Role of Antidiabetics in Pancreatic Cancer Risk Unclear

Rod Franklin

January 31, 2012

January 31, 2012 — A case–control study of general practice patients in the United Kingdom suggests that the use of metformin is not associated with a significant wholesale drop in risk for pancreatic cancer as some previous studies have suggested. Rather, researchers saw a reduction in pancreatic cancer risk only in women who filled 30 or more metformin prescriptions during an extended period of time.

In contrast, the authors found that use of antidiabetics such as sulfonylureas and insulin were associated with an increased risk for pancreatic carcinogenesis, report Michael Bodmer, MD, from the Department of Pharmaceutical Sciences, University of Basel, Switzerland, and colleagues in an article published online January 31 in the American Journal of Gastroenterology.

Drawing on data from the United Kingdom–based General Practice Research Database, the investigators identified a cohort of 2763 patients (1276 men and 1487 women) who had a first-time diagnosis of pancreatic cancer between 1995 and 2009, along with 16,578 matched control patients. Of those, 307 (11.1%) of the patients in the case group had diabetes, as did 1347 (8.1%) in the matched control patients.

To assess the effect of antidiabetic drugs on pancreatic cancer risk, the investigators stratified patients according to the duration of use (short-, medium-, or long-term), based on the number of prescriptions filled for metformin, sulfonylureas, and/or insulin during the study period. Confounders such as smoking, body mass index, alcohol consumption, and duration of diabetes mellitus also were factored into risk estimates.

The authors found that the largest reduction in pancreatic cancer risk (adjusted odds ratio [AOR], 0.43; 95% confidence interval [CI], 0.23 - 0.80) occurred in women who had been prescribed metformin 30 or more times. This compares with a higher adjusted risk (AOR, 1.59; 95% CI, 0.95 - 2.66) for men with diabetes who received 30 or more metformin prescriptions.

For the study group as a whole, however, investigators observed a non–statistically significant progression of risk reduction as use of the agent continued for longer periods. They reported AORs of 1.01 for from 1 to 9 metformin prescriptions (95% CI, 0.67 - 1.54), 0.92 for 10 to 29 prescriptions (95% CI, 0.62 - 1.35), and 0.87 for 30 or more prescriptions (95% CI, 0.59 - 1.29).

These newly published results vary from those of Li et al, who reported reduced risks (OR, 0.38; 95% CI, 0.22 - 0.69; P = .001) for male and female metformin users alike in a 2009 study of 973 patients with pancreatic adenocarcinoma.

Dr. Bodmer and colleagues report in the current paper that long-term use of other antidiabetics may be associated with increased risk of pancreatic cancer. "[L]ong term use of sulfonylureas (adj. OR: 1.90, 95% CI: 1.32-2.74) and insulin (adj. OR 2.29, 95% CI: 1.34-3.92) were associated with a materially increased risk of pancreatic cancer," the authors write.

The investigators note cautiously that the women in the study group appeared to have a greater risk than the men, with regard to sulfonylureas-related cancer risk, whereas it was the men who demonstrated an elevated risk with long-term insulin treatment.

"As with metformin, these results are based on a limited number of exposed cases and controls and require careful interpretation, since no previously reported data are available suggesting different effects of sulfonylureas or insulin across genders," the authors caution.

Various confounders, drug combinations, and observational controls have been modeled into previous studies that sought to quantify the theorized effects of metformin, insulin, and other antidiabetic agents on pancreatic and nonpancreatic tumor development. One analysis found that patients with diabetes who relied on insulin alone faced as much as 4.5 times the estimated risk for pancreatic cancer, as measured in cancer events per 1000 patient years

Although scientists have targeted different primary outcome measures with each research effort, Dr. Bodmer and colleagues note that their most recent inquiry does not alter a central observation: Diabetes mellitus appears to be both a cause of and a risk factor for pancreatic cancer.

The work was partially supported by the Swiss Cancer League and the Research Fund of the University of Basel. The authors have disclosed no relevant financial relationships.

Am J Gastroenterol. Published online January 31, 2012.

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