Association of Metabolic Syndrome With Risk of Lung Cancer

Abstract

BackgroundBoth the incidence of lung cancer and the prevalence of metabolic syndrome (MetS) have been increasing worldwide. The relationship between MetS and lung cancer remains controversial.Research QuestionWhat is the risk of lung cancer associated with MetS and its components?Study Design and MethodsMultivariable Cox regression models were used to estimate the hazard ratio (HR) of MetS-related variables on lung cancer risk, both overall and by histologic subtype, in the UK Biobank. Stratified analyses were conducted by sex, tobacco use status, and use of medication. HR curves were used to test the nonlinear associations between the metabolic markers and the risk of lung cancer.ResultsOf the 331,877 participants included in this study, a total of 77,173 participants had a diagnosis of MetS at enrollment. During a median follow-up of 10.9 years, lung cancer as the primary site developed in 2,425 participants. The HRs of MetS were 1.21 (95% CI, 1.09-1.33), 1.28 (95% CI, 1.10-1.50), and 1.16 (95% CI, 0.94-1.44) for the overall risk of lung cancer, adenocarcinoma, and squamous cell carcinoma, respectively. The HRs increased with the number of metabolic abnormalities from 1.11 to approximately 1.4 or 1.5 for those with one to five disorders. Positive association with lung cancer was observed for low high-density lipoprotein cholesterol (HDL-C), elevated waist circumference, and hyperglycemia. The relationship between MetS and lung cancer was modified by sex, with a stronger effect in women (P = .031). The risk of lung cancer resulting from MetS was elevated mainly among tobacco users, although the modification effect of tobacco use was not statistically significant. A nonlinear association was found between lung cancer and HDL-C, waist circumference, and glycated hemoglobin.InterpretationThe increased risk of lung cancer associated with MetS suggests the importance of taking metabolic status and markers into consideration for the primary prevention of lung cancer and the selection of high-risk populations for lung cancer screening. Both the incidence of lung cancer and the prevalence of metabolic syndrome (MetS) have been increasing worldwide. The relationship between MetS and lung cancer remains controversial. What is the risk of lung cancer associated with MetS and its components? Multivariable Cox regression models were used to estimate the hazard ratio (HR) of MetS-related variables on lung cancer risk, both overall and by histologic subtype, in the UK Biobank. Stratified analyses were conducted by sex, tobacco use status, and use of medication. HR curves were used to test the nonlinear associations between the metabolic markers and the risk of lung cancer. Of the 331,877 participants included in this study, a total of 77,173 participants had a diagnosis of MetS at enrollment. During a median follow-up of 10.9 years, lung cancer as the primary site developed in 2,425 participants. The HRs of MetS were 1.21 (95% CI, 1.09-1.33), 1.28 (95% CI, 1.10-1.50), and 1.16 (95% CI, 0.94-1.44) for the overall risk of lung cancer, adenocarcinoma, and squamous cell carcinoma, respectively. The HRs increased with the number of metabolic abnormalities from 1.11 to approximately 1.4 or 1.5 for those with one to five disorders. Positive association with lung cancer was observed for low high-density lipoprotein cholesterol (HDL-C), elevated waist circumference, and hyperglycemia. The relationship between MetS and lung cancer was modified by sex, with a stronger effect in women (P = .031). The risk of lung cancer resulting from MetS was elevated mainly among tobacco users, although the modification effect of tobacco use was not statistically significant. A nonlinear association was found between lung cancer and HDL-C, waist circumference, and glycated hemoglobin. The increased risk of lung cancer associated with MetS suggests the importance of taking metabolic status and markers into consideration for the primary prevention of lung cancer and the selection of high-risk populations for lung cancer screening. Take-home PointsStudy Question: Is the risk of lung cancer associated with metabolic syndrome (MetS) and its components?Results: MetS, low high-density lipoprotein cholesterol, elevated waist circumference, and hyperglycemia are risk factors of lung cancer, especially in women and tobacco users.Interpretation: It is important to take metabolic status and markers into consideration in the primary prevention of lung cancer and the selection of