Insulin Sensitizers May Reduce Cancer Risk in Women

Male medicine doctor hands hold jar of pills while looking on a laptop computerPeople with diabetes have a higher rate of cancer compared to the general population, however, new evidence suggests that the type of anti-diabetic agent prescribed may impact this risk among women. Insulin sensitizers may reduce the risk of cancer among women while insulin secretagogues may increase this risk, according to a large retrospective analysis published in Diabetes, Obesity and Metabolism.

"Clearly, when prescribing anti-diabetic medications, it's important to consider the impact a drug has on fueling cancer growth," said lead author Sangeeta Kashyap, MD, an endocrinologist and Associate Professor of Medicine at Cleveland Clinic's Endocrinology and Metabolism Institute, in Cleveland, Ohio.

"With the recent publication by Sun et al, the differentiation of cancer risk by oral antihyperglycaemic agent therapy (OAA) has become sharper," commented Meei-Shyuan Lee, DrPH, of the School of Public Health, National Defense Medical Center, Taiwan. "That metformin—a biguanide—but not sulfonylureas decreases the risk of cancer in general and of primary liver cell, colorectal and pancreatic cancers in particular (taking into account all other OAAs) was made clear by Lee et al in a large cohort of dominantly Han Chinese subjects," she said.

"Sun et al, in this study using the Cleveland Clinic Diabetes Registry, extend the 'total cancer' findings to a U.S. population, and to the use of thiazolidinediones by comparison with sulfonylureas," Dr. Lee said. "They propose that the difference in risk with different OAAs is a function of whether the OAAs are insulin sensitizers or secretagogues. This is plausible. It is also possible that certain OAAs deal with a common underlying pathogenesis for diabetes and tumorigenesis, the more we understand about energy dysregulation and each disorder," Dr. Lee said.

Large Registry Study
The study authors cross-indexed the electronic health record-based Cleveland Clinic Diabetes Registry (25,613 patients) with a histology-based tumor registry (48,051 cancer occurrences) over an 8-year period (1998–2006). More than 892 incident cancer cases were identified, the most common being prostate cancer (14.5%) and breast cancer (11.7%).

After adjusting for other potential cancer risk factors, use of insulin sensitizers (metformin and thiazolidinedione) was associated with a 21% decreased cancer risk compared with use of insulin secretagogues (meglitinide and sulphonylurea) in women with type 2 diabetes. Furthermore, use of the insulin sensitizer thiazolidinedione in particular was associated with a 32% decreased cancer risk in women compared with use of insulin secretagogues.

These associations were not found among men, possibly because of the "interplay between insulin resistance and hyperinsulinaemia effects on growth factors and bioavailable sex hormone and sex hormone-binding globulin levels that may differentially impact gender-specific malignancies," the authors noted.

Weighing the Risks and Benefits of Metformin
"Although the Sun et al study finds more significance for reduced cancer risk with glitazones than with metformin, the case for preferring the former over the latter as a candidate for cancer risk reduction must take into account broader safety and efficacy considerations, as well as cost, where metformin has decided advantage," commented Dr. Lee. "This applies to all-cause and cardiovascular mortality. As the risk reduction role of metformin emerges for less-well recognized complications, like neurodegeneration (dementia, Parkinson's disease and affective disorders), so its place in diabetes management grows. Likewise, the ability of metformin to offset the risk of sulfonylureas in Parkinson's disease and its possible synergy with sulfonylureas in affective disorders, begs the question of what the glitazones may do in these situations," she said.

The need for more clarification of the gender differences in the effects of OAA on cancer risk is supported by both the Lee at al and Sun et al studies; however, "these differences are not ones of adverse effects of insulin sensitizers," Dr. Lee said.

"Needless to say," Dr. Lee concluded, "intervention studies are required to verify the increasing evidence that all OAAs are not equal when it comes to the risk of cancer in diabetes, but the present data do encourage the use of insulin sensitizers over secretagogues."

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