To our knowledge, the current case-control study is the first to demonstrate a statistically significant association between antidiabetic therapy and risk of pancreatic cancer. Our major observations are that diabetics who ever used metformin, especially those with >5 years of use, had a reduced risk of pancreatic cancer compared to never-users. In addition, there were some suggestive observations that diabetics who had used insulin or insulin secretagogues (sulfonylureas and meglitinides) had increased risk of pancreatic cancer compared to never users. These observations are consistent with findings from two previous epidemiological investigations,12,13
and add evidence that antidiabetic therapy can affect the development of human cancer.
Metformin, a biguanide, is an oral hypoglycemic agent commonly used for the treatment of DM2. The current study demonstrated a robust protective effect of metformin against pancreatic cancer in diabetes. Although the number of patients with diabetes in this study was relatively small, the study has more than 80% power in detecting an OR of 0.3. Other diabetes-associated factors, such as the duration of diabetes, smoking, overweight or obesity, as well as glycemic control did not have a significant confounding effect on the relationship between metformin use and risk for pancreatic cancer. Even though a higher frequency of insulin use was observed among never users of metformin compared to ever users, the protective effect of metformin remained statistically significant when the analysis was restricted to insulin never users.
Metformin reduces the level of glucose by decreasing hepatic glucose production, increasing glucose utilization and fatty acid oxidation. Like TZDs but unlike insulin and insulin secretagogues, metformin decreases the plasma insulin level.22
Metformin also has a modest weight-reducing effect, while the other classes of agents tend to cause weight gain.23
Based on the current understanding, the direct molecular mechanism of action of metformin involves activation of the AMP activated protein kinase (AMPK) which is a metabolite-sensing protein kinase family that is sensitive to increases in the AMP/ATP ratio.24
AMPK activation not only regulates many metabolic enzymes but also has been shown to inhibit the mTOR pathway, which may in turn regulate cell proliferation.25
Furthermore, AMPK has recently been found to play a role in cell polarity and cell division.26
Therefore, in addition to amelioration of hyperglycemia and hyperinsulinemia (factors that mediate the adverse impact of DM2 on cancer), metformin has direct effects on cancer cells to block the mitogenic effects of insulin and IGF-1 at post-receptor levels by blocking the PI3K/Akt/mTOR signaling pathway and by inhibiting cell division. Indeed, cell culture experiments as well as animal model experiments have demonstrated a direct antineoplastic effect of metformin.27-29
Thus, the protective effect of metformin against pancreatic cancer observed in our study could be explained by the combination of all the effects of this drug discussed above.
The association of insulin ever-use and increased risk of pancreatic cancer was confounded by two factors: duration of diabetes and glycemic control. Among pancreatic cancer cases, many patients started to use insulin ≤2 years prior to their cancer diagnoses, perhaps because of worsening of diabetes caused by the cancer. Thus, the association between short-term insulin use and pancreatic cancer suggest reverse causality, i.e., occult pancreatic cancer worsened diabetes within the 2 years prior to diagnosis of pancreatic cancer, causing the patients to initiate insulin therapy for glycemic control. On the other hand, we did observe a weak but significant association between long-term insulin use (>5 years) and increased risk of pancreatic cancer (OR, 2.78; 95% CI, 1.00-7.73; P=0.049). However the statistical power was limited because this observation was made in a very small number of study subjects (17 cases and 9 controls). The association between long-term insulin use and risk of pancreatic cancer needs to be further investigated in a larger study.
Insulin secretagogues as a monotherapy for DM2 showed the highest risk of pancreatic cancer in this study. However, because of the small number of insulin secretagogues ever-users among controls, this observation could be by chance alone. Among diabetic subjects, the risk of pancreatic cancer was increased in short-term users but not long-term users of insulin secretagogues compared with never users, which do not support a role of this type of treatment on cancer. Because of the previous positive findings, the association between insulin secretagogue use and risk of pancreatic cancer should be investigated further in a larger study.
Our study has several potential limitations. As in any case-control study, recall bias is a concern. However, after cross-checking the diabetes history and information on current medications given by case subjects against their medical records, we found a high level of consistency. Moreover, a previous study indicated that 3% of survey respondents inaccurately reported their own prior histories of diabetes, which was the minimum misclassification rate among several medical conditions.30
Our study was conducted in a single tertiary-care referral hospital, so the data may not be generalizable to the general population. However, the prevalence of diabetes among controls in our study was quite comparable to previously reported frequencies in population-based case-control studies of pancreatic cancer.31,32
Even though our study has a large sample size, the statistical power is still limited when the analysis was restricted to diabetic subjects. Therefore, our observations need to be confirmed in large studies. Last but not least, our study design could not demonstrate whether the reduced cancer risk is due to less severe diabetes that lead to the choice of metformin or it was due to better-controlled diabetes by use of metformin. More detailed history on time and duration of each type of antidiabetic therapy use is required to address this question.
Because pancreatic cancer is a rapidly fatal but a relatively uncommon cancer, epidemiological research on this disease is challenging. Our report seeks for replication efforts from other study populations to confirm or refute a possible role of antidiabetic therapy in pancreatic cancer. If the finding that metformin is protective against pancreatic cancer is confirmed, metformin may offer a tool for the primary prevention of pancreatic cancer among people with DM2.11