Causal relevance of new-onset type 2 diabetes mellitus and cancer risk in Chinese adults

Background The prevalence of type 2 diabetes mellitus (T2DM) is increasing in China, and T2DM is linked to higher risk of several cancers, particularly obesity-related cancers (ORCs). Whether these associations are causal remains unclear due to potential biases. Methods We conducted a matched cohort study within the China Kadoorie Biobank (512,724 participants recruited 2004-08) to examine causal associations between new-onset T2DM and cancer incidence. To minimise bias, we: (i) included only incident T2DM cases, (ii) applied sex-specific sequential longitudinal matching, (iii) restricted analysis to pre-diagnosis body mass index (BMI), and (iv) accounted for detection time bias. Cox models stratified on the matched set estimated sex-specific hazard ratios (HRs) and 95% confidence intervals (CIs). Results were triangulated with two-sample Mendelian randomisation (MR). Findings After 1:3 matching, 8,657 men and 13,680 women with new-onset T2DM were retained, matched to 25,852 and 40,938 unexposed individuals, respectively. During follow-up to 31 Dec 2018, the incidence rate (IR) of total cancer was 1,365.1 per 100,000 person-years (95% CI 1,250.1-1,480.0) in men with T2DM versus 800.2 (749.7-850.7) in unexposed matches, and 864.7 (794.5-935.0) in women with T2DM versus 629.4 (594.7-664.1) in unexposed matches. T2DM was associated with increased risk of total cancer in men (HR 1.57, 95% CI 1.38-1.79) and women (HR 1.30, 95% CI 1.15-1.47). There was evidence of associations with liver (men HR 2.12, 95% CI 1.42-3.15; women HR 2.39, 95% CI 1.42-4.04) and pancreatic cancer (men HR 2.57, 95% CI 1.35-4.92; women HR 3.95, 95% CI 1.92-8.13). In MR, liability to T2DM was causally related with pancreatic cancer (pooled OR 1.08, 95% CI 1.02-1.15, P = 0.01), but not other cancers. Triangulation supported a causal link between T2DM and pancreatic cancer in East Asians. Interpretation These findings provide strong evidence for a causal relationship only between T2DM and pancreatic cancer risk in Chinese, while evidence for other cancer sites was weak or discordant.