Association of Type 2 Diabetes With Cancer: A Meta-analysis With Bias Analysis for Unmeasured Confounding in 151 Cohorts Comprising 32 Million People

Abstract

BACKGROUND AND PURPOSEWhether the association between type 2 diabetes (T2D) and cancer is causal remains controversial. The goal of this work is to assess the robustness of the observational associations between T2D and cancer to unmeasured confounding.

Diabetes and pancreatic cancer: Exploring the two-way traffic

“…A recent report involving a large population ( n = 112818 females and 46207 males respectively) over 30 years of cumulative exposure showed an increased risk of PDAC with long-standing diabetes over time (age-adjusted hazard ratio [HR] 2.16 [95%CI: 1.78-2.60])[ 11 ]. Another recently published meta-analysis also suggested an increased PC related mortality with T2DM (relative risk [RR] 1.67; [95%CI: 1.30-2.14])[ 12 ].…”

The complex role of Wnt ligands in type 2 diabetes mellitus and related complications

“… 152 However, most of these activators are targeting components in canonical Wnt pathway rather than Wnts, and their efficacy and safety are only evaluated in cells or diseased animal models rather than in clinical trials. Furthermore, activation of canonical Wnt pathway may accelerate the progression of some diabetic complications, and diabetic patients have an increased risk of cancers due to the direct effect of hyperglycaemia and indirect effects of insulin resistance, hyperinsulinaemia and chronic inflammation, 155 , 156 and overactivation of canonical Wnt pathway serves as primary determinant for most human malignancies; hence, systemic application of Wnt activators on diabetic patients may aggravate certain diabetic complications or increase the risk of cancer incidence.…”

“…However, most of these activators are targeting components in canonical Wnt pathway rather than Wnts, and their efficacy and safety are only evaluated in cells or diseased animal models rather than in clinical trials. Furthermore, activation of canonical Wnt pathway may accelerate the progression of some diabetic complications, and diabetic patients have an increased risk of cancers due to the direct effect of hyperglycaemia and indirect effects of insulin resistance, hyperinsulinaemia and chronic inflammation,155,156 and overactivation of canonical Wnt pathway serves as primary determinant for most human malignancies; hence, systemic application of Wnt activators on diabetic patients may aggravate certain diabetic complications or increase the risk of cancer incidence.Compared with the conflicting role of canonical Wnt pathway, non-canonical Wnt pathways are consistently overactivated in diabetes and related complications, and the expression of related Wnts, including Wnt4, Wnt5a, Wnt5b and Wnt11, is increased in diseased tissues in diabetic environment. Therefore, inhibition of the non-canonical Wnt pathway is a promising therapeutic approach for the treatment obesity, T2DM and related complications.…”

Methods to address confounding and other biases in meta-analyses: Review and recommendations

“…Given the results of these simple sensitivity analyses, we recommend that the metaanalyst then attempt to assess and report whether it is actually plausible that the metaanalyzed studies are subject to confounding as severe as that indicated by the E-values and by G(r, q). Examples can be found in existing meta-analyses (3,10,26). This assessment would be based on substantive knowledge of the exposures and outcomes under consideration and the ROB assessments described in Section 2.…”