DOI: 10.4225/03/58b8ddc023bf9
title: Metabolic disease and cancer: disentangling true associations from bias

description: Background

Diabetes is one of the biggest challenges of the 21st century. In 2015, 415 million people worldwide were living with diabetes. In addition, one-quarter of the world’s adult population have the metabolic syndrome (MetS) which directly increases the risk of diabetes, cardiovascular disease (CVD) and all-cause mortality. Diabetes and the MetS are becoming increasingly prevalent worldwide and both are thought to be associated with an increased incidence and mortality from many cancers. Cancer is the second leading cause of death in economically developed countries and the third leading cause of death in developing countries. Together, these are common diseases with a considerable impact on public health. Therefore, improving our understanding of risk factors and consequences of these diseases is of increasing importance to improve screening programs, identify preventive strategies and develop novel therapies.

The aim of this thesis is to contribute to current knowledge gaps in the association of diabetes and the MetS with cancer. Specifically, the three broad aims of this thesis are:

i. To examine secular trends in excess all-cause and cause-specifi c mortality in type 1 and type 2 diabetes compared with the general population, overall and by age-group;
ii. To quantify associations of type 1 and type 2 diabetes with cancer; and
iii. To quantify associations of the MetS and individual components of the MetS with cancer.

Further, this thesis aims to address methodological concerns not addressed in previous research of metabolic disease and cancer.

Methods

To adequately address these questions prospective, population-based studies with high quality databases and long follow-up time are needed. Publications included in this thesis pertain to results derived from analyses conducted using four national data sources: the National Diabetes Service Scheme (NDSS); the Australian and New Zealand Diabetes and Cancer Collaboration (ANZDCC); the National Death Index (NDI); and the Australian Cancer Database (ACD). The NDSS is a large-scale administrative database of Australians with diagnosed diabetes and the ANZDCC is a large pooled cohort comprised of 18 population-based cohort studies within Australia and New Zealand (ANZ). Both the NDSS and ANZDCC cohorts were linked to the ACD and the NDI to obtain incident cancer and mortality outcomes, respectively.

Key Findings

Several key findings have arisen from this work:
1. Age-standardised mortality rates (ASMRs) for all-cause, CVD and diabetes mortality have decreased in people with type 1 and type 2 diabetes in the last decade, while cancer ASMRs remain unchanged.
2. Improvements in mortality are seen among older age groups (40–60 and 60–80). However this is not seen across the entire age spectrum with younger ages (0–40) not experiencing the same declines in mortality and even more concerning, for type 2 diabetes, increases in all-cause and cancer mortality were noted in this age group.
3. Cancer is a leading cause of death in people with diabetes and the proportion of deaths due to cancer is increasing over time.
4. Using underlying cause of death to quantify the mortality burden among people with diabetes will underestimate by &gt;50% of deaths attributed to CVD.
5. People with type 1 and type 2 diabetes are at increased risk for a number of site-specifi c cancers and risk estimates are similar between type 1 and type 2 diabetes.
6. Detection bias and reverse causation explain some, but not all, of the associations between diabetes and cancer.
7. The MetS is associated with an increased risk for overall and colorectal cancers and these associations are driven largely by obesity and hypertension. However, the MetS is not a useful tool for deciding who is and who is not likely to get cancer.
8. Measures of central and general obesity are similarly predictive of cancer risk, though stronger associations with central obesity suggest a key role in the pathogenesis of cancer.
9. Hypertension, both treated and untreated, is associated with a modest increased risk for cancer incidence and mortality. Similar risks in treated and untreated suggest the increased cancer risk is not due to anti-hypertensive treatment.

Conclusion

This thesis has added to the current evidence-base on the association between metabolic disease and cancer. This work has wide-ranging clinical and public health implications. These include insights into the potential mechanisms of cancer; assessment of the burden and consequences of metabolic disease; recommendations to clinicians to be vigilant in ensuring diabetes patients are up to date with cancer screening according to screening guidelines for the general population; aggressive management of risk factors among young-onset type 2 diabetes to prevent premature mortality; the need to adapt our health care systems to meet the changing needs of diabetes patients in the future and the need for lifestyle modification programs to prevent both type 2
diabetes and cancer. Considering the high prevalence of diabetes and the MetS, even a small increase in cancer risk could have severe consequences at the population level. Therefore, it is imperative that we use this and similar data to inform policies that will improve the health and care of people living with metabolic disease.