Metabolic Abnormalities Boost Obesity-Related Cancer Risk

Becky McCall

May 15, 2023

In one of the first studies to examine this phenomenon, metabolically unhealthy obesity is associated with an increased risk, of around 1.5-fold higher, of any obesity-related cancer, and an even higher risk, of two- to threefold higher, for specific cancers, such as endometrial, liver, and renal cell cancers, compared with metabolically healthy normal weight. 

Even in people with so-called "metabolically healthy" obesity, the risk for overall obesity-related cancer is increased compared with normal-weight, metabolically healthy individuals; however, the associations here are weaker than in people with metabolically unhealthy obesity.

"The type of metabolic obesity phenotype is important when assessing obesity-related cancer risk," lead researcher Ming Sun, PhD, from Lund University, Malmö, Sweden, told Medscape Medical News. "In general, metabolic aberrations further increased the obesity-induced cancer risk, suggesting that obesity and metabolic aberrations are useful targets for prevention."

"This synergy means that when obesity and metabolic unhealth occur together, that's particularly bad," added Tanja Stocks, PhD, senior author, also of Lund University.

"But the data also highlight that even obesity and overweight alone comprise an increased risk of cancer," Stock noted.

Sun said the findings have important public health implications, suggesting that "a significant number of cancer cases could potentially be prevented by targeting the co-existence of metabolic problems and obesity, in particular for obesity-related cancers among men."

The results will be presented as a poster by Sun at the European Congress on Obesity (ECO) 2023, being held in Dublin, Ireland, and have been published in the Journal of the National Cancer Institute.

Metabolically Unhealthy Obesity Worst for Cancer Risks

Andrew G. Renehan, PhD, FRCS, professor of cancer studies and surgery, University of Manchester, UK, welcomed the new work, saying it addresses the issue with very large study numbers. "[It] nicely demonstrates that there are clear examples where metabolically unhealthy overweight and obese phenotypes have increased cancer risk relative to [metabolically] healthy overweight and obese phenotypes," he said.

"There is a clear need for clinically based research addressing these hypotheses...but these studies will additionally need to factor in other dimensions such as the selection of treatment for metabolic aberrations, both medical and surgical, and the consequent metabolic control resulting from these interventions," Renehan observed.

Vibhu Chittajallu, MD, a gastroenterologist based at University Hospitals Cleveland Medical Center, Ohio, said it was beneficial to see another study further validating the association of obesity with the development of obesity-associated cancers.

"This is an interesting study [because it focuses] on the role of metabolic syndrome in obesity and how it affects the risk of development of obesity-associated cancers," he told Medscape Medical News.

"I believe that the results of this study further strengthen the need for improved management of obesity and metabolic syndrome to reduce the risk of obesity-associated cancer formation that plays a role in preventable and premature deaths in adult patients with obesity."

Synergy Between Metabolic Aberrations and Obesity, and Cancer Risk

Sun and colleagues note that obesity is an established risk factor for several cancers. It is often accompanied by metabolic aberrations, which have been a commonly proposed mechanism to link obesity with cancer. During the last decade, obesity with or without metabolic aberrations — commonly termed "metabolically unhealthy" or "healthy obesity" — has been extensively investigated in the cardiovascular field; however, studies regarding cancer are limited.

According to Sun, this new study is the first to look at the synergistic effect of unhealthy metabolism and body mass index (BMI) — the latter was further categorized as normal weight (BMI < 25 kg/m2), overweight (BMI < 30 kg/m2) and obesity (BMI ≤ 30 kg/m2) — and the association with cancer risk, both overall and in relation to site-specific cancers.

Data were drawn from 797,193 European individuals (in Norway, Sweden, and Austria), of whom 23,630 developed an obesity-related cancer during the follow-up period. A metabolic score comprising mid-blood pressure, plasma glucose and triglycerides was used to provide a measure of healthy or unhealthy metabolic status. Relative risks (hazard ratios, HRs) for overall and site-specific cancers were determined. Comparisons were made with metabolically healthy people of normal weight (effectively controls).

When different metabolic scores and BMIs were combined, participants fell into six categories: metabolically unhealthy obesity (6.8% of participants); metabolically healthy obesity (3.4%), metabolically unhealthy overweight (15.4%), metabolically healthy overweight (19.8%), metabolically unhealthy normal weight (12.5%), and metabolically healthy normal weight (42.0%).

Metabolically unhealthy women with obesity had a hazard ratio (HR) of 1.43 for overall obesity-related cancers, compared with metabolically healthy women of normal weight. Of particular note, were risks of two cancer types in women with metabolically unhealthy obesity: renal cancer, with an HR of 2.43, and endometrial cancer, with an HR of 3.0, compared with controls.

Even in metabolically healthy women with obesity (compared with metabolically healthy women of normal weight), there was an increased risk of endometrial cancer, with an HR of 2.36.

"If you look at individual cancers, in particular, endometrial cancer, this seems to be very much driven by obesity and not so much by the metabolic factor," remarked Stocks.

In males, compared with metabolically healthy men of normal weight, metabolically unhealthy men with obesity had an overall obesity-related cancer risk of HR 1.91. Specifically, the risk of renal cell cancer was more than doubled, with an HR of 2.59. The HR for colon cancer was 1.85, and that for rectal cancer and pancreatic cancer was similar, both having HRs of 1.32.

Again, risk was lower in metabolically healthy men with obesity, although still higher than metabolically healthy normal-weight men.

European Congress on Obesity (ECO) 2023. Abstract P2.027. Presented Friday 19 May, 2023.

Sun, Stocks, Chitajallu, and Renehan have reported no relevant financial relationships.

J Natl Cancer Inst. 2023;115:456-467. Full text

For more news, follow Medscape on Facebook, Twitter, Instagram, and YouTube


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.