Evidence from two large prospective studies found that type 2 diabetes was independently associated with a greater risk of renal cell carcinoma (RCC) in women, but not in men. The results were published in Diabetes Care.
Prior studies evaluating the association between type 2 diabetes and the risk of RCC have yielded conflicting results. The Nurses’ Health Study (NHS), a large prospective study which collected baseline medical information with a questionnaire from 121,701 female nurses in 1976, reported that type 2 diabetes in women was associated with a 60% increased risk of RCC. The NHS is updated every two years.
Rebecca E. Graff, PhD, from the Harvard T.H. Chan School of Public Health in Boston, MA, and colleagues, set out to update the NHS analysis with additional follow-up time and cases. Moreover, they wanted to replicate the analysis in a cohort of men using the Health Professionals Follow-up Study (HPFS), which enrolled 51,529 male medical professionals who responded to a similar questionnaire starting in 1986.
Participants were excluded if they reported cancer at baseline (other than nonmelanoma skin cancer), type 1 diabetes, or diabetes before the age of 30. The final study population included 117,570 participants in the NHS and 48,866 participants in the HPFS.
Diagnosis of RCC was ascertained on each biennial questionnaire, and cases were confirmed by pathology. Histologic subtypes of RCC included clear cell, papillary, chromophobe, collecting duct, and unspecified histologies. TNM stage (2010 criteria) and Fuhrman grade (1-4) or differentiation (well, moderately, poorly, and undifferentiated) were obtained from pathology reports.
Participants with RCC-specific deaths were considered fatal RCC case subjects. Follow-up for mortality in these study populations was roughly 98%.
At baseline, 0.72% of women and 1.3% of men had type 2 diabetes. This increased to 12% and 9.4%, respectively, by the end of follow-up. Individuals with type 2 diabetes in both cohorts had higher BMI and prevalence of hypertension, were less physically active, and consumed less alcohol.
Smoking patterns were similar for women with and without type 2 diabetes; men with type 2 diabetes were less likely to be never smokers.
During 38 years of follow-up in the NHS, 418 incident RCC cases were noted, including 120 fatal cases. Women with type 2 diabetes had a statistically significant greater risk of developing RCC than women without type 2 diabetes (multivariable hazard ratio [HR]: 1.53). The HR for fatal RCC was not significant (HR: 1.35).
Alternatively, men with type 2 diabetes did not have a greater risk of total RCC (HR: 0.89). During 28 years of follow-up in the HPFS, there were 302 incident RCC cases, including 87 fatal cases. For fatal RCC, the HR in men was 1.23.
Hypertension accounted for the largest portion of the difference between the age-adjusted and fully adjusted estimates in both men and women. There was no statistically significant interaction between type 2 diabetes and hypertension or obesity.
A meta-analysis of the NHS and HPFS results did not yield evidence of an association between type 2 diabetes and risk of RCC (HR: 1.20) or fatal RCC (HR: 1.30).
In the NHS, analyses of RCC by histologic subtype suggested a stronger association for type 2 diabetes with non-clear cell RCC (HR: 2.68) than with clear cell RCC (HR: 1.35); in the HPFS, there were no significant associations between type 2 diabetes status and risk of RCC according to histologic subtype, stage, or differentiation.
Women with a duration of type 2 diabetes ≤5 years showed a statistically significant association with RCC risk (HR: 2.15) compared to women without type 2 diabetes; however, women with a duration >5 years did not (HR: 1.22). Among men, there was no association for either duration category.
There was no statistically significant interaction between type 2 diabetes and hypertension or obesity; however, the power was low for these analyses.
The authors explained that overall, men are at greater risk of RCC than women, with a 2:1 male:female incidence ratio. They suggested that underlying biologic differences may explain the difference in risk of RCC between women and men with type 2 diabetes.
Among women, the risk of RCC was significantly higher within the first 5 years after type 2 diabetes diagnosis. The investigators think that the association between diabetes and RCC could be due to increased medical scrutiny or to hyperinsulinemia, which occurs early in the course of type 2 diabetes.
Despite the prospective design and large size, the study had several limitations. There were not adequate numbers of patients for subgroup analyses, risk factors such as chronic kidney disease could not be controlled, and the cohort was primarily Caucasian (>90%). In addition, the severity of the disease and glucose control could not be assessed, and there was no information regarding medication use.
“In this large prospective study, we found that type 2 diabetes was associated with a significantly greater risk of RCC in women, independent of obesity, hypertension, and smoking,” the authors concluded. “The association was strongest for non-clear cell RCC. Type 2 diabetes was not significantly associated with risk of fatal RCC in women or with overall or fatal RCC in men.”
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