Duration of type 2 diabetes and cancer incidence
As rates of heart disease in diabetes fall thanks to improved prevention and treatment, cancer is coming to prominence as a complication and cause of excess death. However, a new paper in Diabetes Care reports that age rather than duration of type 2 diabetes affects incidence of all cancers, the four most common cancers and those that are related to obesity. Dr Susan Aldridge reports.
Improvements in the early identification and treatment of cardiovascular risk factors have contributed to decreased mortality and increased life expectancy among people with type 2 diabetes over the past 20 years or so. This means that non-cardiovascular diseases are now more prominent as complications of type 2 diabetes, particularly among older people. Cancer is one of these complications and recent research has suggested that cancer may be overtaking cardiovascular disease as the leading cause of excess deaths among people with diabetes.
The literature has shown increased risk of some cancers in people with type 2 diabetes, with the strength of the association with pancreatic and liver cancer being higher than that with others, such as lung cancer. A higher body mass index (BMI), which is one of the most important risk factors for type 2 diabetes, creates insulin resistance and hyperinsulinemia, which could in itself increase the risk of cancer. Longer life expectancy in type 2 diabetes means longer disease duration and prolonged exposure to these two factors. This might explain the higher risks of cancer incidence observed among older individuals with type 2 diabetes. Older age in itself is also a risk factor for cancer, so a higher risk among those with longer disease duration might be attributed to ageing rather than diabetes.
There is currently little evidence about diabetes duration and cancer incidence, but it’s important to have this information to optimise effective strategies for early detection of cancer. For instance, if long duration of type 2 diabetes does turn out to be a risk factor, then maybe cancer screening could be incorporated into regular diabetes checks. In a new study, Francesco Zaccardi at Leicester Diabetes Centre and colleagues elsewhere in the UK, aimed to clarify the association of age and type 2 diabetes duration with the risk of cancer incidence in people with type 2 diabetes.
They identified a group of 130,764 individuals with type 2 diabetes from the Clinical Practice Research Datalink (CPRD) GOLD database, which collects data from primary care and is linked to the Hospital Episode Statistics (HES) and the Office for National Statistics (ONS) databases for details on hospitalisations and mortality. Data on age of type 2 diabetes diagnosis – from 1 January 1998 to 30 November 2018 – and BMI came from the CRPD, while the HES and ONS provided data on cancer incidence for all cancers, the four most common cancers in the UK (lung, colorectal, breast and prostate) and those that are considered to be causally linked with higher body fat (breast, colorectal, endometrial, gallbladder, gastric cardia, kidney, liver, multiple myeloma, oesophageal, ovarian, pancreatic and thyroid).
Participants were followed from their diagnosis date until the occurrence of cancer, death or the end of the study. In their analysis of the data, the researchers used two timescales – one for chronological age, one for diabetes duration – in order to separate the impact of both factors and age at diagnosis on cancer incidence.
Cancer incidence and diabetes duration
During a median follow-up of eight years and a total of 1,089,923 person-years of observation, there were 18,977 incident cancers, affecting 15.3% of the men and 13.5% of the women in the study. Incidence rates of all cancers were progressively higher as people got older. For men aged under 40 at diagnosis, the incidence rate was 1.9 per 1,000 person-years compared with 49.4 per 1,000 person-years in those aged 80 or more; the corresponding figures for women were 3.5 and 28.7. The same pattern was observed for common and obesity-related cancers.
However, analysis showed no evidence of an association between diabetes duration and all cancers, common cancers and obesity-related cancers. These findings suggest that the higher risk of cancer in individuals with longer diabetes duration that has previously been reported is likely explained by the older age associated with longer duration. This contrasts with previous studies that show there is an association with longer duration of diabetes and higher risk of vascular diseases and death.
The declining trends in cardiovascular morbidity and mortality in recent years mean that people are living longer with diabetes and metabolic abnormalities, which might be expected to increase the risk of carcinogenesis, but longer disease duration is necessarily associated with older age and age-related pathophysiological changes that can increase the risk of cancer. Separating the association of diabetes duration from that of age is essential in disentangling their relative impact and the authors point out that they have done this via the methodology adopted in this study.
They looked at associations for a wide range of ages at diagnosis and diabetes duration. They also modelled a time-varying association of age and duration using two timescales. This approach has been advocated as the one of choice when the aim is to explore the association of both disease duration and age on outcomes.
Previous studies on diabetes and cancer have described associations of variable directions and magnitudes, likely because they differ in their design and analyses, so comparisons with this new study are limited. However, some investigations have used the same design and so can be compared – a study of people with type 2 diabetes in Canada (1994-2006) and in two cohorts with both type 1 and type 2 diabetes in Denmark (1995-2009) and Australia (1997-2008). These showed similar patterns to the current study.
The role of BMI
The fact remains that many studies have shown an increased risk of several types of cancer in those with type 2 diabetes compared with those without the condition. The authors wonder if the increased cancer risk occurs earlier in the trajectory of metabolic abnormalities that ultimately leads to type 2 diabetes. They turn to the impact of obesity on the relationship between age, diabetes duration and cancer risk.
If excess body fat, and therefore increased insulin resistance, are among the potential mechanisms linking type 2 diabetes to cancer, then higher incidence rates should be expected among those with higher BMI. This was generally observed in this study, but there was still no association with diabetes duration and cancer risk.
This lack of a differential impact of duration on cancer incidence across BMI levels does suggest that the insulin resistance-related mechanisms enhancing cancer risk develop early on, even before the clinical diabetes-based diagnosis of type 2 diabetes and have a minor or zero impact thereafter. Importantly, this also suggests that the potentially actionable window to reduce the impact of excess body fat and insulin resistance occurs earlier than the time frame to reduce the long-term effects of hyperglycaemia. This will have implications in the area of cancer prevention and early detection, and is worthy of further investigation.
Looking at the finer detail of this study reveals an increase in cancer incidence around the time of diagnosis. It is possible that subclinical cancer might lead to hyperglycaemia which, in turn, leads to a diabetes diagnosis – a case of reverse causality that needs to be further investigated.
Furthermore, this study focused upon cancer incidence, but the pattern for cancer mortality might be different because what happens after cancer diagnosis might have a relatively greater impact than diabetes duration on the risk of all-cause and cancer-specific mortality. Nor did this study investigate the role of other risk factors, including the use of glucose-lowering medication, which might have confounded the relationship between diabetes duration and cancer.
In conclusion then, this study of a large cohort of individuals with type 2 diabetes did not find evidence of an association between diabetes duration and the incidence of cancer. The higher rates observed among those with longer duration are most likely a phenomenon of ageing. Therefore, strategies to prevent cancer among those who have diabetes should be guided by the individual’s age rather than diabetes duration.
To read this paper, go to: Zaccardi F, Ling S, Brown K, Davies M and Khunti K. Duration of type 2 diabetes and incidence of cancer: an observational study in England. Diabetes Care. https://doi.org/10.2337/dc23-1013
To learn more about other conditions associated with diabetes, enrol on the EASD e-Learning course ‘Multimorbidity and diabetes’.
Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.