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

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.