Disproportionately increased risk of adiposity-related cancers in adults with early onset type 2 diabetes and obesity

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, focusing 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 (4,037,693 people). 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). Conclusion Risk of incident adiposity-related cancer is driven most strongly by the combination of obesity and T2D, versus either alone, particularly in younger adults (< 40 years). The impact of early onset obesity and T2D provides a critical public health problem that demands targeted screening and management.