The article provides more evidence that diabetes and obesity increase the risk of malignancy, particularly of colorectal, gallbladder, pancreas, kidney, liver, endometrial, postmenopausal breast, ovarian, gastric cardia, thyroid cancer, esophageal adenocarcinoma and multiple myeloma. It is estimated that 430 million adults have diabetes worldwide, while 2.0 billions are overweight or obese. How could this global health problem be meaningfully approached?
THE LANCET, DIABETES & ENDOCRINOLOGY
Diabetes and high body-mass index (BMI) are associated with increased risk of several cancers, and are increasing in prevalence in most countries. We estimated the cancer incidence attributable to diabetes and high BMI as individual risk factors and in combination, by country and sex.
We estimated population attributable fractions for 12 cancers by age and sex for 175 countries in 2012. We defined high BMI as a BMI greater than or equal to 25 kg/m2. We used comprehensive prevalence estimates of diabetes and BMI categories in 2002, assuming a 10-year lag between exposure to diabetes or high BMI and incidence of cancer, combined with relative risks from published estimates, to quantify contribution of diabetes and high BMI to site-specific cancers, individually and combined as independent risk factors and in a conservative scenario in which we assumed full overlap of risk of diabetes and high BMI. We then used GLOBOCAN cancer incidence data to estimate the number of cancer cases attributable to the two risk factors. We also estimated the number of cancer cases in 2012 that were attributable to increases in the prevalence of diabetes and high BMI from 1980 to 2002. All analyses were done at individual country level and grouped by region for reporting.
We estimated that 5.6% of all incident cancers in 2012 were attributable to the combined effects of diabetes and high BMI as independent risk factors, corresponding to 792,600 new cases. 187 600 (24.5%) of 766 000 cases of liver cancer and 121 700 (38.4%) of 317 000 cases of endometrial cancer were attributable to these risk factors.
In the conservative scenario, about 4.5% (626 900 new cases) of all incident cancers assessed were attributable to diabetes and high BMI combined. Individually, high BMI (544,300 cases) was responsible for twice as many cancer cases as diabetes (280 100 cases). 26.1% of diabetes-related cancers (equating to 77 000 new cases) and 31.9% of high BMI-related cancers (174 040 new cases) were attributable to increases in the prevalence of these risk factors from 1980 to 2002.
A substantial number of cancer cases are attributable to diabetes and high BMI. As the prevalence of these cancer risk factors increases, clinical and public health efforts should focus on identifying optimal preventive and screening measures for whole populations and individual patients.
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Diabetes and high BMI, defined as a BMI greater than or equal to 25 kg/m2, are leading causes of mortality and morbidity globally and their prevalence has increased substantially over the past four decades in most countries. The global age-standardised adult prevalence of diabetes was reported to be 9.0% in men and 7.9% in women in 2014, affecting about 422 million adults. In 2016, the age-standardised adult prevalence of overweight and obesity (those with BMI ≥25 kg/m2) was estimated to be 38·5% in men and 39·2% in women, affecting approximately 2.01 billion adults globally.
The International Agency for Research on Cancer (IARC) and the World Cancer Research Fund (WCRF) have concluded that there is a causal association between high BMI and colorectal, gallbladder, pancreas, kidney, liver, endometrial, postmenopausal breast, ovarian, gastric cardia, and thyroid cancer, as well as oesophageal adenocarcinoma and multiple myeloma.
A study in 2015 estimated that about 3·6% of all cancer cases in 2012 were attributable to high BMI. Since then, high BMI has been thought to have a causal relationship with additional site-specific cancers, and more recent and more detailed global BMI prevalence estimates, based on substantially more data, have become available. Diabetes is increasingly recognised as a risk factor for colorectal, pancreatic, liver, gallbladder, breast, and endometrial cancer, but the global cancer burden attributable to diabetes has not been quantified. Furthermore, since high BMI is an important risk factor for diabetes, priority setting for public health and clinical interventions requires information on the cancer burden attributable to both high BMI and diabetes. We aimed to estimate the proportion of global cancer incidence in 2012 that was attributable to diabetes and high BMI individually and combined, under varying assumptions about the independence of their effects.
We estimated that approximately 6% of cancer cases worldwide in 2012 were attributable to diabetes and high BMI, with high BMI being responsible for almost twice as many cases as diabetes.
About a third of cancer cases attributable to diabetes and a quarter of cases attributable to high BMI were due to increases in the prevalence of these risk factors from 1980 to 2002. Given the continued rise in the prevalence of these risk factors since 2002, the attributable cancer burden is likely to continue to increase in coming decades. Approximately one in four liver and esophageal adenocarcinomas and 38·4% of endometrial cancers worldwide in 2012 were estimated to be attributable to diabetes and high BMI.
In our analysis LMICs had the largest increases in numbers of cancer cases attributable both to diabetes, and diabetes and high BMI combined, which is particularly important to note because these countries are generally less well equipped to manage the burden of complex non-communicable diseases (NCDs) than high-income countries.
Proposed biological mechanisms underlying the link between diabetes, high BMI, and cancer include hyperinsulinaemia, hyperglycaemia, chronic inflammation, and dysregulation of sex hormone activity. Insulin itself could be oncogenic, and results from several analyses showed that people with hyperinsulinaemia were at increased risk of breast and colorectal cancer irrespective of their BMI. Prospective studies and large-scale consortia with more accurate assessments of adiposity, diabetes, and metabolic health, which incorporate molecular tools, will be needed to draw conclusions about the underlying mechanisms that link diabetes, high BMI, and cancer, and inform clinical interventions.
To our knowledge, this is the only study to have quantified the global burden of cancer attributable to diabetes and to diabetes combined with high BMI, by use of robust evidence from WCRF for BMI and high quality meta-analyses for diabetes. Our findings are important to policy makers developing coordinated approaches to tackle the rising prevalence of diabetes, high BMI, and all of their sequelae. The cancers judged to have a convincing association with diabetes by the umbrella meta-analysis were restricted to those for which the effect of study bias was expected to be lowest.
Our results suggest that the increases in diabetes and BMI worldwide could lead to a substantial increase in the cancer burden in future decades. For example, when we used 2025 projections for diabetes and BMI prevalence we found that a substantially larger share of cancers would be attributable to these risk factors in the future than in 2012. PAFs for all site-specific cancers would be significantly higher if trends in diabetes and BMI continue as projected, with the largest increases in gallbladder, liver, and endometrial cancers. These projections are particularly alarming in view of the high, and growing, economic cost of cancers and metabolic diseases, and highlight the importance of integrated control measures to tackle common modifiable risk factors, alongside clinician awareness of diabetes and high BMI as established risk factors for common cancers.
Population-based strategies to prevent diabetes and high BMI have great potential impact—not least because many NCDs have overlapping risk factors, comorbidities, and shared sequelae—but have so far often failed, largely because of reluctance by governments and policy makers to pursue structural interventions that tackle key risks for NCDs, such as diet and physical inactivity. Future efforts should focus on identifying the most effective clinical interventions to prevent development of NCDs in at-risk groups and their sequelae, such as cancer. Primary care interventions, such as glucose-modifying medications, can be effective in preventing diabetes complications such as macrovascular disease, but this approach relies on early identification and close monitoring of people with diabetes, which can be challenging in LMICs that have limited resources. As well as coordinated approaches to halt and reverse the rise in NCDs, global efforts and clinical guidance should reflect the importance of cancer as a sequela of both diabetes and high BMI, and NCD control measures should be integrated into clinical guidelines to identify opportunities to reduce morbidity in this group of patients.