high-risk populations for lung cancer screening. Study Question: Is the risk of lung cancer associated with metabolic syndrome (MetS) and its components? Results: MetS, low high-density lipoprotein cholesterol, elevated waist circumference, and hyperglycemia are risk factors of lung cancer, especially in women and tobacco users. Interpretation: It is important to take metabolic status and markers into consideration in the primary prevention of lung cancer and the selection of high-risk populations for lung cancer screening. Lung cancer is one of the most commonly diagnosed cancers and the leading cause of cancer deaths globally.1International Agency for Research on Cancer, World Health OrganizationGlobal cancer observatory. International Agency for Research on Cancer website.https://gco.iarc.fr/Date accessed: January 4, 2023Google Scholar The incidence of lung cancer has increased rapidly over the past decades and is projected to reach 3.6 million cases by 2040.1International Agency for Research on Cancer, World Health OrganizationGlobal cancer observatory. International Agency for Research on Cancer website.https://gco.iarc.fr/Date accessed: January 4, 2023Google Scholar Known risk factors, such as age, sex, socioeconomic factors, tobacco use, COPD, and family history of lung cancer, have been used widely in the prediction of lung cancer risk and selection of high-risk populations for screening.2Tammemägi M.C. Katki H.A. Hocking W.G. et al.Selection criteria for lung cancer screening.N Engl J Med. 2013; 368: 728-736Crossref PubMed Scopus (0) Google Scholar, 3Field J.K. Vulkan D. Davies M.P.A. Duffy S.W. Gabe R. Liverpool Lung Project lung cancer risk stratification model: calibration and prospective validation.Thorax. 2021; 76: 161-168Crossref PubMed Scopus (16) Google Scholar, 4Krist A.H. Davidson K.W. Mangione C.M. et al.Screening for lung cancer: US Preventive Services Task Force Recommendation Statement.JAMA. 2021; 325: 962-970Crossref PubMed Scopus (537) Google Scholar However, approximately 30% of cases of lung cancer still would be missed by using these risk factors as selection criteria.5Robbins H.A. Alcala K. Swerdlow A.J. et al.Comparative performance of lung cancer risk models to define lung screening eligibility in the United Kingdom.Br J Cancer. 2021; 124: 2026-2034Crossref PubMed Scopus (17) Google Scholar Therefore, it is important to expand our knowledge regarding risk factors related to lung cancer development. Metabolic syndrome (MetS) is a cluster of interrelated risk factors including hypertension, dyslipidemia, central obesity, and insulin resistance. Individuals with MetS are more prone to several types of diseases such as cardiovascular diseases and diabetes.6Alberti K.G. Eckel R.H. Grundy S.M. et al.Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity.Circulation. 2009; 120: 1640-1645Crossref PubMed Scopus (10635) Google Scholar MetS is becoming an emerging public health concern because of its high prevalence globally. Between 20% and 30% of the adult population are estimated to have MetS in most countries worldwide and the prevalence keeps rising.7Grundy S.M. Metabolic syndrome pandemic.Arterioscler Thromb Vasc Biol. 2008; 28: 629-636Crossref PubMed Scopus (1141) Google Scholar In the United States, the prevalence of MetS increased from 33% in 2011 and 2012 to 37% in 2015 and 2016, and the upward trend was more notable among the younger generations and women.8Hirode G. Wong R.J. Trends in the prevalence of metabolic syndrome in the United States, 2011-2016.JAMA. 2020; 323: 2526-2528Crossref PubMed Scopus (281) Google Scholar Similar upward trends also were observed in different parts of the world.9O’Neill S. O’Driscoll L. Metabolic syndrome: a closer look at the growing epidemic and its associated pathologies.Obes Rev. 2015; 16: 1-12Crossref PubMed Scopus (1023) Google Scholar Growing evidence shows the association between MetS and cancer,10Esposito K. Chiodini P. Colao A. Lenzi A. Giugliano D. Metabolic syndrome and risk of cancer: a systematic review and meta-analysis.Diabetes Care. 2012; 35: 2402-2411Crossref PubMed Scopus (789) Google Scholar,11Uzunlulu M. Telci Caklili O. Oguz A. Association between metabolic syndrome and cancer.Ann Nutr Metab. 