Open access Protocol Metabolic syndrome and risk of cancer: a study protocol of case–control study using data from the Information System for the Development of Research in Primary Care (SIDIAP) in Catalonia Diana Puente,1,5 Tomàs López-Jiménez,1,5 Xavier Cos-Claramunt,2,3 Yolanda Ortega,4 Talita Duarte-Salles1 To cite: Puente D, López- Abstract Jiménez T, Cos-Claramunt X, Strengths and limitations of this study Background Metabolic syndrome (MS) is defined by the et al. Metabolic syndrome and clustering of specific metabolic disorders in one subject. risk of cancer: a study protocol ►► Data on cancer diagnoses in the Information System MS is highly prevalent globally and currently considered of case–control study using for Research in Primary Care database are reliable. a growing public health concern. MS comprises obesity, data from the Information ►► Long follow-up times. System for the Development hypertension, dyslipidaemia and insulin resistance. ►► Underestimation of the prevalence of some diseases of Research in Primary Care Mechanisms linking MS with cancer are poorly understood, and left truncation. (SIDIAP) in Catalonia. BMJ Open and it is as yet unknown if MS confers a greater risk than ►► Waist circumference is only available for a small 2019;9:e025365. doi:10.1136/ the risk entailed by each of its separate components. The proportion of individuals. bmjopen-2018-025365 main objective of this study is to compare the association ►► Under-recording and quality of variables in the pri- between MS and 14 site-specific cancer against the ►► Prepublication history for mary care setting. this paper is available online. association between one or two individual components To view these files, please visit of MS and cancer. The secondary objective is to evaluate the journal online (http://​dx.​doi.​ the time elapsed since the diagnosis of MS and the measured by waist circumference, hyperten- org/​10.​1136/​bmjopen-​2018-​ subsequent onset of cancer within the 2006–2017 period 025365). by sex. sion, dyslipidaemia and insulin resistance.1 It Methods and analysis A case–control study will be is a growing public health problem due to its Received 11 July 2018 conducted for the main objective and a cohort of patients high global prevalence. For instance, a study Revised 20 March 2019 from the USA indicated a prevalence of MS with MS will be followed for the evaluation of the second Accepted 16 May 2019 objective. Incident cases of fourteen types of cancer in around 24% in the general population and patients ≥40 years of age diagnosed prospectively will of 50% in patients with ischaemic cardiop- be selected from electronic primary care records in the athy and other vascular conditions and also Information System for Research in Primary Care (SIDIAP a significant increase in prevalence with age.2 database; www.​sidiap.​org). The SIDIAP database includes In Spain, previous studies have shown that the anonymous data from 6 million people (80% of the Catalan prevalence of MS ranges between 23% and population) registered in 286 primary healthcare centres. 31%; it increases with age, and until 65 years Each matched control (four controls for each case) will have the same inclusion date, the same sex and age of age, it is higher in men than in women; (±1 year) than the paired case. Logistic regression and conversely, the prevalence of MS after 65 a descriptive analysis and Kaplan-Meier analysis will be years of age is higher in women.3 4 performed, in accordance with the objectives. While MS was initially considered a risk Ethics and dissemination The protocol of the study was factor for diabetes and cardiovascular disease,5 approved by the IDIAP Jordi Gol Clinical Research Ethics emerging studies suggest that it is also a risk © Author(s) (or their Committee (protocol P17/212). The study’s findings will factor for different types of cancer. However, employer(s)) 2019. Re-use be published in a peer-reviewed journal and disseminated to our knowledge, no evidence exists to date permitted under CC BY-NC. No at national and international conferences and oral commercial re-use. See rights to indicate whether MS confers a higher risk presentations to researchers, clinicians and policy makers. and permissions. Published by of cancer than its individual components.6 BMJ. According to various studies,7–10 MS is asso- For numbered affiliations see ciated with a higher risk of liver, colorectal end of article. Introduction and bladder cancer in men and endome- Correspondence to Metabolic syndrome (MS) consists in the clus- trial, pancreatic, colorectal, ovarian and Dr Diana Puente; tering of various cardiometabolic risk factors postmenopausal breast cancer in women. ​dpuente@​idiapjgol.