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Obesity, diabetes linked to cancer, but treatment approach need not change
LAS VEGAS — With more research suggesting relationships between obesity, diabetes and cancer, and patients questioning what role their medications play, endocrinologists can feel confident continuing to offer the same individualized therapy they have been, in most cases. That was the message at the Cancer, Obesity and Diabetes symposium at the American Association of Clinical Endocrinologists 23rd Annual Scientific & Clinical Congress.
The symposium followed the AACE Cancer Conference Consensus, which gathered experts to try to better understand the associations and consider treatment options, said Yehuda Handelsman, MD, FACP, FACE, FNLA, president-elect of the American College of Endocrinology, who co-chaired the task force.
“In light of several papers and many sensational headlines discouraging the use of medications for hyperglycemia for fear of them causing cancer, at the end of the day, the purpose of the consensus was to provide practical recommendations and implications for practice to physicians, clinicians, general health care, patients and scientists, and to highlight future research needs,” Handelsman said. “We wanted to give practical recommendations and assure clinicians’ ability to continue to manage patients with diabetes confidently, with currently FDA-approved medications, though exercise caution in those at risk for certain cancers.”
Yehuda Handelsman
Recognizing that people with diabetes are at risk for cancer, the task force highlighted the need for early screening to detect cancer and early intervention for prevention, according to Handelsman, who said he looks forward to seeing more prospective studies in the field.
During the 2-day consensus, leaders in metabolism, pathophysiology, molecular biology, epidemiology and clinicians explored the research and found compelling data linking both conditions with cancer.
“The epidemiology clearly shows there’s an association between obesity, diabetes and cancer — and then mortality,” said Derek LeRoith, MD, the other task force chair and a member of the Endocrine Today Editorial Board. “Many studies have come out over the last decade, weekly, showing us this. So that’s clear.”
Because obesity and diabetes are chronic, multifactorial diseases and the sequence of events in creating conditions for cancer not fully known, the researchers said understanding the relationships is complex.
Looking at causation is important, as are the potential effects of diabetes-related medications, according to LeRoith, of the Mount Sinai School of Medicine.
“There’s different stages of carcinogenesis,” LeRoith said. “Basically, you have a normal cell, you initiate cancer and then you progress. This normal-to-initiation, which is an oncogenic process, can take many years.”
This knowledge invites a line of questioning around the length of time it takes to develop cancer, as well as giving medications, LeRoith said, particularly as to whether the drugs are affecting progression of an already established cancer.
LeRoith said there is no evidence to show medications such as insulin and insulin-like growth factor I initiate cancer; an oncogenic process is required. The researchers are, however, investigating the roles of hyperinsulinemia and insulin resistance in cancer development.
Many other factors have been investigated, including caloric intake, nutrients, IGF, leptin, adiponectin and others. Still, endogenous hyperinsulinemia has shown the strongest correlation and been the most compelling, with a process believed to occur through a mitogenic insulin receptor.
“We and others believe that hyperinsulinemia is working through this insulin receptor, driving cancer cells that have already been created because of the oncogenic process,” LeRoith said.
The presenters said many questions remain surrounding the effect of diabetes-related medications, including metformin, on cancer because much of the conversation is still based on speculation and associations. Answers will come with controlled studies.
“One of the things we don’t know is what does a drug do,” Handelsman said. “In some cases, thiazolidinediones have been shown to reduce cancer — but is that because it improves insulin sensitivity or because it improves inflammation?”
The consensus recommends cancer screening and lifestyle changes should start earlier. However, the findings to date should not change clinical practice.
“We’ve tried to give guidelines, both written and in discussions,” LeRoith said. “Nevertheless, all these are new drugs, we really don’t know the long-term effects, and we have to stay vigilant. That’s the important thing.”
For more information:
Handelsman Y, LeRoith D. S51. Cancer, Obesity and Diabetes. Presented at: AACE 23rd Annual Scientific & Clinical Congress; May 13-18, 2014; Las Vegas.
Disclosure:
Handelsman reports that he has received consultant and speaker fees and research grants from various pharmaceutical companies.
LeRoith reports he has received consultant honoraria from AstraZeneca/Bristol-Myers Squibb, Janssen Pharmaceuticals, Merck & Co. and Sanofi-Aventis US.
Perspective
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It has been demonstrated via observational studies that there is an association between diabetes, obesity and cancer. There is a complex interplay of diabetes, pancreatitis and cancer. It is hypothesized that insulin resistance, hyperinsulinemia and increased IGF-1 and IGF-2 signaling pathways may, to some degree, account for the relationship between these conditions.
The state of diabetes itself increases the risk of malignancy. Obesity itself increases the risk of malignancy. Now, to add more variability into this dynamic, are diabetes medications.
The symposium was an off-shoot of an AACE consensus global conference co-chaired by Derek LeRoith, MD, and Yehuda Handelsman, MD, that examined the totality of evidence around the relationship between diabetes, cancer and diabetes medications. The conclusion at the symposium regarding diabetes-related medications was: follow the guidelines and the standards of care, treat the patients in an individualized fashion and follow the prescribing information for all of them — with the exception of bladder cancer and TZDs. If you have history or active bladder cancer, do not use pioglitazone. The remainder of the diabetes medications seem to have no signal. You have to follow the prescribing information. For example, glucagon-like peptide-1 agonists are contraindicated in people with medullary thyroid cancer and multiple endocrine neoplasia type 2.
Questions about the relative contributions of obesity and diabetes to cancer development remain. What role, if any, do various levels of hyperglycemia play? Do patients with diabetes and controlled glucose have a decreased risk for cancer compared with those with uncontrolled glucose? Future studies of medications should be designed to detect cancer-related outcomes in addition to efficacy and safety outcomes. Randomized controlled trials of sufficient size and duration are needed to minimize bias, confounding and chance.
Epidemiology demonstrates a significant increase of cancer in obesity, insulin-resistant states and, ultimately, diabetes; early cancer screening is critical in patients with these conditions. There is currently insufficient evidence to warrant withholding of the use of certain glucose-lowering medications on the basis of cancer concerns. Further collaborative research between clinicians, as well as basic, clinical and epidemiologic researchers, is necessary to complete the evidence on these complex issues.
Right now, the main controversy is patients asking: “Doctor, does this diabetes medication cause cancer?” With regard to insulin, there is no evidence of cancer risk from randomized controlled trials. With regard to GLP-1 agonists and DPP-IV inhibitors, there is no evidence of medullary thyroid cancer or pancreatic cancer in humans. Metformin has no discernible cancer risk and may have protective benefits on cancer outcomes. The TZD rosiglitazone has no evidence of cancer risk. Pioglitazone may have a possible increase risk for bladder cancer at chronic high doses (>24 months and >28,000 mg cumulative dose). The sodium-glucose cotransporter-2 inhibitors have no evidence of cancer risk. Further collaborative research is necessary to complete the evidence on these complex issues.
In the meantime, I invite clinicians to review the AACE/ACE Consensus Statement on Diabetes and Cancer and the AACE Comprehensive Diabetes Algorithm. These documents reflect our current understanding of the complex interplay between physiology, pathophysiology and pharmacology of chronic disease — diabetes, obesity and cancer — and examine the relative contributions of one to another and medications.
Back to type 2 diabetes management: The most important thing to remember is to use the beta cells. Avoid hypoglycemia and weight gain. Treat patients in a physiologic and personalized manner. The type 2 diabetes therapeutic armamentarium and the AACE algorithm enable the clinicians to do just that. That’s really the take-home message.