Type 2 Diabetes, Body Mass Index and Cancer Mortality: A Population-Based Matched Cohort Study of 1.0 Million Adults in England

Abstract

Background: Individuals with type 2 diabetes (T2D) have higher cancer mortality than individuals without T2D. The underlying mechanisms are likely to be multi-factorial, but the mutual risk factor of excess body fatness (commonly approximated by body mass index, BMI) is thought to be important. We first tested the hypothesis that excess cancer deaths in T2D are mainly from obesity-related cancers (ORCs); and second, that increasing BMI among individuals with T2D is positively associated with ORC mortality. Methods: We conducted a matched cohort study in the Clinical Practice Research Datalink in England, linked with mortality statistics (1998-2015), and derived cohorts with incident T2D (176,886) versus never diabetes (control: 852,946), aged 30 to 85 years. Among individuals with T2D, we calculated peri-diagnosis (± 12 months date of T2D diagnosis) BMI. The primary outcome was risk for total cancer mortality, categorised into deaths from obesity-related (ORC: 13 cancer types) and non-ORC. Secondary outcomes were all-cause and cardiovascular disease (CVD) mortalities. We used Cox models with multiple imputations and estimated hazard ratios (HR) and 95% confidence intervals (CIs) for outcomes. We tested for several sources of bias, including accounting for cross-BMI category age differences; reverse causality; alternate time BMI determinations (for example, at 4 to 6 years prior to T2D diagnosis); and competing risks of death. Results: With a mean follow-up of 7.1 years, there were 47,459 cancer deaths (T2D: 9606; non-T2D: 37,853). Compared with the control population, T2D was associated with higher ORC mortality in men (HR: 1.708, 95% CIs: 1.564-2.865) and women (HR: 1.338 95% CIs: 1.240-1.444). Unexpectedly, there was an increase in deaths from non-ORC in women (HR: 1.185, 1.008-1.169), but not men. Among individuals with T2D, overall, associations were generally null or inverse, except for positive associations in specific cancers, such as endometrial (HR per 5 kg/m2: 1.416 95% CIs: 1.252-1.601) and ovarian (HR per 5 kg/m2: 1.144 95% CIs: 1.018-1.286) cancer mortalities. We found evidence of reverse causality, but no evidence of effect modification by age, associations with prior BMI, or competing risk. Interpretation: Individuals with T2D have higher obesity-related cancer mortality than those without T2D, supporting the notion that obesity is an important mechanism of excess cancer mortality in 2TD. The unexpected modest higher non-obesity-related cancer mortality suggests that factors beyond body fatness might be drivers of excess cancer mortality in 2TD. Funding Statement: This work was supported by CRUK via the funding to Cancer Research UK Manchester Centre: [C147/A18083] and [C147/A25254]. Declaration of Interests: AGR has received lecture honoraria from Merck Serona and Janssen-Cilag, and independent research funding and lecture honoraria from Novo Nordisk and Sanofi Pasteur MSD. DMA has received independent reaserch funding from Abbvie and the Leo Foundation. All other authors declare no competing interests. Ethics Approval Statement: This study is based on data from the Clinical Practice Research Datalink obtained under licence from the UK Medicines and Healthcare products Regulatory Agency. The data is provided by patients and collected by the NHS as part of their care and support. The study was approved by the independent scientific advisory committee (ISAC) for Clinical Practice Research Datalink research (protocol number: 17_137R).