Though there have been many epidemiologic studies of the association between PaC and DM 2
, few have closely evaluated the relationship between new-onset DM and PaC. Many have excluded PaC occurring within a year of diagnosis of PaC and not all have stratified the risk based on duration of DM 2
. This is the first epidemiologic study in which FBG values were abstracted from medical records for 5 years preceding diagnosis of PaC and DM diagnosed if, in that time period, they were either on anti-diabetic medications and/or met glycemic criteria for DM (FBG ≥126 mg/dl). Using this approach we show that the prevalence of DM in PaC (40%) is substantially higher than that reported in previous epidemiologic studies (5−20%) and similar to the prevalence of DM in studies that have screened PaC subjects for DM using FBG measurement 11, 12
or oral glucose tolerance test (OGTT) (45−64%) 13, 14
. We also show that the DM in over half the diabetic PaC patients is new-onset, i.e., ≤24 months prior to cancer diagnosis. The findings provide strong epidemiologic evidence to support the notion that if PaC-associated DM (PaCDM) can be distinguished from primary type 2 DM, older subjects with new-onset DM may benefit from screening for asymptomatic PaC.
The best estimates of the prevalence of type 2 DM in the general population are available from the National Health and Nutrition Examination Surveys (NHANES). In NHANES 1999−2000, 15% (CI 12.6−17.5) of 6,596 United States subjects ≥60 years reported a previous diagnosis of DM by a physician or health care professional; an additional 4.2% had a fasting plasma glucose of ≥126 mg/dl. In our study, in which prior treatment of DM or an FBG of ≥126 mg/dl was used to define DM, 19.2% of control subjects without PaC met criteria for DM, a figure remarkably similar to the combined prevalence of diagnosed and undiagnosed DM in the NHANES 1999−2000 study.
While the prevalence of DM in non-cancer subjects in our study remained stable throughout the study period, for PaC subjects it was temporally associated with the diagnosis of cancer. The prevalence of DM in PaC and non-cancer subjects was similar >36 months before index date. However, a marked and continuous increase in prevalence of DM was seen from 24 to 36 months before diagnosis until the date of diagnosis of PaC. Eventually 40.2% of PaC met criteria for DM compared to 19.2% of non-cancer subjects. The high prevalence of DM in PaC in our study is very similar to the 46% prevalence of DM at diagnosis of PaC in an earlier study of 130 PaC patients using the same criteria 12
. In yet another study of 532 incident PaC studied at diagnosis of cancer using the same criteria, 47% had DM 11
. In small studies using OGTT to diagnose DM in PaC, the reported prevalence is up to 64% 14, 15
. Thus, when screened for DM using FBG measurements or OGTT nearly half the patients with PaC have DM. Remarkably the prevalence of DM in PaC is much higher than in other well known diabetogenic states such as morbid obesity 16
, polycystic ovarian syndrome 17
and pregnancy 18
The reason for the low prevalence of DM (<20%) reported from studies using medical records and self (or proxy) report to identify DM is that a high proportion of DM in PaC remains undiagnosed. In the NHANES 1999−2000 study, ~25% of type 2 DM in the general population is undiagnosed. In our study, the proportion of subjects who were identified as having DM based on FBG of ≥126 mg/dl but who did not have a clinical mention of DM was greater in cases versus controls (107/1172 (9.1%) vs 136/2141 (6.3%), p =0.003). It is not surprising that a greater proportion of PaC had undiagnosed DM. The time-interval between onset of type 2 DM and its clinical diagnosis is 4 to 7 years 19
. In PaC the cancer becomes symptomatic before the DM is diagnosed. Additionally, we found that in patients with symptomatic PaC, physicians often do not record a new diagnosis of DM because the focus of medical attention is on the newly diagnosed PaC and not on the newly elevated fasting glucose values.
A limitation of our study is that a significant proportion of cases was seen only once, close to their date of PaC diagnosis and did not have prior FBG values in our institutional medical records. While these cases contributed to the analyses of prevalence of DM in PaC, they were uninformative in terms of understanding the temporal association of DM and PaC. However, the results of our analyses of temporal trends were unchanged when we restricted our study to cases that had been seen at least once ≥6 months prior to their PaC diagnosis, presumably when they did not have cancer specific symptoms (data not shown).
