Metabolically (Un)Healthy Obesity and Risk of Obesity-Related Cancers

A Pooled Study

Ming Sun, MSc; Josef Fritz, PhD; Christel Häggström; Tone Bjørge, MD, PhD; Gabriele Nagel, MD, PhD; Jonas Manjer, MD, PhD; Anders Engeland, PhD; Emanuel Zitt, MD; Bethany van Guelpen, MD, PhD; Pär Stattin, MD, PhD; Hanno Ulmer, MD, PhD; Tanja Stocks, PhD


J Natl Cancer Inst. 2023;115(4):456-467. 

In This Article

Abstract and Introduction


Background: Studies of obesity with or without metabolic aberrations, commonly termed metabolically unhealthy or healthy obesity, in relation to cancer risk are scarce.

Methods: We investigated body mass index (normal weight, overweight, obesity) jointly and in interaction with metabolic health status in relation to obesity-related cancer risk (n = 23 630) among 797 193 European individuals. A metabolic score comprising mid-blood pressure, plasma glucose, and triglycerides was used to define metabolically healthy and unhealthy status. Hazard ratios (HRs) and multiplicative interactions were assessed using Cox regression, and additive interactions were assessed using the relative excess risk for interaction. All statistical tests were 2-sided.

Results: Metabolically unhealthy obesity, with a baseline prevalence of 7%, was, compared with metabolically healthy normal weight, associated with an increased relative risk of any obesity-related cancer and of colon, rectal, pancreas, endometrial, liver, gallbladder, and renal cell cancer (P < .05), with the highest risk estimates for endometrial, liver, and renal cell cancer (HR = 2.55–3.00). Metabolically healthy obesity showed a higher relative risk for any obesity-related cancer and colon (in men), endometrial, renal cell, liver, and gallbladder cancer, though the risk relationships were weaker. There were no multiplicative interactions, but there were additive, positive interactions between body mass index and metabolic health status on obesity-related and rectal cancer among men and on endometrial cancer (P < .05).

Conclusions: This study highlights that the type of metabolic obesity phenotype is important when assessing obesity-related cancer risk. In general, metabolic aberrations further increased the obesity-induced cancer risk, suggesting that obesity and metabolic aberrations are useful targets for prevention.


Obesity is an established risk factor for several cancers.[1,2] It is often accompanied by metabolic aberrations, which have been a commonly proposed mechanism to link obesity with cancer.[3,4] The metabolic syndrome, a cluster of conditions including obesity and metabolic aberrations, has been shown to be associated with an increased risk of some obesity-related cancers,[5,6] such as pancreatic,[5–9] postmenopausal breast,[5,10] liver,[5,6,11,12] colorectal,[5,6,13,14] endometrial,[5,6,15,16] and renal cell cancer.[6,17]

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;[18–20] however, studies regarding cancer are limited. A meta-analysis published in 2020 showed an increased risk of cancer among metabolically healthy obese individuals, but it was based on only 7 studies of different cancer forms and did not summarize the findings for other combinations of body size and metabolic health status.[21] A recent prospective study did this and suggested that the impact of obesity on cancer risk varies by metabolic health status and cancer form;[22] however, more evidence is needed for specific cancers. Moreover, the potential interaction between body size and metabolic health status on obesity-related cancer risk has been sparsely investigated. Knowledge on this could clarify whether obesity and metabolic aberrations jointly exhibit a greater cancer risk than their individual parts, thereby identifying groups of individuals who are more likely to benefit from interventions aiming at reducing their risk of cancer.[23]

In this pooled cohort study, we comprehensively and systematically investigated the association of metabolically unhealthy and healthy overweight and obesity with the risk of obesity-related cancer overall and for specific sites. We specifically examined whether overweight and obesity conveyed an increased risk of obesity-related cancer in metabolically healthy individuals and whether multiplicative and additive interactions existed between body mass index (BMI) and metabolic health status on obesity-related cancer risk.