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Journal of Surgical Research Updates, 2013, 1, 26-28
Is Type 2 Diabetes Mellitus a Risk Factor for Pancreatic Cancer and is Metformin Able to Prevent this Risk? Raffaele Pezzilli* Department of Digestive Diseases and Internal Medicine, Sant’Orsola-Malpighi Hospital, Bologna, Italy Abstract: Type 2 diabetes mellitus represents a public health worldwide emergency and more than 300 million people in the world now have diabetes; it has been associated with cancer in general and for pancreatic cancer in particular. The question of whether diabetes mellitus type 2, is a risk factor for pancreatic cancer is complicated by the possible presence of obesity and by the medication used to treat it (insulin and metformin). We have briefly reviewed the data both for and against the possibility that pancreatic cancer is a consequence of type 2 diabetes mellitus, and whether the drugs used for this form of diabetes have a protective effect on pancreatic cancer development. We believe that more studies are necessary in order to definitively identify type 2 diabetes mellitus as a risk factor for pancreatic cancer and also as to the ability of metformin to reduce this cancer risk. Finally, the exact mechanism of metformin in preventing gastrointestinal cancer in general and pancreatic cancer in particular requires further investigation.
Keywords Diabetes Mellitus, Metformin, Obesity, Pancreatic Neoplasms, Risk Factors. INTRODUCTION At present, the only possibility to cure pancreatic cancer is the resective surgery and to diagnose it as soon as possible. Type 2 diabetes mellitus represents a public health worldwide emergency and more than 300 million people in the world now have diabetes [1]; most importantly, there is no worldwide surveillance network for this disease [2]. Type 2 diabetes mellitus has also been associated with cancer in general [3], with digestive cancers, such as liver cancer and colon cancer [4], and also with pancreatic cancer [4]. The question of whether diabetes mellitus type 2, is a risk factor for pancreatic cancer is complicated by the possible presence of obesity and by the medication used to treat it (insulin and metformin). Therefore, we briefly review the data both for and against the possibility that pancreatic cancer is a consequence of type 2 diabetes mellitus and whether the drugs used for this form of diabetes have a protective effect on pancreatic cancer development.
were excluded because review articles, case reports or, finally, because they did not fitted with the aim of the study. TYPE 2 DIABETES MELLITUS AND PANCREATIC CANCER The risk of pancreatic cancer in patients having type 2 diabetes mellitus varies from 1.8 [5,6] to 2.85 [4]. In addition, the results of a meta-analysis study showed that the combined summary odds ratio was 1.82 (95% confidence interval, 1.66-1.89), with evidence of heterogeneity across the studies which was, in part, explained by the fact that a high risk had been reported in the smaller studies; in addition, patients in whom diabetes had been diagnosed less than 4 years earlier had a 50% greater risk of pancreatic cancer as compared to those who had had diabetes for more than 5 years [7]. The authors concluded that there was a modest causal association between type 2 diabetes mellitus and pancreatic cancer. CONFOUNDING FACTORS: OBESITY, SMOKING HABIT AND RACIAL DISPARITIES
SEARCH STRATEGY On July 24, 2012, we carried out a PubMed/Medline search using the following strategy: “Diabetes Mellitus, Type 2” [Mesh] and “Pancreatic Neoplasms” [Mesh] with these limits “humans” [species] and English [language]); other papers were manually extracted from the references of the papers selected. From 1966, a total of 173 papers were found and, of these, we selected 12 papers [4-15]; the remaining 161 papers
*Address correspondence to this author at the Department of Digestive Diseases and Internal Medicine, Sant’Orsola-Malpighi Hospital, Via Massarenti, 9, 40138 Bologna, Italy; Tel: +39-051.636.4148; Fax: +39-051.636.4148; E-mail:
[email protected]
A prospective study reported a positive relationship between overall obesity, abdominal adiposity, diabetes and smoking, and the risk of pancreatic cancer involving a Swedish population [8]. These data were also subsequently confirmed in Japanese patients [9]. An American study showed racial disparities in obese patients because the population attributable risk due to smoking, family history, diabetes, cholecystectomy, and overweight/obesity was 24.3% in whites and 21.8% in blacks [10]. Finally, a meta-analysis showed that the risk of pancreatic cancer was weakly associated with obesity and that the small magnitude of