2016; 68: 173-179Crossref PubMed Scopus (135) Google Scholar but the relationship between MetS and lung cancer remains controversial. Although increased risk of lung cancer was reported among those with MetS in a few studies,12López-Jiménez T. Duarte-Salles T. Plana-Ripoll O. Recalde M. Xavier-Cos F. Puente D. Association between metabolic syndrome and 13 types of cancer in Catalonia: a matched case-control study.PLoS One. 2022; 17e0264634Crossref Scopus (10) Google Scholar,13Sin S. Lee C.H. Choi S.M. Han K.D. Lee J. Metabolic syndrome and risk of lung cancer: an analysis of Korean national health insurance corporation database.J Clin Endocrinol Metab. 2020; 105: dgaa596Crossref Scopus (10) Google Scholar a meta-analysis including five cohort studies found no association of MetS with lung cancer risk.14Qiao L. Ma D. Lv H. et al.Metabolic syndrome and the incidence of lung cancer: a meta-analysis of cohort studies.Diabetol Metab Syndr. 2020; 12: 95Crossref PubMed Scopus (6) Google Scholar However, these studies largely were underpowered to test the null hypothesis, and the small sample size of each cohort precludes further investigations on effect modifiers. In the present study, based on a large-scale cohort with enough size, we aimed to investigate the association of MetS, number of metabolic abnormalities, MetS components, and metabolic markers with the risk of lung cancer. We also assessed the effect modification by sex, tobacco use status, and use of medication. The UK Biobank is a multicenter, population-based, prospective cohort of more than half a million participants registered with the UK National Health Service. The design of the UK Biobank has been described previously.15Sudlow C. Gallacher J. Allen N. et al.UK Biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age.PLoS Med. 2015; 12e1001779Crossref PubMed Scopus (4274) Google Scholar Briefly, men and women between 37 and 73 years of age were recruited from 22 assessment centers across England, Scotland, and Wales between 2006 and 2010. During the baseline survey, participants took touch screen and nurse-led questionnaires, underwent physical measurement, and provided biological samples. Participants were followed up for incidence of cancer through linkage to the National Cancer Registries until January 31, 2021, for Scotland and February 29, 2020, for England and In the present study, we those with cancers at baseline for cancer, as using the International of at baseline and with for of the five MetS and MetS was based on a joint K.G. Eckel R.H. Grundy S.M. et al.Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity.Circulation. 2009; 120: 1640-1645Crossref PubMed Scopus (10635) Google Scholar five metabolic elevated or low high-density lipoprotein cholesterol in men and in elevated waist in men and in women for and hyperglycemia of and were and the were and in the were by and because were for most participants in the UK we used the more of glycated with a of for W.G. of in the diagnosis of in the The of World Health Med. 2012; Scopus Google D. et al.Metabolic syndrome and cancer risk in the UK J Cancer. 2021; Scopus Google Scholar The number of MetS was and the of of the a diagnosis of We used the International of to define cases of lung cancer. Participants were a cancer in than was diagnosed lung cancer, because of the in from primary cancer and the different risk of lung cancer among those with a cancer participants were followed up until lung cancer to or were to the International of for and histologic were based on the World Health S. A. G. et and risk of cancer in the into Cancer and J Cancer. 2020; Scopus Google et 2015 World Health of lung of and the 2015; PubMed Scopus Google and squamous cell and cell and small cell and and a used also was because of evidence of among these M. L. H. et of follow-up and on of from lung cancer screening J Cancer. 2022; Scopus (0) Google Scholar on was through and physical included baseline age sex, and and into five use status included and tobacco users. was a reported or or the criteria of to ratio of and were C. M. et of in participants from the UK Biobank: a PubMed Scopus (0) Google Scholar history of lung cancer or was was as and was further into and of or were as and from biological were and those or were because of the small number of participants. were described using for variables and for The and M.C. Katki H.A. Hocking W.G. et al.Selection criteria for lung cancer screening.N Engl J Med. 2013; 368: 728-736Crossref PubMed Scopus (0) Google Scholar test were used to baseline between with MetS and of lung cancer were by MetS, number of metabolic abnormalities, and MetS The hazard was by based on The hazard ratio (HR) of MetS-related variables on lung cancer risk was by Cox regression Cox models were by assessment because of of the hazard for this and were for age, sex, COPD, family history of lung