Oral Diabetes Drugs May Lower Cancer Risk in Women with Type 2 Diabetes

By Sangeeta Kashyap, MD

Sangeeta Kashyap, MD

Patients with type 2 diabetes have an increased risk of cancer development versus the general population. Large observational studies have indicated that both diabetes and cancer are influenced by common risk factors including advancing age, genetic predisposition, male gender, obesity and poor lifestyle. However, drugs used to treat type 2 diabetes mellitus have also been implicated in overall cancer risk, and an increasing body of evidence suggests that clinicians need to carefully consider the possibility of an anti-diabetic drug potentially fueling cancer development.

Dramatic differences

For example, data show the use of sulfonylurea elevates endogenous insulin levels and potentiates associated insulin-like growth factor-1 (IGF-1) pathways. These pathways are considered mitogenic and increase risk of tumor development. In contrast, metformin reduces insulin resistance and hyperinsulinemia via 51 adenosine monophosphate-activated kinase pathways and appears to protect against certain cancers including breast, prostate and colorectal malignancies. Thiazolidinedione also reduces insulin resistance, but its role in tumor formation is debatable. We investigated the determinants of cancer risk, particularly oral pharmacologic classes, in a type 2 diabetes mellitus cohort with histology-based identification of incident cancers.

Key findings

Our retrospective study examined data in Cleveland Clinic’s Diabetes Registry (25,613 patients) that were crossmatched with our Tumor Registry (48,051 cancers), over an eight-year period (1998-2006).

We identified 892 incident cancer cases, with prostate cancer in men and breast malignancies in women being most frequent. In women, thiazolidinedione use was associated with a 32 percent decreased cancer risk compared with sulfonylurea use. Comparison of insulin secretagogues (sulfonylurea, meglitinide) versus insulin sensitizers (metformin, thiazolidinedione) demonstrated a 21 percent decreased cancer risk with insulin sensitizers. Oral diabetes therapy showed no significant difference in men.

Adjustments were made for age, body mass index, LDL and HDL cholesterol levels, triglycerides, coronary heart disease, diabetes oral monotherapy, race, gender, hemoglobin A1c, statin use, income, insulin use, glomerular filtration rate, new diabetes status, prior cancer, prior cerebrovascular accident (stroke or transient ischemic event), systolic/ diastolic blood pressure, tobacco use (ever/never), and the propensity score for receiving a biguanide.

Impact on tomorrow’s care

In conclusion, oral insulin sensitizers, particularly thiazolidinedione, are associated with decreased malignancy risk in women with type 2 diabetes mellitus. The findings in this study, which appeared in the journal Diabetes, Obesity and Metabolism, contribute to a growing body of evidence that drugs increasing endogenous insulin levels may promote carcinogenesis. The startling differences demonstrated between men and women need to be re-examined in future research.

Dr. Kashyap is an endocrinologist in the Endocrinology & Metabolism Institute and Associate Professor of Medicine at Cleveland Clinic Lerner College of Medicine. She can be reached at 216.445.2679 or kashyas@ccf.org.