The two published meta-analyses of the epidemiologic studies on the association between DM and PaC 2, 20
have both found a positive but weak association between long-standing DM and PaC; the OR for DM ≥4 years in the most recent meta-analysis was 1.5 (95% CI 1.3−1.8). In our study the prevalence of DM in cases and controls was similar >36 months prior to PaC diagnosis. Many previous studies 21-27
have also failed to observe a significant association between DM and PaC after exclusion of cases in which DM was diagnosed 1−5 years before PaC diagnosis. Thus, while a weak association may exist between long-standing DM and PaC, it is likely to have limited clinical utility, both in terms of understanding the pathogenesis of PaC or its early detection.
The very high prevalence of new-onset DM in PaC suggests that the incidence of PaC would be higher in subjects with new-onset DM than in the general population. We have found in a recent study that subjects with new-onset DM have an 8-fold higher likelihood of being diagnosed with PaC within 3 years of meeting criteria for DM compared to the general population 3
. Other investigators have screened subjects with new-onset DM with cancer-related symptoms such as jaundice, abdominal pain, weight loss and increased levels of Ca 19−9 for PaC 8, 9
and found a high prevalence of PaC (5.2 to 13.6%), but its resectability rate was low. This is essentially because cancer-related symptoms occur shortly before the diagnosis of PaC. In our study the median duration of symptoms prior to diagnosis of cancer was only 2 months. This suggests that the strategy to use cancer-related symptoms as a means to suspect PaC in new-onset DM is unlikely to detect resectable cancer 8, 9
Since PaC patients seldom exhibit disease-specific symptoms until late in the course of the disease, early detection of small tumors will require screening of asymptomatic subjects for PaC. Screening for asymptomatic PaC is a challenge because of lack of a high-risk group and lack of a biomarker of early PaC. Screening un-selected populations for asymptomatic PaC will not be cost effective. For example, the age-adjusted incidence of PaC in subjects ≥50 years of age is 38/100,00028
. If a test with 99% sensitivity and 99% specificity for PaC is used to screen 100,000 subjects ≥50 years of age, the test would identify nearly all PaCs in the population screened (n=37); but the test would also falsely identify another 1000 subjects as having PaC. Thus screening for asymptomatic PaC will require at least two “sieves” to enrich the population to allow cost-effective screening 29
. We believe that new-onset DM can serve as the first sieve.
Our study shows that in many PaC patients, onset of DM occurs when they would have no cancer-related symptoms. Thus new-onset DM is the only clue to the presence of asymptomatic PaC. Previous authors have suggested that subjects with new-onset DM who are lean and/or lack a family history of DM should be targeted for screening 7
. When we compared the profile of diabetic PaC subjects with controls to identify pre-morbid demographic indicators of PaCDM, we found statistical but not clinically useful differences between the two groups in BMI, proportion of subjects who were smokers or those with parental history of pancreatic cancer. Therefore, we believe that the success of any strategy to use hyperglycemia and DM to identify undiagnosed PaC will depend largely on our ability to differentiate PaCDM from type 2 DM using a serologic marker.
Only a prospective study can determine the clinical validity of the observation that older subjects with new-onset DM would benefit from further screening for PaC. However, since prevalence of PaC in new-onset DM is <1%, a large number of subjects with new-onset DM would have to be followed prospectively to have sufficient incident PaC cases in the study. Screening for PaC in new-onset DM will become practical only if we can accurately distinguish PaCDM from type 2 DM. To increase the prevalence of PaC in new-onset DM from 1% to 10%, a biomarker would have to have a specificity of 93% for PaCDM. Our hope is that the mediator of DM in PaC will also serve as a marker to distinguish PaCDM from type 2 DM.
The very high prevalence of diabetes in PaC and its close temporal association with the diagnosis of cancer provide strong epidemiologic evidence to support the notion that PaC causes DM. Further support for this hypothesis is provided by small clinical studies in which resection of the tumor has been shown to improve glucose tolerance and reverse the metabolic defect 13, 30, 31
. That PaCDM may be a paraneoplastic phenomenon caused by tumor secreted products is also suggested by the experimental observations that PaC cell line supernatants are metabolically active. They have been shown to induce glucose intolerance in SCID mice 32
, alter glucose metabolism in the liver 33
and skeletal muscle 34, 35
and cause selective amylin secretion from ß islet cells 36
. This provides hope that the mediator of PaCDM can be identified.
In summary, our study shows DM is present in a high proportion of patients with PaC and is often of recent onset. Based on available evidence we believe that if the PaC-associated DM can be distinguished from type 2 DM, older subjects with new-onset DM would benefit from further screening for PaC.