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Diabetes-cancer link raises flags
Accumulating data provide more evidence of the negative and positive relationships between diabetes therapies and cancer risk.
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It is now widely accepted that the relative risk for developing most epithelial cancers is increased in patients with obesity, particularly if they have type 2 diabetes. Furthermore, if these patients develop cancer, they have increased risk for mortality compared with normal-weight people or patients without diabetes. The higher a patient’s insulin requirements, the greater risk for cancer. Potential mediators that may increase the risk for cancer development include: hyperinsulinemia; the insulin-like growth factors; hyperglycemia; hyperlipidemia; and altered adipocytokine balance, such as reduced adiponectin or increased leptin or inflammatory cytokines.
Although therapies are being devised that may affect one or more of these potential factors, prevention of this devastating complication may lie in the intensification of lifestyle interventions. According to Sjostrom and colleagues in The New England Journal of Medicine, this is supported by the impressive reduction in cancer deaths after weight-loss surgery.
Examining risks
Some studies have suggested that glargine, a long-acting insulin analogue, may increase the risk for cancer in patients. A 2011 study by Suissa and colleagues in Diabetologia suggested that use of insulin glargine for longer than 5 years promotes this effect. A different study by Hemkens and colleagues in Diabetologia (2009) found that patients who received more than 50 U of insulin glargine daily may also be at risk. These data came from registry studies, not controlled trials; it is, therefore, hard to interpret these findings and make appropriate conclusions. A more recent study in 2011 by Ruiter showed less cancer risk when using insulin glargine compared with human insulin, except for in the case of breast cancer. The major diabetes organizations, such as the American Diabetes Association, European Association for the Study of Diabetes, American Association of Clinical Endocrinologists and the FDA have suggested that physicians and patients not change their medications based merely on these studies. However, the practicing physician should always be aware of these ongoing issues.
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Of additional interest to the scientific and practicing communities are recent reports that have raised interest about the possible effects of other commonly used diabetes medications on the incidence of cancer in patients with type 2 diabetes. Epidemiological studies, such as the study by Currie and colleagues in a 2009 issue of Diabetologia, have shown that patients receiving different antidiabetic agents demonstrate differential outcomes; those on metformin appear to have a lower incidence of cancer than those on sulfonylureas and/or insulin. Because metformin, as an insulin-sensitizing agent, may lower circulating insulin levels and improve insulin resistance in metabolic tissues, it was postulated in a 2008 article in Clinical Breast Cancer that this may be its mode of action in protecting to some degree from the cancer risk. Recent studies in cancer cells have shown that metformin may also inhibit cancer cell proliferation. Metformin enhances AMP-activated protein kinase (AMPK), which in turn inhibits mammalian target of rapamycin (mTOR), a physiological stimulus to cell proliferation — the end result is inhibited cell growth. It has recently been discovered that metformin may even impede cell growth independently of AMPK; Ben Sahra and colleagues investigated these actions in a 2011 study in Cancer Research. Indeed, there are now several trials using metformin as adjunct therapy for cancer chemotherapy in women with breast cancer and other malignancies.
Other non-insulin drugs have a less positive balance sheet. The insulin-sensitizing agent pioglitazone (Actos, Takeda), a thiazolidinedione, has been associated with increased incidence of bladder cancer in one well-published 2011 cohort study in Diabetes Care, leading to its ban in France and Germany. Conversely, thiazolidinediones may have beneficial effects on the incidence and even treatment of breast cancer and thyroid cancer.
Initial concern with glucagon-like peptide 1 agonists arose when Bjerre Knudsen and colleagues treated rats with liraglutide (Victoza, Novo Nordisk). The rats demonstrated increased thyroid C-cell tumors, although this effect was not reported in patients in trials presented to the FDA for approval of the drug. Using the FDA database for adverse events reporting, a study published in Gastroenterology in 2011 showed an increase in thyroid and pancreatic cancer associated with the use of exenatide (Byetta, Amylin), but not with the dipeptidyl-peptidase IV inhibitor sitagliptin (Januvia, Merck). Finally, an FDA advisory committee advised against admitting sodium-glucose co-transporter 2 (SGLT-2) inhibitor dapagliflozin (Bristol-Myers Squibb, AstraZeneca) to the market after phase 3 clinical trials demonstrated increased bladder and breast cancers in women. Such analyses, although hypothesis-generating, must be interpreted cautiously because no causality was established.
Interpreting available data
Undoubtedly, when drugs are reported to be associated with an adverse event as serious as cancer, a red flag should always be raised. Scientists and pharmaceutical companies are obligated to investigate both at a preclinical level and during marketing and postmarketing periods.
In the meantime, one should bear in mind that the risk for cancer is clearly increased in patients with type 2 diabetes, even more so if they are obese. Since improvements in the control of diabetes should reduce the abnormality associated with poor metabolic control, as suggested by some for the metformin effect, one hopes that these improvements by whatever means may affect the risk for cancer and cancer-related mortality.
Moreover, one has to weigh how many cardiovascular events and microvascular complications are prevented against how many additional cancers occur. It is theoretically possible that good weight management and improved metabolic parameters may outweigh any adverse event such as an increased risk for cancer.
Derek LeRoith, MD, PhD, is chief of the division of endocrinology, diabetes and bone diseases at Mount Sinai School of Medicine in New York. Disclosure: Dr. LeRoith is a consultant for Amylin, Merck, Novartis and Sanofi-Aventis.
For more information:
- Ben Sahra I. Cancer Res. 2011;71:4366-4372.
- Bjerre Knudsen L. Endocrinology. 2010;15:1473-1486.
- Currie CJ. Diabetologia. 2009;52:1766-1777.
- Dormandy JA. Lancet. 2005;366:1279-1289.
- Elashoff M. Gastroenterology. 2011;141:150-156.
- Goodwin PJ. Clin Breast Cancer. 2008;8:501-505.
- Hemkens LG. Diabetologia. 2009;52:1732-1744.
- LeRoith D. Endocrine Today. 2009;7:3-4.
- Piccinni C. Diabetes Care. 2011; 34:1369-1371.
- Ruiter R. Diabetologia. 2011; doi:10.1007/S00125-011-2312-4.
- Sjöström L. N Engl J Med. 2007;357:741-752.
- Suissa S. Diabetologia. 2011;54:2254-2262.