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

BackgroundThe 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. MethodsWe 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). FindingsAfter 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. InterpretationThese 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. FundingChina Scholarship Council; NIHR Manchester Biomedical Research Centre Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe systematically searched PubMed and Google Scholar for observational studies and/or Mendelian randomisation (MR) studies describing the associations between type 2 diabetes mellitus (T2DM) and incident cancer in Chinese. Existing Chinese cohort studies consistently suggested a modest excess risk in overall cancer incidence--driven mainly by liver, pancreas, colorectum, and in women, breast--but the strength of evidence was limited by recurring methodological shortcomings (e.g., inadequate covariate adjustment, immortal time and survivor biases, competing-risk bias). In MR studies among East Asians, except for pancreatic cancer, "counterintuitive" inverse associations were reported for several digestive cancers (e.g., stomach, liver, colorectum, oesophagus), raising concerns about potential flaws in the design of the source genome-wide association studies (GWAS). Overall, current evidence is constrained by substantial heterogeneity across studies, the likelihood of residual confounding (particularly from adiposity and lifestyle factors), other sources of bias, and possible publication bias. Robust, population-specific studies are needed to clarify the causal relationships between T2DM and site-specific cancer risks in China. Added value of this studyTo our knowledge, this is the first national-level prospective cohort study in China to employ a sex-specific, longitudinal matching strategy explicitly designed to minimise multiple sources of bias when evaluating the potential causal link between T2DM and cancer. Using rigorous methodology and triangulation with MR evidence, our findings provide causal support for an effect of T2DM on pancreatic cancer risk only. By contrast, many previously reported associations with other cancers, such as colorectum or female breast, are likely due to a range of biases. Implications of all the available evidenceOur findings, together with prior research, indicate that the excess risks of most cancers observed in people living with T2DM are unlikely to be causal. The exception is pancreatic cancer, for which convergent evidence from both observational and genetic analyses supports a causal role of T2DM. In China--where diabetes prevalence is rising sharply-- these results suggest that cancer prevention strategies should not treat T2DM as a broad carcinogenic exposure but rather focus on modifiable upstream determinants such as adiposity and lifestyle factors.