​org such as obesity, specifically central obesity as Evidence concerning the possible association Puente D, et al. BMJ Open 2019;9:e025365. doi:10.1136/bmjopen-2018-025365 1 Open access with prostate cancer is still conflicting. Whereas a study by the Catalan population, and thus facilitates the study of Esposito et al11 did not find any association between MS less prevalent cancer types that have been scarcely studied and prostate cancer, a recent publication by Gacci et al12 to date. Research studies with databases provide large found a slight correlation. Data and publications for less amounts of information (clinical, laboratory and phar- prevalent types of cancer (incidence <6/100 000/year)13 maceutical data) at a reasonable cost. In addition, long and for thyroid cancer, multiple myeloma, non-Hodgkin follow-up times are made possible since the electronic lymphoma and leukaemias are currently scarce. However, medical records started in 2005. Arguably, the main a recent meta-analysis found a higher risk of haematolog- justification of this study on MS and its relationship with ical cancer14 in patients with MS. cancer is that MS can be modified by adopting healthy The pathophysiology that underlies the association of lifestyles that reduce obesity, cholesterol and blood pres- MS with cancer is as yet poorly understood. Components sure. Indeed, healthy lifestyles can contribute to reduce of MS such as obesity,15 glucose levels16 and high blood the prevalence of MS in the adult population.24 pressure16 17 are associated with higher risk of various The current study will provide scientific evidence for types of cancer. In the pathophysiology of MS, adipose the future implementation on new preventive strategies tissue is known to deregulate cytokine production, in primary healthcare and to obtain significant results causing a chronic inflammatory state that can ultimately in the fight against cancer. Patients with MS could be mediate tumorous development. Additionally, adipose encouraged to be screened for cancer and, more impor- tissue has been linked to insulin resistance,18 although tantly, to adopt healthier lifestyles as prevention strategy.8 insulin resistance is not found in all obese patients.19 It is The main objective of this project will be to investigate thus possible for the association between MS and cancer the association of MS with 14 types of cancer diagnosed in to be mediated by the coexistence of obesity and insulin the electronic primary care records from 1 January 2006 resistance as the main factors.8 There are some patients to 31 December 2017 in SIDIAP database, as well as to who besides having MS also have hyperinsulinaemia, compare the association between MS and cancer versus because the pancreas compensates the insulin resistance 0, 1 or 2 single MS components. As secondary objec- with insulin extrasecretion. Other studies suggest that tive, from the cohort of patients with MS obtained from high-density lipoprotein cholesterol (HDL-C) cholesterol the case–control study, we will analyse the time elapsed is inversely correlated with cancer.6 20 between diagnosis of MS and onset of cancer. Whether MS carries a higher risk than the risk of each separate MS component is unclear. Recent research looks to elucidate if the effect of MS as a whole is stronger than Methods and analysis the effect of each component individually. Indeed, our Design study would allow us to analyse this aspect. For instance, Case–control study for the main objective and in a in the case of endometrial cancer, obesity on its own subgroup of patients, longitudinal study to evaluate time carries a higher risk than MS as a whole.21 MS is slightly of MS exposure to onset of cancer. associated with prostate cancer, but a stronger associa- tion exists between prostate cancer and hypertension.12 Data collection With respect to kidney cancer, the time of progression This study collects all information from SIDIAP data- to cancer has shown to be shorter in patients with MS, base. In Spain, primary care doctors and nurses have a whereas it remains unchanged when considering any pivotal role in the public health system since they have single component of MS.22 In postmenopausal breast primary responsibility for the health of the population. cancer, the association with MS is also higher than with The Spanish public health system has a coverage of over individual components.21 In conclusion, it is yet unclear if 98% of the population, most of which visit their GP at the risk of MS is higher than the risk of MS single compo- least once a year. The computerisation of primary care nents in some types of cancer. medical records in Catalonia started in 2005. The SIDIAP This project will contribute new evidence on the associ- is a reliable database with information from primary ation between MS and cancer using a large database with care records for use in biomedical research. From electronic primary care records of people that attended 2005, the SIDIAP collects information of approximately primary care centres in Catalonia during the 2006–2017 6 million patients23 25 and is thus representative of the period. In addition, we will be able to determine the time whole Catalan region. The SIDIAP includes information of exposure to MS, that is, from the MS diagnosis until collected by primary care professionals during visits such the diagnosis of cancer. With these data, we will be able as physical measurements, clinical diagnoses, laboratory to evaluate the role of MS in cancer risk and the risk of tests, treatments, referral to specialist, sociodemographic cancer with one or two MS components. Additionally, the and lifestyles information. use of an anonymised and validated databases facilitates the agile retrieval of retrospective data. Our database, Sample size known as the Information System for the Development of In the SIDIAP database, we have over 350 000 patients Research in Primary Care (SIDIAP) (​www.