cancer, tobacco use status, and elevated and waist circumference, was not included in the We the of MetS on both overall lung cancer and of lung cancer and squamous cell We not because of a low number of Stratified analyses were conducted by and and tobacco use status and elevated low HDL-C, and we also the analysis by use of medication. We analyses to the modification of these The of the was by the We the relationship between the metabolic markers HDL-C, waist circumference, and and the risk of lung cancer. the or the were J. M. J. and on of and evidence from 2021; Scopus Google Scholar and were from the HR curves in the for L. C. F. A. an for of hazard ratio curves of Med. 2013; PubMed Scopus Google Scholar were used to test the nonlinear with the median as for the We several analyses to the of our we participants with a up of years to the for lung cancer at baseline metabolic we those with of to its on the metabolic in the we from the total cases of lung cancer the of we further for of tobacco use among tobacco users, at or and in the we use in the of MetS D. G. Davies analysis of in primary prevention use in UK 2022; Scopus Google Scholar and D. G. Davies analysis of in primary prevention use in UK 2022; Scopus Google Scholar and K.G. from UK Biobank are different to those in primary for from studies and J 2022; PubMed Scopus Google Scholar as of elevated elevated HDL-C, and elevated and the association between MetS the and lung cancer analyses were with was as a of Of the 331,877 participants included in this study, the age was years, and of participants were A total of 77,173 participants MetS at with a prevalence of of the participants to MetS status are in Participants with MetS were and had socioeconomic socioeconomic with those of tobacco users, those with tobacco family history of lung cancer, COPD, and were observed among those with MetS Metabolic abnormalities among the with of the participants at one The prevalence of each MetS from to of the Study by MetS = = = use circumference, are as or = glycated = high-density lipoprotein MetS = metabolic in a are as or = glycated = high-density lipoprotein MetS = metabolic a total of of follow-up 10.9 cancer with lung as the primary site developed in 2,425 with and cases of adenocarcinoma, squamous cell carcinoma, and small cell carcinoma, respectively. The incidence of lung cancer were and in the MetS and and increased with the number of metabolic Lung cancer incidence were for MetS the incidence among those with hyperglycemia. A statistically association was found between MetS and lung cancer risk, with an HR of 1.21 (95% CI, 1.09-1.33), for The HRs increased with the number of metabolic abnormalities from 1.11 to approximately 1.4 to 1.5 for those with one to five disorders. A association with lung cancer was observed for MetS low CI, elevated waist CI, and hyperglycemia CI, associations in analyses of Lung Cancer by MetS and the Association of of Lung of of (95% HR (95% models were by assessment and for age, sex, COPD, family history of lung cancer, tobacco use status, and elevated and waist circumference, was not included in the metabolic abnormalities for waist = high-density lipoprotein HR = hazard MetS = metabolic The models were by assessment and for age, sex, COPD, family history of lung cancer, tobacco use status, and elevated and waist circumference, was not included in the in a = high-density lipoprotein HR = hazard MetS = metabolic incidence were found in participants with MetS for both and squamous cell carcinoma, with and with and among those MetS The HRs of MetS were 1.28 (95% CI, and 1.16 (95% CI, 0.94-1.44) on the risk of and squamous cell carcinoma, respectively. The trend for number of metabolic abnormalities were for both histologic waist a with HRs of approximately 1.5 (95% of of and for of metabolic abnormalities for waist = high-density lipoprotein MetS = metabolic in a = high-density lipoprotein MetS = metabolic The relationship between MetS and lung cancer risk was modified by sex, with a stronger effect in with women with MetS a risk of lung cancer CI, CI, with = for the between and The risk of lung cancer among those with five metabolic abnormalities among those in for the trend with number of metabolic abnormalities was not statistically significant. The HRs were in women for MetS components, and the was statistically for Similar were observed for histologic although the in HRs with a number of metabolic abnormalities in women was more for squamous cell The modification effect of tobacco use was not for MetS-related However, the risk of lung cancer resulting from MetS was elevated mainly among tobacco users. 