Synergistic effects of obesity and type 2 diabetes on adiposity-related cancer risk across age strata

Alex E Henney; Megan Heague; Uazman Alam; Daniel J Cuthbertson

doi:10.1186/s12916-026-04842-8

Synergistic effects of obesity and type 2 diabetes on adiposity-related cancer risk across age strata

BMC Med. 2026 Apr 13. doi: 10.1186/s12916-026-04842-8. Online ahead of print.

Authors

Alex E Henney^{1

2

3}, Megan Heague¹, Uazman Alam^{1

2

3

4}, Daniel J Cuthbertson^{5

6

7}

Affiliations

¹ Department of Cardiovascular and Metabolic Medicine, University of Liverpool, Liverpool, UK.
² Metabolism and Nutrition Research Group, Liverpool University Hospitals NHS Foundation Trust, Liverpool, Merseyside, UK.
³ Liverpool Centre for Cardiovascular Sciences, University of Liverpool and Liverpool University Hospitals NHS Foundation Trust, Liverpool, Merseyside, UK.
⁴ Centre for Biomechanics and Rehabilitation Technologies, Staffordshire University, Stoke-On-Trent, UK.
⁵ Department of Cardiovascular and Metabolic Medicine, University of Liverpool, Liverpool, UK. dan.cuthbertson@liverpool.ac.uk.
⁶ Metabolism and Nutrition Research Group, Liverpool University Hospitals NHS Foundation Trust, Liverpool, Merseyside, UK. dan.cuthbertson@liverpool.ac.uk.
⁷ Liverpool Centre for Cardiovascular Sciences, University of Liverpool and Liverpool University Hospitals NHS Foundation Trust, Liverpool, Merseyside, UK. dan.cuthbertson@liverpool.ac.uk.

PMID: 41975400
DOI: 10.1186/s12916-026-04842-8

Abstract

Background: Obesity and type 2 diabetes (T2D) each independently increase cancer risk, but their combined impact is less understood. With rising early-onset obesity, T2D, and cancer in younger populations, we assessed how diagnoses of both obesity and T2D affect adiposity-related cancer incidence compared to each condition alone, focussing on age-specific trends.

Methods: We performed a retrospective (real-world) cohort analysis in a large global federated database (TriNetX, Cambridge MA, USA). Three cohorts were generated and compared with a reference arm, patients without obesity or T2D: cohort 1-patients with obesity, without T2D; cohort 2-patients with T2D, without obesity, and cohort 3-patients with both obesity and T2D. Cohorts underwent propensity score matching (PSM) 1:1 of confounders. We examined 5-year rates of incident cancer (including thirteen (traditional) adiposity-related cancers and an expanded list of 24 adiposity-related cancers), performing stratified analyses by age (younger, middle-aged, and older adults (< 40, 40-60, > 60 years), respectively), ethnicity (white, and non-white), and sex (male and female).

Results: After PSM, we compared 2,655,891 people with only obesity, 290,965 with only T2D and 705,499 people with both obesity and T2D, against the reference (1:1). The highest risk was observed in patients with both obesity and T2D (traditional cancers (HR 1.48 [95% CI 1.15, 1.51]) and all adiposity-related cancers (1.30 [1.27, 1.32])). T2D increased the risk of both traditional (1.35 [1.31, 1.39]) and all adiposity-related cancers (1.27 [1.23, 1.31]) to a greater extent than obesity only (increased risk of traditional adiposity-related cancers (1.07 [1.05, 1.09]), but not all adiposity-related cancers (0.99 [0.98, 1.01]). Concerningly, the highest risk of all traditional and adiposity-related cancers was seen in younger (< 40 years) adults with obesity and T2D (1.40 [1.10, 1.79] and 1.58 [1.21, 2.05], respectively).

Conclusions: Risk of incident adiposity-related cancer is driven most strongly by the combination of obesity and T2D, versus either alone, across all age groups, including those with early-onset disease. The impact of early-onset obesity and T2D provides a critical public health problem that demands targeted screening and management.

Keywords: Adiposity; Cancer; Diabetes; Obesity.