Source: Healio interviews
Disclosures: Gallagher reports she has received advisory or consultant fees from Novartis, Seattle Genetics and SynDevRx. Pearson-Stuttard reports he has received personal fees from Novo Nordisk. Bergman and Song report no relevant financial disclosures.
February 18, 2021
6 min read
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Cancer replaces vascular disease as leading cause of excess death in diabetes

Source: Healio interviews
Disclosures: Gallagher reports she has received advisory or consultant fees from Novartis, Seattle Genetics and SynDevRx. Pearson-Stuttard reports he has received personal fees from Novo Nordisk. Bergman and Song report no relevant financial disclosures.
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A large epidemiological analysis shows cancer has replaced vascular disease as the leading cause of excess death among people with diabetes, suggesting improved lifestyle habits and cardiovascular disease prevention efforts may be working.

“One of the things we have observed generally is life expectancy for people with diabetes is increasing,” Jonathan Pearson-Stuttard, MD, FRSPH, a Wellcome Trust clinical research fellow and epidemiologist with Imperial College London School of Public Health and vice chair of the Royal Society for Public Health, told Healio. “There has been some evidence from the U.S. that this has led to a diversification in cause of death. But studies to date, including those done in the U.S., have not been as granular as ours — with less information on what makes up 'other' non-vascular, non-cancer causes of death.”

People without diabetes had larger declines in cancer-related deaths from 2001 to 2018 compared with people with diabetes.

For the past 30 years, deaths attributable to vascular disease have declined overall globally due to a combination of factors, such as reduction of salt and saturated fat intake, lower smoking rates, blood pressure control, improvements in therapeutics and better survival rates after myocardial infarction. A new primary care database analysis, published in February in The Lancet Diabetes & Endocrinology, revealed these improvements were even better for people with diabetes vs. those without.

Jonathan Pearson-Stuttard

“If you ask anyone in the diabetes field, they say vascular disease is the biggest risk for people with diabetes,” Pearson-Stuttard said. “The good news is, what we have been doing has been working, and more so for those with diabetes.”

The flip side, according to the data, is gains in cancer mortality have been much more modest. Additionally, unlike vascular disease, where the best improvements have been observed among people with diabetes, the reverse was true for cancer.

“Cancer gains have been slower and more slow among people with diabetes compared with those without diabetes,” Pearson-Stuttard said. “When you look at the data by age group, we see that, among older adults, there is no improvement, and perhaps a worsening among people with diabetes.”

Primary care data

In an epidemiological analysis of primary care records, Pearson-Stuttard and colleagues analyzed data from 313,907 adults with diabetes between 2001 and 2018, using data from the Clinical Practice Research Datalink linked with U.K. Office for National Statistics mortality data. Researchers used Poisson regression models to estimate annual death rates for deaths from all causes and 12 specific causes for men and women with diabetes, and also estimated mortality rates for age- and sex-matched adults without diabetes from the same data set.

From 2001 to 2018, researchers found that total mortality declined by 32% in men with diabetes and 31% in women with diabetes, with similar trends for those without diabetes — a 41% decline for men and a 33% decline for women.

For people with diabetes, the largest absolute decline across specific causes of death was for ischemic heart disease (7.2 deaths per 1,000 person-years), stroke (3.6 deaths per 1,000 person-years) and diabetes (2.8 deaths per 1,000 person-years); improvements were similar for men and women. Researchers observed similar patterns among those without diabetes.

Cancer deaths decreased for those with and without diabetes; however, declines in cancer-related mortality were much larger for those without diabetes. Researchers observed declines of 0.4 deaths per 1,000 person-years for diabetes-related cancers and 2.1 deaths per 1,000 person-years for all other cancers among those without diabetes, vs. declines of 0.2 deaths per 1,000 person-years and 0.5 deaths per 1,000 person-years for those with diabetes.

The large decline in vascular disease death rates led to a transition from vascular causes to cancers as the leading contributor to death rates among people with diabetes and to the gap in death rates between those with and without the disease.

Michael Bergman, MD, FACP, clinical professor of medicine and population health at NYU Grossman School of Medicine and director of the NYU Diabetes Prevention Program, noted that the number of absolute cancer deaths is relatively small, which precludes identification of the precise cancers that account for the death rate in the study.

Michael Bergman

“Cancer deaths declined in both populations, but there was less of a decline in the diabetic population vs. the nondiabetic population, so the attributable death rate is twice as high, but it is still a relatively small number,” Bergman told Healio. “Clearly, cancer replaced vascular disease as a cause of excess death. However, other factors seem to be associated with diabetes as well that increase the death rate, including liver disease and dementia, probably related to increased life span and other factors.”

Link between metabolic disturbances, cancer

In commentary accompanying the study, Mingyang Song, MBBS, ScD, assistant professor of clinical epidemiology and nutrition at the Harvard T.H. Chan School of Public Health, noted that cancer has traditionally been considered a distinct spectrum of disease from diabetes. Increasing evidence supports the importance of metabolic disturbances in the cause of cancer, he said.