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The relationship between MetS and lung cancer risk was stronger in Although no statistically modification effect was for tobacco use, the risk of lung cancer resulting from MetS was elevated mainly among tobacco users. our this is the to the of MetS on lung cancer and the modification based on a large-scale of studies on MetS and lung cancer risk are A meta-analysis including five cohort studies not a L. Ma D. Lv H. et al.Metabolic syndrome and the incidence of lung cancer: a meta-analysis of cohort studies.Diabetol Metab Syndr. 2020; 12: 95Crossref PubMed Scopus (6) Google Scholar because of the small sample size of each study, with the number of cases of lung cancer than in S. D. Metabolic risk and cancer in Korean men and 2016; Scopus Google Scholar A Korean based on the national insurance reported cases of lung cancer, with a association between MetS and lung cancer S. Lee C.H. Choi S.M. Han K.D. Lee J. Metabolic syndrome and risk of lung cancer: an analysis of Korean national health insurance corporation database.J Clin Endocrinol Metab. 2020; 105: dgaa596Crossref Scopus (10) Google Scholar is with our The the association between metabolic and lung cancer risk are not by of insulin and of be to the et al.Metabolic syndrome and risk of cancer: 2015; PubMed Google Scholar found be a risk for lung cancer. was associated with risk of lung cancer, is in with the of J. et and risk of cancer in the Health J Clin 2016; PubMed Scopus Google high-density lipoprotein and increased risk of several cohort studies including 2020; PubMed Scopus Google Scholar The relationship between low and lung cancer, on the one the of is with lung cancer on the be related to the of high-density lipoprotein in and in lung cancer high-density lipoprotein and increased risk of several cohort studies including 2020; PubMed Scopus Google Scholar The of on lung cancer is more A relationship was reported in L. 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L. et metabolic of lung cancer: in a PubMed Scopus Google Scholar high insulin insulin and are related to increased lung cancer S. D. of insulin and risk of lung Scopus Google Lee S.M. Diabetes as an risk for lung cancer: a meta-analysis of J Cancer. 2013; PubMed Scopus Google Scholar It is to the nonlinear relationship between a the over the past and lung cancer. A relationship also was found in several cancer such as and L. cancer risk with of J Cancer. PubMed Scopus Google A. M. N. et the range are associated with the risk of J Cancer. 2016; PubMed Scopus Google Scholar A with MetS was in this study, with women lung cancer were associated with a in MetS and a metabolic risk than et in the of metabolic risk factors in 2022; Scopus Google Scholar and factors were found to lung cancer both and by with risk N. M. P. of in lung 2021; Scopus Google Scholar However, a case-control found with men a T. Duarte-Salles T. Plana-Ripoll O. Recalde M. Xavier-Cos F. Puente D. Association between metabolic syndrome and 13 types of cancer in Catalonia: a matched case-control study.PLoS One. 2022; 17e0264634Crossref Scopus (10) Google Scholar The of in the relationship between MetS and lung cancer to be The of MetS on lung cancer was observed mainly among tobacco users, although the was not statistically be the of a low number of cases of lung cancer among those have used of this be we not the years, the over of MetS, the risk of lung cancer. MetS is a and metabolic status have several years it is to its over were at to in However, it is in the the were we those with be MetS an risk factors of lung cancer. It remains MetS or the risk factors the of lung cancer. we not for the risk of both lung cancer and metabolic disorders. However, are to be small this would be largely through our analysis by assessment the of be in the from the analysis by those with follow-up In this study, we found associations between MetS and its and an increased risk of lung cancer. relationship be modified by and tobacco the in the prevalence of MetS it is important to have a of its on lung cancer. Although a association between MetS and lung cancer be through this study, the evidence suggests the importance of taking metabolic status and markers into consideration in the selection of high-risk populations for lung cancer screening and a of lung cancer was by the National of and the and Research and and in

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