Estimation of the independent causal effect of T2DM on cancer incidence

Lemus Villafuerte, Fabiola (2025) Estimation of the independent causal effect of T2DM on cancer incidence. PhD thesis, University of Glasgow.

Abstract

Background:
Diabetes mellitus (DM) is a chronic metabolic disease whose prevalence has risen dramatically over the past two decades, increasing from 108 million cases in 1980 to 537 million in 2021, with projections estimating 783 million cases by 2045 (International Diabetes Federation, 2021). Type 2 diabetes mellitus (T2DM) is the most prevalent form, accounting for over 90% of cases globally. In addition to its micro and macrovascular complications, emerging evidence links T2DM to an elevated cancer risk. While the association between T2DM and cancer has been widely studied, no causally interpretable meta-analyses have been published on the relationship between T2DM and cancer risk across a range of cancer types.

Aim:
This thesis aims to assess the independent causal effect of T2DM on cancer risk across
multiple cancer types. In this context, independent causal effect refers to a relationship that is not influenced by confounding factors.

Methods:
A comprehensive and updated systematic review (SR) was conducted to identify evidence on the association between T2DM and cancer risk across various cancer types. Directed Acyclic Graphs (DAGs) were used to identify the minimum sufficient adjustment set (MSAS) to control for confounders. Studies that accounted for the MSAS in their adjusted analyses were included in the adjusted (causal effect) meta-analyses, which used the DerSimonian and Laird inverse variance method for random-effects models to synthesize data from multiple studies. Subgroup analyses were performed by sex, race, study design, menopausal status (for breast cancer), time since T2DM diagnosis, and antidiabetic drug classes. Additionally, unadjusted (association) meta-analyses were conducted to examine the relationship between T2DM and cancer risk, with corresponding subgroup analyses. Statistical heterogeneity was assessed using the I² statistic, and potential publication bias was examined through funnel plot inspection and Egger’s test. A burden of disease analysis was also conducted to estimate the cancer burden due to T2DM for the cancer types found to be causally associated with T2DM in the meta-analyses.

Findings:
A total of 18,086 publications were screened, and 250 studies were included in the SR, covering 30 countries and 63 cancer types. Of these, at least one effect estimate meeting the MSAS criteria was reported for 31 types. Meta-analyses for 17 cancer types revealed statistically significant causal associations for breast (relative risk [RR] 1.11; 95% confidence interval [CI]: 1.04–1.18), colon (RR 1.30; 95% CI: 1.12–1.50), endometrial (RR 1.94; 95% CI: 1.43–2.63), kidney (RR 1.67; 95% CI: 1.40–1.98), pancreatic (RR 1.73; 95% CI: 1.46–2.05), and prostate cancers (RR 0.81; 95% CI: 0.72–0.91). Subgroup analyses showed no statistically significant differences in cancer risk by sex, geographic region (proxy for race), or study design. For breast cancer, the risk due to T2DM was comparable in premenopausal and postmenopausal women. In the global burden analysis, 2% of cancer cases (105,084 cases) in 2025 are expected to be attributable to T2DM prevalence in 2021 for the cancer types found to be causally associated with T2DM. Endometrial cancer will have the highest burden, with 1 in 20 cases (24,072) attributable to T2DM, followed by pancreatic cancer, with 1 in 25 cases (23,530). Pancreatic cancer is also projected to account for the highest disability-adjusted life years (DALY) and economic burden (INT $21,844.70 million). Regionally, the Middle East and North Africa is projected to experience the highest burden (2.8%), while Africa will have the lowest (0.7%).

Conclusion:
This thesis identifies specific cancer types for which causality with T2DM is interpretable. Recognizing these causally interpretable associations can inform the development of more targeted public health interventions, particularly in cancer screening and prevention strategies for individuals with T2DM.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Subjects: R Medicine > R Medicine (General); R Medicine > RA Public aspects of medicine
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Health Economics and Health Technology Assessment
• Supervisor's Name: Hawkins, Professor Neil
• Date of Award: 2025
• Depositing User: Theses Team
• Unique ID: glathesis:2025-85506
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 07 Oct 2025 13:43
• Last Modified: 07 Oct 2025 13:55
• Thesis DOI: 10.5525/gla.thesis.85506
• URI: https://theses.gla.ac.uk/id/eprint/85506