispanic white, and other), education (high school or less, some college/technical training, college or some postcollege, and master or higher), smoking status (never, former, and current), recreational physical activity (total METs per wk: <5, 5–<10, 10–<20, 20–<30, and >30), alcohol intake (nondrinker, past drinker, <1 drink per month, and current drinker, including frequency: <1 drink per mo, 1 drink/mo to <1 drink/wk, 1–<7 drinks/wk, and >7 drinks/wk), history of HT use (none, estrogen alone, estrogen and progestin, mixed), and previous thyroid disease.
Further adjusted for BMI (<18.5, 18.5–24.9, 25.0–29.9, 30.0–34.9, 35.0–39.9, and >40).
Discussion
We had hypothesized that a diagnosis of diabetes would be associated with increased risk of thyroid cancer, a possibility consistent with several biological mechanisms. The first is via insulin resistance, a key feature of type 2 diabetes (6, 11). The elevated insulin associated with diabetes could promote thyroid cancer growth directly through enhanced cancer cell proliferation or reduced apoptosis or indirectly by stimulating the production of other hormones, such as IGF-1, or TSHs (14, 17, 36). Other possible mechanisms may involve the impact of hyperglycemia on tumor cell growth and proliferation via increased oxidative stress or antidiabetic medications such as insulin or sulfonylureas (18). However, our data failed to support the hypothesis that diabetes, or treatment of diabetes is associated with risk of thyroid cancer among postmenopausal women.
Previous studies regarding the risk of thyroid cancer in patients with diabetes have yielded conflicting results (18–20). That our results failed to support this hypothesis is consistent with most previous studies (37–42) that report no or nonsignificant increases in thyroid cancer risk, with an exception of a study (43) that reported a significantly positive association in women in the National Institutes of Health-American Association of Retired Persons (NIH-AARP) Diet and Health Study. However, a recent pooled study (42) of 5 prospective studies from the United States, including the NIH-AARP study (43), reported no evidence of an association between a history of diabetes and thyroid cancer (HR = 1.08, 95% CI 0.83–1.40).
Although some evidence from experimental research has suggested that metformin may inhibit the growth of thyroid cancer cells possibly via activation of AMP activated protein kinase signaling and inhibition of Akt signaling (24, 25, 44), our data observed that neither metformin nor insulin was significantly associated with risk of thyroid cancer. A study (45) reported that treatment with metformin was associated with higher remission rates from thyroid cancer in diabetic patients. Only one previous epidemiological study (26) examined the association between metformin use and thyroid cancer risk in Taiwanese patients with type 2 diabetes mellitus, and found that metformin use in patients with type 2 diabetes may reduce the risk of thyroid cancer. A similar study (46) based on the same database examined the association between human insulin use and thyroid cancer risk and did not support the role of human insulin therapy in increasing the risk the thyroid cancer in patients with diabetes. The major concern of the 2 studies was that both adjusted for limited potential confounders like obesity, smoking, alcohol drinking, and family history, due to the nature of using the existing databases. In addition, exposures in both studies were defined as ever-users and never-users (those who had ever or never been prescribed metformin or human insulin before entry date), which failed to consider changes in diabetes medications over time.
Several factors may have contributed to our inability to identify an association between diabetes, or diabetes treatment and risk of thyroid cancer among postmenopausal women. First, the association between diabetes and thyroid cancer may be weak. Our study may not have been large enough to be able to detect a weak effect. Second, the self-reported history of diabetes may not have been an adequate surrogate for insulin resistance and hyperinsulinemia. However, the subjects with diabetes had substantially greater BMI and waist to hip ratio compared with the subjects without diabetes, making hyperinsulinemia likely. We also found no relationship between BMI and waist to hip ratio and risk of thyroid cancer when the diabetes patients were excluded. Third, the association between diabetes and thyroid cancer may be modified by women's age with no or weak links among postmenopausal women. Interestingly, a recent study reported an increased prevalence of diabetes only in patients with papillary thyroid carcinoma who were 44 years of age or younger, but not in patients of all ages, comparing with the general population (47).
The strengths of the present study include the long-term follow-up of a large cohort with information collected at multiple time points, central coding of cancer diagnosis, and inclusion of other potential confounders. However, several limitations deserve mention. First, diabetes status was based on self-report and the WHI did not collect self-reports of incident diabetes treated with diet or exercise until 2006. Despite the high positive (82%) and negative (95%) predictive value of self-reported diabetes in WHI (33, 34), this may result in some degree of exposure misclassification, which may bias our effect toward to the null. Second, we excluded women who were diagnosed with diabetes before age 20 and/or who were ever hospitalized for diabetic coma (these were deemed to have a probable type 1 diabetes diagnosis). However, it is possible for type 1 diabetes to occur in those above age 20. Additionally, though less common, diabetic coma occurs in type 2 diabetes as well. Thirds, we were unable to adjust for ionizing radiation exposure during women's childhood as we did not ask this question. Data specific to family history of thyroid cancer are also unavailable Another limitation includes the inability to further examine stratified analyses by potential effect modifiers (such as age, race, BMI) due to insufficient power, despite the fact that the WHI is a large cohort.
In conclusion, the findings from our study do not support the hypothesis that diabetes, or treatment of diabetes are associated with risk of thyroid cancer among postmenopausal women. Studies that specifically assess prediabetes, hyperinsulinemia and insulin resistance may add important information.
Acknowledgments
The Women's Health Initiative program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, and United States Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C.
Disclosure Summary: The authors have nothing to disclose.
Footnotes
- BMI
- body mass index
- CI
- confidence interval
- CT
- clinical trial
- HR
- hazard ratio
- HT
- hormone therapy
- MET
- metabolic equivalent task
- OS
- observational study
- WHI
- Women's Health Initiative.
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