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Diabetes Mellitus, Metformin and Pancreatic Cancer
the summary risk meant that the possibility of confounding could not be excluded [11]. METFORMIN AND PANCREATIC CANCER Other complicating factors, such as the progression of type 2 diabetes and the use of antidiabetic medications can influence the extent of insulin resistance and hyperinsulinemia, sometimes in opposite directions; this topic has recently been studied by Li et al. [12]. The authors investigated the effect of antidiabetic therapies on the risk of pancreatic cancer. A hospital-based case-control study was conducted from 2004 to 2008 involving 973 patients with pancreatic adenocarcinoma, including 259 diabetic patients and 863 controls, 109 of whom were diabetics. Information on diabetes history and other risk factors was collected by personal interview. The frequencies of the use of insulin, insulin secretagogues, metformin and other antidiabetic medications among the diabetic patients were compared between cases and controls. Diabetic patients who had taken metformin had a significantly lower risk of pancreatic cancer as compared to those who had not taken metformin, with adjustments for potential confounders. This difference remained statistically significant when the analysis was restricted to patients with a duration of diabetes >2 years or those who had never used insulin. In contrast, diabetic patients who had taken insulin or insulin secretagogues had a significantly higher risk of pancreatic cancer as compared to diabetic patients who had not taken these drugs. The author concluded that the use of metformin was associated with a reduced risk of pancreatic cancer in diabetic patients while the use of insulin or insulin secretagogues was associated with an increased risk. In addition, Lee et al. have reported that metformin can reduce the incidence of several gastroenterological cancers, including pancreatic cancer in treated type 2 diabetes mellitus [13]. In contrast, it has been reported that the use of metformin is associated with a decreased risk of pancreatic cancer in women only [14]. In addition, a dosage of metformin equal to or less than 500 mg/day is capable of reducing the risk of gastrointestinal cancers. In 2012 Stevens and coworkers [15] examined cancer outcomes and all-cause mortality in published randomized controlled trials and they found that summary relative risks for cancer outcomes in subjects randomized to metformin compared with any comparator were 1.02 (95% CI 0.82, 1.26) across all trials, 0.98 (95% CI 0.77, 1.23) in a subgroup analysis
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of active-comparator trials and 1.36 (95% CI 0.74, 2.49) in a subgroup analysis of placebo/usual care comparator trials; finally, the summary relative risk for all-cause mortality was 0.94 (95% CI 0.79, 1.12) in all trials. Thus, these data do not support the hypothesis that metformin lowers cancer risk. CONCLUSIONS In conclusion, we believe that additional studies are necessary in order to definitively identify type 2 diabetes mellitus as a risk factor for pancreatic cancer and also for the ability of metformin to reduce this cancer risk. Finally, the exact mechanism of metformin in preventing gastrointestinal cancer in general and pancreatic cancer in particular requires further investigation because the hypotheses are quite generic, namely that metformin has a protective effect against carcinogens [16], it reduces the risk of a highfat diet [17], it has antioxidant properties [18] and it exerts tumor growth inhibition activity [19,20]. AUTHOR CONTRIBUTIONS Pezzilli R alone analyzed the data and wrote the manuscript. ACKNOWLEDGEMENTS The author wishes to thank Dr. Maurizio Zani and Dr. Maurizio Iorio of the University of Bologna Clinical Library at Sant’Orsola-Malpighi Hospital for their technical assistance. CONFLICT OF INTEREST The author has no potential conflicts of interest. REFERENCES [1]
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Received on 07-09-2013
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Accepted on 25-11-2013
Published on 30-11-2013
© 2013 Raffaele Pezzilli; Licensee Synergy Publishers. This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.
