Certain Antidiabetic Therapies May Be Associated With Pancreatic Cancer Risks

Deborah Brauser

August 17, 2009

August 18, 2009 — Metformin appears to reduce the risk for pancreatic cancer in patients with diabetes, whereas insulin therapy appears to increase the risk, according to the results of a large case-control study reported in the August issue of Gastroenterology.

"Pancreatic cancer is the fourth leading cause of death from cancer for both men and women in the United States," write Donghui Li, PhD, from the Department of Gastrointestinal Medical Oncology at the University of Texas M.D. Anderson Cancer Center in Houston, and colleagues. Although type 2 diabetes mellitus can occur as a consequence of pancreatic cancer, the study authors write that there is accumulating evidence to strongly support its significant role in pancreatic carcinogenesis.

"Although the association between [type 2 diabetes mellitus] and several types of human cancers is well established, few studies have investigated the role that antidiabetic therapies might have on this relationship," explain the authors.

Role of Antidiabetic Therapy in Pancreatic Cancer

Two recent epidemiologic studies have found that diabetic patients treated with metformin (a biguanide that reduces insulin resistance) were less likely to develop cancer, but those patients treated with insulin or sulfonylurea were more likely to die of cancer. However, those studies did not specify the types of cancer affected.

The authors write, "To our knowledge, no studies have been reported on the association of antidiabetic therapies and pancreatic cancer risk in humans."

For this study, the investigators looked at 973 patients with pancreatic adenocarcinoma (including 259 diabetic patients, 87.6% of whom were white and 59.7% men) and 863 healthy control patients (including 109 diabetic patients, 91.5% of whom were white and 63.2% men) who were already part of an ongoing hospital-based case-control study at M.D. Anderson Cancer Center from 2004 to 2008.

Information on demographics, diabetes history, and other risk factors was collected by personal interview. The frequencies of use of insulin, insulin secretagogues (eg, sulfonylureas and meglitinides), metformin, and other antidiabetic medications (including thiazolidinediones) were compared between patients with pancreatic adenocarcinoma and control patients. Unconditional logistic regression analysis was used to estimate the risk for pancreatic cancer.

Results showed that with adjustments for potential confounders, diabetic patients who had taken metformin had a 62% reduction in the risk for pancreatic cancer compared with those who had never taken it (odds ratio [OR], 0.38; 95% confidence interval [CI], 0.22 – 0.69; P = .001).

This difference remained statistically significant when the analysis was restricted to patients with a duration of diabetes for more than 2 years or those who never used insulin.

In contrast, diabetic patients who had taken insulin or insulin secretagogues had a significantly higher risk for pancreatic cancer, at 4.99- and 2.52-fold higher (P < .001 and P = .005, respectively), compared with diabetics who did not take either drug.

An increase in pancreatic cancer risk was also detected for thiazolidinedione users vs never users, but the difference was not statistically significant (P = .213).

"Because pancreatic cancer is a rapidly fatal but a relatively uncommon cancer, epidemiologic research on this disease is challenging," write the authors. However, "If the finding that metformin is protective against pancreatic cancer is confirmed [in future studies], metformin may offer a tool for the primary prevention of pancreatic cancer among people with [type 2 diabetes mellitus]."

Limitations of the study included potential recall bias (as a result of the case-control study design) and the data possibly not being generalizable (because the study was conducted in a single tertiary-care referral hospital).

In addition, "Our study design could not show whether the reduced cancer risk is due to less severe diabetes that led to the choice of metformin or due to better-controlled diabetes by use of metformin," write the study authors. "More detailed history on time and duration of each type of antidiabetic therapy use is required to address this question."

Metformin for All Treatment Regimens?

In an accompanying editorial, Yu-Xiao Yang, MD, MSCE, from the Division of Gastroenterology in the Center for Clinical Epidemiology and Biostatistics at the University of Pennsylvania School of Medicine in Philadelphia, writes, "A novel and riveting finding of this study is the apparent protective effect of metformin against pancreatic cancer."

He explains, "It is interesting to note that, although both metformin and the [thiazolidinediones] reduced insulin resistance, the [thiazolidinediones] did not seem to be associated with a decreased pancreatic cancer risk in the current study. This argues against the possibility that the protective effect of metformin...is mediated solely through improving insulin resistance."

Dr. Yang adds, "The study also raises the possibility that long-term exogenous insulin therapy may increase the risk of pancreatic cancer." He writes that although this has been observed in 2 of the 3 previous studies that reported on this association, the data were inconsistent. "Thus, the role of long-term insulin use in pancreatic carcinogenesis deserves further investigation in a larger set of patients with more reliable insulin use data."

He then summarizes, "This single-center, case-control study included a relatively small number of patients with [diabetes mellitus], with the conclusions generated from a few users of these medications, but the associations appeared consistent across various sub-groups of the study cohort. At the very least, the observations reported raise testable hypotheses about the effects of metformin and insulin on the risk of pancreatic cancer."

Dr. Yang adds that the current consensus treatment algorithm in type 2 diabetes mellitus proposed by the American Diabetes Association and the European Association for the Study of Diabetes advocates the inclusion of metformin in all treatment regimens. "A possible chemopreventive effect of metformin on pancreatic cancer may provide an additional incentive for patients and physicians to follow this recommendation," he concludes.

This study was supported by grants from the National Institutes of Health and from the M.D. Anderson Cancer Center. The study and editorial authors have disclosed no relevant financial relationships.

Gastroenterology. 2009;137:482–488, 412–415.

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