The findings from this review suggest that earlier reports of a more than two-fold excess risk of pancreatic cancer among individuals with type-II diabetes are likely to have overestimated the strength of the association (Ragozzino et al, 1982
; Friedman and Van Den Eeden, 1993
; Everhart and Wright, 1995
). Although the current data suggest an 80% greater risk of pancreatic cancer among individuals with type-II diabetes, even this may be an exaggeration of the true strength of the relationship, as it does not consider the considerable potential for reverse causality.
The RR of pancreatic cancer was demonstrated to be negatively associated with the duration of diabetes. Among individuals with a long history of diabetes (>5 years), the excess RR of pancreatic cancer was about 50% lower than in individuals for whom the duration of diabetes was shorter (RR 1.5 vs
=0.005). This supports the hypothesis that, in some cases, diabetes may be an early manifestation of the tumour, as otherwise the RR would be expected to increase, rather than decrease, with duration of diabetes. In an earlier review similar RRs of pancreatic cancer by duration of diabetes were reported (Everhart and Wright, 1995
) but, the categories for duration of diabetes, unlike in the current meta-analysis, were not mutually exclusive (i.e.>5 years diabetes duration was a subset of the >1 year group) and therefore, the RR for the >1 year duration of diabetes was likely to have been diluted by the inclusion of cases with a longer history of diabetes (and hence a smaller RR).
Evidence from the literature further supports the hypothesis that pancreatic cancer can induce a diabetic state. First, several studies have shown that the risk of pancreatic cancer among individuals with diabetes is lessened after exclusion of those with less that 1 year of diabetes, indicating that a component of the RR associated with diabetes is explained by individuals who are diagnosed with the malignancy within a short period of being diagnosed with diabetes (Ragozzino et al, 1982
; Cuzick and Babiker, 1989
). Second, in studies among individuals with pancreatic cancer who underwent tumour resection, insulin sensitivity and diabetes status were reported as showing substantial improvement 3 months after surgery (Permert et al, 1993
). And third, molecular studies of sera from pancreatic cancer patients have identified peptides that are suggested to be diabetogenic (Wang et al, 2003
Although the above arguments support the idea of reverse causality, the finding of a 50% increased RR of pancreatic cancer among individuals with chronic diabetes (>5 years) supports a modest causal relationship between diabetes and pancreatic cancer. This is true especially when considering that in individuals with a long history of diabetes (>5 years), it is unlikely that a malignancy that has a particularly low 1-year survival rate (fewer than 20% of individuals are alive at 1-year following diagnosis) could induce diabetes many years prior to its diagnosis. In addition, the presence of a graded dose–response association between fasting glucose and pancreatic cancer, reported by some large prospective studies, supports a causal relationship (Batty et al, 2004
; Jee et al, 2005
Inherent in any review process of published studies is the possibility of publication bias that may have resulted in an overestimate of the size of any association between two variables. There was some evidence to suggest that there was some publication bias such that the smaller studies were more likely to report a positive association between diabetes and pancreatic cancer. However, the exclusion of any small negative studies is unlikely to have materially altered the overall summary estimate. Confounding is also likely to have been present since diabetes and pancreatic cancer share several risk factors such as cigarette smoking and obesity. However, adjustment for a wide range of potential confounders only marginally attenuated the relationship between diabetes and pancreatic cancer. It is also possible that the use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDS) may have been a potential confounder. For example, in a prospective follow-up study of over 28
000 postmenopausal women, women who reported using aspirin and other NSAIDS had a significantly lower RR of pancreatic cancer compared to non-users (RR 0.57 95% CI 0.36–0.90) (Anderson et al, 2002
). In recent years, individuals with diabetes have been more likely to receive advice to take aspirin than people without diabetes in order to lower the risk of cardiovascular disease (CVD). For example, in the UK Prospective Diabetes Study, it was reported that between 1996/1997 and 2000/2001, aspirin use in patients without pre-existing CVD increased from 17 to 31% (P
< 0.0001) (Cull et al, 2004
). Aspirin has been reported to reduce the risk of several types of cancer (Garcia Rodriguez and Huerta-Alvarez, 1998
; Thun et al, 1993
); hence, the association between diabetes and pancreatic cancer may have been attenuated by aspirin use and indeed in studies published before 1995, the RR was significantly higher than in those published after this date (RR 2.3 vs
Furthermore, most studies included in this review did not differentiate between Type-I and Type-II diabetes, which may have slightly underestimated the overall association, since it has been reported that Type-1 diabetes is not associated with pancreatic cancer (Zendehdel et al, 2003
). The literature, however, regarding cancer mortality among individuals with type 1 diabetes, is limited by small sample size and short length of follow-up (Mihara et al, 1986
; Martinenghi et al, 1997
) and therefore do not preclude a possible association. However, it is likely that the substantial majority of individuals with diabetes included in these studies had type-II diabetes, since this is by far the most common form particularly in older individuals. Additional limitations of this review include the reliance, in the large majority of studies, on self-reported diabetes and the potential for misclassification on death certificates of site-specific cancers, although the sensitivity analyses did not show any difference in the risk between those studies that used self-reported diabetes compared with those that diagnosed diabetes either through medical records or by an oral glucose tolerance test.
To date, only cigarette smoking, and possibly obesity, has been identified as being causally associated with pancreatic cancer. The evidence from this review indicates that type-II diabetes is likely to be a third modifiable risk factor (Knowler et al, 2002
; Davey Smith et al, 2005
) and unless the increasing worldwide prevalence of all three risk factors is halted, the incidence of pancreatic cancer will rise substantially within the next couple of decades.