Mingyang Song

“We would expect at some point cancer would overtake vascular disease as a leading cause of death, both in the general population and among people with diabetes,” Song told Healio. “What surprises me most is the magnitude of the gap. If you look at the number for total cancer deaths, it is almost twice as high as vascular disease. That magnitude highlights the urgency of this issue.”

Compared with people without diabetes, those with diabetes are nearly twice as likely to develop liver and pancreatic cancer, 1.5 to two times more likely to develop endometrial and gallbladder cancer and 1.1 to 1.4 times more likely to develop kidney, colorectal, bladder and breast cancer, Song wrote. Globally, an estimated 5.7% of all incident cancers in 2012 were attributable to the combined effects of adiposity and diabetes.

“Cancer is becoming an important issue for people with diabetes, as obesity is such a strong risk factor for some cancers,” Song said. “This is a problem we should not neglect. This needs to be a focus in the clinic when providers talk to patients.”

Value of cancer screenings

Current recommendations for cancer screenings do not differ for people with or without diabetes. Additionally, there are no specific screening tests that have been shown to reduce deaths from most of the cancer types associated with diabetes, according to Emily Gallagher, MD, PhD, MRCPI, assistant professor of endocrinology, diabetes and bone disease and associate program director for the internal medicine residency program at the Icahn School of Medicine at Mount Sinai.

Emily Gallagher

“We need to conduct studies to see if screening for specific diabetes-related cancers, specifically in people with diabetes, reduces cancer mortality in this population,” Gallagher, who studies links between obesity, type 2 diabetes and cancer, told Healio. “Additionally, we also need to study preventive strategies.”

The process of insulin resistance associated with metabolic syndrome and prediabetes occurs for many years before hyperglycemia and overt type 2 diabetes develops, indicating cancer prevention strategies should likely also begin early, Gallagher said.

“As mentioned in the commentary, in some studies the increased cancer risk associated with diabetes peaked approximately 8 years after the diagnosis of diabetes and then declined, suggesting that it is the hyperinsulinemia associated with prediabetes and the metabolic syndrome that may be driving the increased risk for cancer,” Gallagher said. “This means that cancer preventive strategies would need to be put in place prior to the development of diabetes.”

Bergman said enhanced cancer surveillance for specific cancers associated with diabetes is worth considering.

“We don’t know the cost for increasing cancer surveillance, particularly in the diabetic population,” Bergman said. “But it makes sense to look at this very carefully. Also worth noting is that prediabetes, a precursor to type 2 diabetes affecting well over 80 million people in the U.S., is also associated with an increased risk for cancer, but that risk is approximately 50% lower than in people with overt diabetes. It is logical that the same cancers associated with type 2 diabetes, are also associated with prediabetes.”

Data spur questions

Experts agree that many open research questions remain regarding cancer and diabetes.

“We know people with diabetes have a higher risk for vascular disease, and we have prevention-specific actions in their care pathways, but we do not have any specific screening or prevention approaches in cancer,” Pearson-Stuttard said. “What is difficult about that is it is very unlikely that every single person with diabetes has that increased risk for cancer. We are not quite sure what that driving mechanism is. It is probably high insulin levels or insulin-like growth factor I levels, but the evidence isn’t there yet to inform new, specific measures.”

Recent studies have also shown a possible cancer prevention benefit with the diabetes drug metformin; these new data are likely to only heighten that discussion, Gallagher said.

“Patients frequently ask about the potential anti-cancer effects of metformin, and while I tell them that there are no large randomized controlled trials that definitely show a benefit with metformin, there are no studies that have shown a negative impact on cancer outcomes,” Gallagher said. “As it is indicated for diabetes management anyway as first-line therapy, I definitely advocate for it. The question is, should we be prescribing it earlier, for people with prediabetes?”

As research continues, Song said clinicians should “bring the cancer perspective” into the discussion when talking with patients.

“Motivate the patient to do more with lifestyle changes,” Song said. “Regarding the research side, there is a lot that can be done. Should people with diabetes be considered a high-risk group that warrants earlier cancer screenings? More work still needs to be done to answer that question. As the obesity rate rises, this problem will become greater in the clinic.”

References:

Pearson-Stuttard J, et al. Lancet Diabetes Endocrinol. 2021;doi:10.1016/s2213-8587(20)30431-9.

Song M. Lancet Diabetes Endocrinol. 2021;doi:10.1016/s2213-8587(21)00016-4.

For more information:

Michael Bergman, MD, FACP, can be reached at michael.bergman@nyulangone.org.

Emily Gallagher, MD, PhD, MRCPI, can be reached at emily.gallagher@mssm.edu.

Jonathan Pearson-Stuttard, PhD, can be reached at j.pearson-stuttard@imperial.ac.uk.

Mingyang Song, MBBS, ScD, can be reached at mis911@mail.harvard.edu.