A class of oral diabetes medications that has drawn controversy in recent years reduces the risk of cancer in women taking it by almost a third, says a large new study conducted by researchers at the Cleveland Clinic.
In preventing cancer, the researchers found that insulin sensitizers, including the drugs metformin, rosiglitazone and pioglitazone (the latter two marketed as Avandia and Actos) were more powerful than insulin secretagogues such as glyburide, glipizide and glimepiride.
The effect was seen only in women taking the medications, not in men with Type 2 diabetes. And it was most robust in women taking the class of insulin sensitizer drugs called thiazolidinediones, or TZDs (Avandia and Actos), which were introduced in the late 1990s. When researchers included women taking metformin to treat their Type 2 diabetes with those taking TZDs, they saw cancer-risk reduction of 22% over that provided by glyburide, glipizide and glimepiride.
The findings, published Thursday in the journal Diabetes, Obesity and Metabolism, come within a week of a decision by the Food & Drug Administration to lift most restrictions on the use of the drug Avandia in treating American diabetes patients. After a Cleveland Clinic cardiologist, Dr. Steven Nissen, published a study suggesting that patients taking Avandia were more likely to suffer heart attack or stroke, the FDA had clamped down on the drug's use. Until recently, the drug was used by as few as 3,000 people in the U.S., and had been banned in Europe.
To discern the cancer-prevention effect of diabetes medications, researchers picked an eight-year stretch (1998-2006) and combed through and cross-indexed two Cleveland Clinic databases for that period. One registry tracked 25,613 patients with Type 2 diabetes who were on a single diabetes medication and another collected tissue samples on 48,051 cancer occurrences. In that period, 892 cases of cancer were seen in patients who had Type 2 diabetes.
After adjusting for such risk factors as age, obesity, smoking, hypertension and cholesterol abnormalities, the researchers found that women whose medications increased their organs' and muscles' sensitivity to insulin were less likely to have developed cancers than those who used diabetes medications that boosted insulin production by the pancreas.
"This is good news," said the study's lead author, Dr. Sangeeta Kashyap of the Cleveland Clinic's Endocrinology and Metabolism Institute. Noting that insulin sensitizer medications are widely available as inexpensive generic drugs, Kashyap said that evidence of their additional clinical value should get endocrinologists to think more broadly about their patients' risks when plotting a treatment course.
"This tells us doctors when we’re treating people for diabetes that we need to think not just about their heart disease risk or the possibility of weight gain, but about cancer too," said Kashyap. "And when it comes to cancer, the choice of agents we prescribe makes a difference."
Cancer is 30% to 50% more common in patients with diabetes than in those without the metabolic disorder, and women with diabetes appear to be at especially high risk of cancers of the breast and reproductive tract. A wide range of cancer cells appear to be studded with insulin receptors, and insulin behaves in the body as a growth factor. As a result, malignancies seem to take hold more readily and grow more aggressively in circumstances where insulin levels in the blood are high, as they are in diabetes.
For many years, diabetic patients' high risk of developing, and dying of, cardiovascular disease hid the link between diabetes and cancer, Kashyap said. Now that patients with Type 2 diabetes are having their blood sugar better controlled, they are living long enough to become more vulnerable to cancer.
But why was the effect seen in women and not it men? The Cleveland Clinic researchers acknowledge they're stumped. It may be that sex hormones play a role in whether high circulating insulin levels promote tumor growth, they speculated.
Dr. Therese Bevers, medical director of M.D. Anderson's cancer prevention center, suggested that some cancer-lowering measures that may be more widespread in men -- say, taking anti-inflammatory drugs -- may be enough to have made it appear that women were more protected by the drugs than men. It's important for clinical trials to test medications' effects, she said.
"This kind of data is what generates hypotheses," said Bevers, who was not involved in the current research. "Then we gather animal data, and design early-phase trials in humans for chemoprevention." Because the study discerns associations but not whether there's a cause-and-effect relationship between certain diabetes drugs and cancer risk, it's "too preliminary" to use it to guide clinical decisions about how best to treat a patient's diabetes, she said.
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