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Diabetes does not increase cancer risk equally -- women with diabetes are at slightly higher risk than men, according to a meta-analysis of published research.

Women with diabetes had a 27% increase in risk for any type of cancer (relative risk 1.27; 95% CI 1.21 to 1.32), compared with a 19% risk increase for men with diabetes (RR 1.19; 95% CI 1.13 to 1.25), said researchers led by Toshiaki Ohkuma, PhD, of the University of New South Wales, Australia.

Overall, cancer risk was approximately 6% higher in women than men with diabetes. The pooled women-to-men ratio of relative risk (RRR) was 1.06 (95% CI 1.03 to 1.09). In addition, cancer mortality risk was 3% higher in women than men (RRR 1.03; 95% CI 0.99 to 1.06), Ohkuma's group reported online in .

An analysis by cancer site found that, compared with men, women had significantly higher risk for kidney (RR 1.11; 95% CI 1.04 to 1.08), oral (RR 1.13; 95% CI 1.00 to 1.28), and stomach cancer (RR 1.14; 95% CI 1.07 to 1.22) as well as leukemia (RR 1.15; 95% CI 1.02 to 1.28), but significantly lower risk for liver cancer (RR 0.88; 95% CI 0.79 to 0.99).

"Diabetes has been associated with the risk of all-site and some site-specific cancers in several systematic reviews and meta-analyses," the study authors said. However, "there has been no systematic overview of the evidence available on sex differences in the association between diabetes and cancer. In this study, we conducted the most comprehensive systematic review and meta-analysis, to date, to estimate the relative effect of diabetes on the risk of cancer in women compared with men."

"The study indicates the importance of a sex-specific approach to quantification of the role of diabetes in cancer prevention and treatment."

The meta-analysis included 47 observational studies involving 121 cohorts, more than 19 million individuals, and more than one million cancer events.

The studies included individuals with both type 1 and type 2 diabetes, and reported sex-specific relative risk estimates for the association between diabetes and cancer. The investigators used random-effects meta-analyses with inverse-variance weighting to calculate pooled sex-specific relative risks and women-to-men ratios of relative risk for any type of cancer as well as site-specific cancers.

Possible Reasons for the Difference

There are several possible explanations for the higher cancer risk in women with diabetes, Ohkuma and colleagues said. One potential mechanism is poor glycemic control, since historically, women tend to be under-treated or to receive less-intensive care than men. In addition, recent evidence suggests that women are less adherent to glucose-lowering medication than men are. The hyperglycemia associated with poor glucose control may have carcinogenic effects linked to oxidative stress.

"As such, the carcinogenic effects of hyperglycemia may be enhanced in women and subsequently lead to an increased cancer risk compared with men," the researchers said.

Another possible explanation is that women tend to have undiagnosed diabetes for a longer time than men. The average duration of impaired glucose tolerance or impaired fasting glucose has been found to be more than 2 years longer in women than men. Women may therefore be exposed to insulin resistance and hyperinsulinemia for longer periods of time, and hyperinsulinemia is known to promote cancer cell proliferation by stimulating the insulin receptor and insulin-like growth factor 1.

Finally, a third explanation may be that diabetes has been shown to have a protective effect against prostate cancer, and the results may be driven by that phenomenon, the study authors said.

Limitations of the meta-analysis, the researchers stated, included that there were differences among the studies in design, duration, and endpoints, and in how well they adjusted for potential confounders. In addition, some of the studies lacked information on the duration of diabetes and the degree of glycemic control. Finally, there may have been unmeasured confounding factors specific to particular types of cancer, such as Helicobacter pylori infection for stomach cancer and hepatitis virus infection for liver cancer.

"In conclusion, diabetes is a risk factor for all-site cancer in both sexes, with a stronger effect in women than men," the authors wrote. "Sex differences varied across the location of the cancer, heightening the importance of a sex-specific approach to quantification of the role of diabetes in cancer research, prevention, and treatment. Further studies are needed to clarify the mechanisms underlying the sex differences in the diabetes-cancer association."

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