​sidiap.​org),23 with cancer, of which 171 275 correspond to the subtypes includes approximately 6 million people, that is, 80% of considered in the study. Furthermore, we estimate that 2 Puente D, et al. BMJ Open 2019;9:e025365. doi:10.1136/bmjopen-2018-025365 Open access approximately 400 000 patients could be exposed to MS. 5. Fasting glucose levels ≥100 mg/dL. Assuming an OR=1.3 (power of 80%, alpha risk 5%, no For the diagnosis of MS, at least 3 of 5 cardiometabolic losses, 18% controls exposed to MS and four controls parameters are required. per case), we would need a minimum of 939 cases of MS and its components will be used to construct a cancer and 3756 controls for the main objective. This composite variable: 0, 1, 2 and ≥3 (MS) components. study involves all cases in the SIDIAP, and thus, we exceed The first pathological value of one of these variables the minimum cancer cases required. There are more registered in the database will be taken as the reference than 2000 patients for each type of cancer registered in date, and from that moment, it will be considered that a SIDIAP and included in the study, with the exception patient is exposed to this factor in a constant and fixed of Hodgkin’s disease. In this case, we will have approxi- manner until the end of the study. In a sensitivity analysis, mately 725 patients, and assuming an OR=1.3, the power we will consider two measures of parameters separated will be 69%. at least by 2 weeks (maximum 1 year) to ensure that the patient has that pathological component of MS. Study population and inclusion/exclusion criteria We will assume two considerations in relation to the All participants in the SIDIAP database of ≥40 years of age WHO definition of MS27: since we anticipate that waist collected from 1 January 2006 to 31 December 2017. circumference will be mostly unavailable for the majority The case – control study aims to analyse the cases of of individuals, we will also consider a body mass index cancer that have been exposed to MS or to 0, 1 or 2 single >30 kg/m2 as an MS component. Since this represents components of MS and evaluate if the risk of MS on cancer a strong limitation, we will perform a sensitivity analysis is greater than the risk provided by 1 or 2 components. including only those individuals who have a registered Patients with incident cancer between 1 January 2008 and waist circumference measurement in the database. 31 December 2017 will be selected. It is required that the A first diagnosis can indicate the first time a condition is cancer case has to be exposed for a minimum of two years recorded in the data base but not necessarily the moment to the MS; in other words, the onset of exposure to MS from which the patient is exposed to a specific condition. must be at least two years before the diagnosis of cancer. Specifically, this situation is a fact in those cases where the Secondary cancers and metastases will be excluded. The data of registration is in 2006, when the data start to be date of the diagnosis of cancer will be considered the collected in the database. For this reason, we will carry index date. Four controls will be selected for each case, out a sensitivity analysis including only those patients who considering as index date of the control the date of the have the first registration of a component from 2007. selection of the case. The onset of the exposure to MS in the controls, as in the cases, must begin at least two years Cancer case before to index date. Each paired case– control will be of We will use the ICD-10 to define cancer and we will only the same sex and age (± 1 year). consider incident cases. We will select the most preva- The cohort of patients diagnosed with MS selected in lent types of cancer with published evidence of associa- the case–control study will be followed, the time elapsed tion with MS such as colon (ICD-10 code: C18), rectum until the onset of cancer will be evaluated and the cancer- (ICD-10 code: C20), prostate (ICD-10 code: C61), liver free time will be thus calculated and compared by sex. (ICD-10 code: C22), bladder (ICD-10 code: C67), endo- metrium (ICD-10 code: C54), pancreas (ICD-10 code: Study variables C25) and breast (ICD-10 code: C50). Although few MS and components published data are available, we will also include lung For the construction of the variable MS, the criteria cancer (ICD-10 code: C34) and kidney cancer (ICD-10 defined by the International Diabetes Federation Task code: C64) because of their high prevalence. Finally, Force on Epidemiology and Prevention; National Heart, we will include types of cancer for which little evidence Lung, and Blood Institute; American Heart Association; available, which might also be associated with MS such World Heart Federation; International Atherosclerosis as thyroid cancer (ICD-10 code: C73), Hodgkin disease Society; and International Association for the Study of (ICD-10 code: C81), non-Hodgkin lymphoma (ICD-10 Obesity1 26 27 published by Alberti et al in 2009 was used: code: C82–85) and leukaemias (ICD-10 code: C91–95). 