Expert Blog

Diabetes Agents and Carcinogenesis

Irl B. Hirsch, MD
It is difficult to forget the dramatic controversy that occurred in the summer of 2009 when four observational studies[1] were published in the journal Diabetologia three of which suggested an association between insulin glargine and certain forms of cancer.  [2] While this particular relationship is still not completely resolved, the bulk of evidence thus far does not support this initial concern. Still, those publications had a greater impact: they pointed us to appreciate that both diabetes and obesity are independent risk factors for certain cancers. Most epidemiologic analyses have shown cancer is more common in people with diabetes (prostate cancer is the exception) while BMI appears to be a risk for many types of cancer in both men and women.[3] 
It therefore is not surprising that many are asking a simple question: with so many new diabetes agents, could any of them promote malignancy? In the past year we’ve learned of new concerns with pioglitazone and bladder cancer, resulting in new warnings.[4] At this year’s European Association for the Study of Diabetes (EASD) in Lisbon, this topic was as hot as the weather, culminating in a debate on the last day. In this debate, Dr. Peter Butler, reviewing his recently published analysis of the FDA data base,[5] noted an increased risk of both pancreatitis and pancreatic cancer with both sitagliptin and exenatide (both GLP-1 therapies). He supported this conclusion with animal studies and cell-culture studies. His opponent in the debate, Dr. Michael Nauck, argued that currently available data do not support that GLP-1 therapies increase the risk of cancer, adding that the biology underlying this possibility is not plausible because these types of malignancies take much more time to develop. 
Which side is correct? Even in the debate Dr. Butler agreed it is too early to confirm if there is a real cancer signal here or not. What I know is that this is not a topic that will be going away any time soon. Even in its most conservative mood, moreover, it would be impossible for the FDA to delay approval for a diabetes drug to wait for data proving an increased risk of cancer for any single agent. It would simply take too long. Furthermore, from a pure numbers point of view, the greatest enemy by far is still cardiovascular disease (CVD), and it is quite possible some of the newer agents will result in a benefit in CVD risk over time. Although some will say this is wishful thinking on my part, in the end we will require a better benefit-risk analysis than the information we have now. 
For argument’s sake, however, let’s take a theoretical example. A new GLP-1 agonist is found to reduce the risk of CVD events by 25% in a population where 50% will die from heart disease. That same drug increases the risk of cancer by 25% in a population where the risk of death from cancer is 5%. In this theoretical example, would you take your chances with this drug (especially if you could screen for the cancer)? Add to this the fact that we know that metformin protects against most types of cancer, and in this example we learn that this GLP-1 agonist with metformin mitigates all risks of cancer. While prompting an interesting discussion, this example is not nearly as complex as the actual science, which will hopefully someday become clearer. 
I am quite curious about whether this analysis makes sense to others and whether they think new concerns about carcinogenesis are warranted.




Submitted by Jeff Unger MD on

I am finding the link between cancer and diabetes fascinating from a primary care perspective. In the July publication of the American Family Physician, the author of an article entitled "Insulin Management in Type 2 Diabetes” actually stated that "Insulin Glargine has been linked to cancer due to increased IGF binding." She gave no explanation, leaving the reader only with this misinterpreted opinion. I am in the process of writing a letter to the editor disputing this and many other aspects of her article which were misinterpreted (even going so far as to suggest that we prescribe human insulins preferentially to analogues. Below are some of my thoughts for the author and other members of our primary care readership:

