Results of a large, observational, case-control study published in Gut suggested a causal relationship between the development of new-onset type 2 diabetes (T2D) and pancreatic cancer.
Previously identified potential risk factors for pancreatic cancer include obesity, hypertension, dyslipidemia, hyperinsulinemia, and T2D. Nevertheless, it is difficult to determine whether these risk factors are causally related to the development of pancreatic cancer due to the potential for confounding bias and reverse causality bias resulting from the co-occurrence of many of these conditions, as well as other variables such as the use of antidiabetic medications. In addition, few studies have separately investigated new-onset T2D (diagnosed within the last 2 years), and long-standing T2D (of more than 2 years duration) as distinct etiological factors within the context of pancreatic cancer.
This study used Mendelian randomization (MR), an analytical approach involving the use of different gene variants associated with different risk factors as genetic proxies to evaluate whether a causal relationship existed between the risk factors of interest and the outcome of pancreatic cancer (and vice versa).
Specifically, these genetic proxies were identified using several large genome-wide association studies (GWAS) of the prespecified risk factors. They were then evaluated for association in a total of 2018 patients with pancreatic cancer and 1540 controls who were included in the European Study into Digestive Illnesses and Genetics (PanGenEU) study database.
Bidirectional multivariate Mendelian randomization analyses, adjusted for patient-specific factors, were performed to evaluate the impact of T2D subtype on pancreatic cancer risk, as well as the impact of pancreatic cancer on the risk of developing different T2D subtypes.
A key finding of this study was that compared with those without T2D, no causal relationship was demonstrated between either new-onset T2D (odds ratio [OR], 1.06; 95% CI, 0.95-1.17) or long-standing T2D (OR, 1.08; 95% CI, 0.86-1.29) and development of pancreatic cancer.
However, reverse causality was observed for the presence of pancreatic cancer and development of new-onset T2D (OR, 2.85; 95% CI, 2.04-3.98), but not development of long-standing T2D (OR, 1.38; 95% CI, 0.95-1.99).
In addition, in the context of weight loss after age 50 years, the OR of pancreatic cancer for those with new-onset T2D and long-standing T2D were 13.08 (95% CI, 6.05-34.11; P =.0441) and 2.38 (95% CI, 1.61-3.11; P =.2868), respectively, compared with those without T2D. Conversely, some evidence for long-standing T2D as an intermediate step between obesity and pancreatic cancer risk was also observed.
“Recently diagnosed patients with T2DM, that is, [new-onset T2D], can be a target group for routine [pancreatic cancer] screening and surveillance if early signs of [pancreatic cancer] disease (ie, weight loss) [are] present,” the study authors wrote.
In their concluding remarks, the study authors noted that the “findings of this study do not support a causal effect of [long-standing T2D] on [pancreatic cancer], but suggest that [pancreatic cancer] causes new-onset T2D.”
They also commented that “differences in [pancreatic cancer] risk by T2DM subtypes and mediating effects by obesity point to a complex multipathway mechanism underlying pancreatic carcinogenesis. These mechanisms need to be fully explored to pursue [pancreatic cancer] prevention efforts in the population.”
Molina-Montes E, Coscia C, Gomez-Rubio P, et al Deciphering the complex interplay between pancreatic cancer, diabetes mellitus subtypes and obesity/BMI through causal inference and mediation analyses. Gut [published online May 14, 2020]. doi: 10.1136/gutjnl-2019-319990