Uncertainty remains as to whether diabetes is a marker of underlying biologic dysfunction which increase cancer risk or whether the cancer-diabetes association is secondary to common risk factors such as obesity, environmental influences or loss of protective genetic mechanisms. Overweight individuals (BMI > 30 kg/m2) have a higher risk for many types of cancer compared with those individual with normal BMIs (18.5-< 25 kg/m2). The cancers most consistently associated with obesity are breast, colon, endometrium, pancreas, espophages, gallbladder, kidney, liver and prostate. (Giovannucci E, Harlan DM, Archer MC, et al. Diabetes and cancer. A Consensus report. Diabetes Care. 2010. 33:1674-1685). Unfortunately, the association between weight loss effecting a positive reduction in cancer risk is less clear. The Nurses’ Health Study did demonstrate a statistically significant inverse associatoion between weight loss and postmenopausal breast cancer (Eliassen AH, Colditz GA, Rosner B, et al. Adult wieht change and risk of postmenopausal breast cancer. JAMA. 2006; 296:193-201). The role of bariatric surgery in reducing cancer occurrence and mortality has not been established through prospective trials. Insulin growth factor-1 (IGF-1) is a polypeptide protein hormone similar in molecular structure to insulin. The IGF-1 receptor (IGF-1R) mediates the effects of IGF-1 at the sites of target tissues throughout the body. The IGF-1R and insulin receptors share 60 % homology. Once bound by a ligand, the receptor is activated inducing cell signaling cascades within the targeted tissue. IGF-1R has been implicated in breast, prostate and lung cancers.( Jones HE, Goddard L, Gee JM, et al.Insulin-like growth factor-I receptor signaling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells. Endocr. Relat. Cancer 2004. 11 (4): 793–814). Increased levels of the IGF-IR are expressed in the majority of primary and metastatic prostate cancer tumor cells. (Hellawell GO, Turner GD, Davies DR, et al. Expression of the type 1 insulin-like growth factor receptor is up-regulated in primary prostate cancer and commonly persists in metastatic disease. Cancer Res. 2002. 62 (10): 2942–50). In addition, IGF-IR signaling is required for survival and growth when prostate cancer cells progress to androgen independence.
Insulin is produced by the pancreatic beta cells, while IGF-1 is synthesized primarily in the liver in response to the action of growth hormone. Insulin increases the expression of growth hormone receptors and enhances postreceptor signaling; therefore, hyperinsulininemia may lead to increased production of IGF-1. IGF-1 plays an important role in childhood growth and continues to have anabolic effects in adults. Selective receptor activation of either IGF-1 or insulin may induce either metabolic or mitogenic effects. Does a biological link between IGF-1 and cancer actually exist? In a cohort of men older than 50 years from the Rancho Bernardo Study, a significant association was found between IGF-1 levels and cancer mortality after adjusting for other risk factors. Those men with an IGF-1 concentration greater than 100 ng/mL had an adjusted risk of cancer mortality of 1.82 compared with men whose IGF-1 concentration was less than 100 ng/mL.( Major JM, Laughlin GA, Kritz-Silverstein D, Wingard DL, et al. Insulin-like growth factor-I and cancer mortality in older men. J Clin Endocrinol Metab. 2010;95:1054–1059). Further observational studies involving persons with diabetes have reported that those treated with insulin or insulin secretagogues have an increased risk of developing cancer compared with those taking metformin. Whether these results are because secretagogues and insulin confer an increased risk, or whether metformin has a protective effect is unclear. (Bowker SL, Majumdar SR, Veugelers P,et al. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care. 2006;29:254–258). Inhaled insulin was suggested to carry an increased risk of lung cancer, although large studies were never performed to investigate this possible association before it was withdrawn from the market. In light of the epidemiologic data, the association of diabetes and obesity with the increased risk of developing cancer appears to possibly be through hyperinsulinemia and/or increased IGF-1 levels.
IGF-1 activation can cause relocation of transmembrane glycoproteins (integrins) to the edge of migrating cells which enhance cancer metastasis. (Canonici A, Steelant W, Rigot V, et al. Insulin-like growth factor-I receptor, E-cadherin and alpha v integrin form a dynamic complex under the control of alpha-catenin. Int J Cancer. 2008;122:572–582). Rodent experimentation suggest that insulin, IGF-1 and IGF-2 can lead to cancer growth and metastasis by upregulating factors that enable both angiogenesis and metastasis while inhibiting pro-apoptotic factors. (.Wang YZ, Wong YC. Sex hormone-induced prostatic carcinogenesis in the noble rat: The role of insulin-like growth factor-I (IGF-I) and vascular endothelial growth factor (VEGF) in the development of prostate cancer. Prostate. 1998;35:165–177). (Fukuda R, Hirota K, Fan F, et al. Insulin-like growth factor 1 induces hypoxia-inducible factor 1-mediated vascular endothelial growth factor expression, which is dependent on MAP kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells. J Biol Chem. 2002;277:38205–38211).
In summary, increased insulin, IGF-1, and IGF-2 signaling through the insulin receptor and IGF-1 receptor can induce tumorigenesis by up-regulating the insulin receptor and IGF-1 receptor signaling pathways. Disrupting these receptors or blocking their activity in animal prevents tumor growth and metastasis by inhibiting downstream signaling. (Canonici A, Steelant W, Rigot V, et al. Insulin-like growth factor-I receptor, E-cadherin and alpha v integrin form a dynamic complex under the control of alpha-catenin. Int J Cancer. 2008;122:572–582).
Hyperglycemia may directly influence cancer growth and metastasis. Many cancers are dependent upon glycolysis for energy. The metabolic process of glycolysis requires greater quantities of glucose than oxidative phosphorylation. Thus, tumors may become glucose dependent for growth and spread. (Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009;324: 1029–1033). Positron emission tomography (PET) scanning, detects pairs of gamma rays emitted indirectly by a positron-emitting tracer injected into the body. The biologically active molecule chose for PET scanning is (fluorodeoxyglucose)FDG, a glucose analogue, which accumulates in tissues of heightened metabolic activity depending on regional glucose uptake, such as rapidly growing malignant tumors.(Phelps ME. PET: physics, instrumentation, and scanners. Springer. 2006. 8-10. ISBN: 0387349464). Whether hyperglycemia directly stimulates tumor growth or secondarily stimulates hyperinsulinemia is uncertain. Perhaps each cell type may have different modulating factors which predispose to tumor progression.
To date, there has been no scientific evidence linking any of the currently basal insulin analogs to a heighted cancer risk. Thus, this statement needs to be addressed and should NEVER have passed a peer review process.

Good to read through the blog. I think the malignancy phobia has been overinflated. Thus, we may be denying a deserving treatment to many, often stalling the pharmacological progress and looking sideways when we need to look straight. Link a drug with data from ill-conceived studies and you sure kill it. Certain illness like diabetes, obesity and renal failure direly need a significant advancement to be able to deal with their increasing incidence.
I often wonder whether a situation like prevails today would have stalled insulin use too after the grand discovery by Banting and Best.
Vinod Nikhra, MD
New Delhi, India

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