1. High blood pressure (defined using the International Statistical Classification of Diseases and Related Health Other covariables Problems, version 10 (ICD-10) codes)): I10–I15 or dis- We will retrieve the following variables from the SIDIAP: pensed pharmacological treatment of any antihyper- sex; age; the MEDEA index ("Mortalidad en áreas tensive drug or blood pressure ≥130/85 mm Hg. pequeñas Españolas y Desigualdades Socioeconómicas 2. Waist circumference ≥102 cm for men and ≥88 cm for y Ambientales": a deprivation index for urban census women. sectors that identifies the areas with the most unfavourable 3. HDL-Cholesterol (High Density Lipoprotein) or drug socioeconomic conditions, categorised in quintiles)28; treatment for reduced HDL-C or blood levels <40 mg/ smoking (non-smoker, smoker and ex-smoker); alcohol dL in men and <50 mg/dL in women. consumption calculated in standard units (the categories 4. Triglycerides) ≥150 mg/dL. are determined by an alcohol calculator incorporated Puente D, et al. BMJ Open 2019;9:e025365. doi:10.1136/bmjopen-2018-025365 3 Open access Table 1 Study variables from the SIDIAP database in Catalonia, 2006–2017 Variables Period Main variable Metabolic syndrome. First diagnosis 2006–2017. (independent) Components: HBP, waist circumference, BMI, HDL, TG and First diagnosis 2006–2017 of 0, 1, 2 MS fasting glucose. components and no diagnosis of 3 MS components. Dependent variable Incident cancers: ICD-10 codes and location. Incident cancer 2008–2017 (at least 2 years of exposure). Covariables Sex, age, the MEDEA index, smoking status, alcohol Collected 2 years before cancer consumption, physical activity, drugs, urban/rural setting, diagnosis number of visits to the GP, number of pregnancies, age at menarche and menopause. MEDEA index: deprivation index for urban census sectors that identifies the areas with the most unfavourable socioeconomic conditions. BMI, body mass index; GP, general practitioner; HDL, high-density lipoprotein; HPB, high blood pressure; ICD-10, International Statistical Classification of Diseases and Related Health Problems, version 10; MS, metabolic syndrome; SIDIAP, Information System for the Development of Research in Primary Care; TG, triglycerides. into the electronic clinical record) (no alcohol, low, 3. We will conduct an analysis with those patients who in moderate and high consumption); physical activity 2006 have not registered any parameter and the first (none, low, moderate and high); use of drugs (ATC classi- registration is in 2007. fication system (Anatomical Therapeutic Chemical Classi- All analyses will be carried out with the statistical pack- fication) and information collected from drugs dispensed ages SPSS V.24 and Stata V.15. in pharmacies); area (rural and urban); number of visits to the primary healthcare centre; number of pregnancies; Patient and public involvement age at menarche; and menopause (yes/no) and its date. The study is based on real world data in which the These data will be collected at least two years before the anonymity and confidentiality of the data are guaranteed. diagnosis of cancer. Even so, although patient are not involved in the devel- A summary of the variables collected from SIDIAP is opment of study, patient involvement will be guaranteed presented in table 1. in the dissemination of data through different channels of communication, adapting the results of the study Statistical analysis to citizen participation and adapting it to the natural Descriptive statistics will be used for each variable to iden- language of citizens/patients. The dissemination of the tify asymmetric distributions. The continuous variables possible effects of the MS on cancer risk can be useful to will be analysed as mean (SD) or median (25th and 75th encourage citizens to reduce MS through and improve- centiles) based on the normality/non-normality of the ment of lifestyles. distribution, and categorical variables will be described as This study is not a randomised clinical trial. percentages. To evaluate baseline differences, the appro- priate statistics will be applied based on the type of vari- able and their distribution (χ2, F-distribution, Student’s Discussion t-distribution, analysis of variance, Mann-Whitney U and This project will contribute new evidence on the associ- Kruskal-Wallis). ation between MS and 14 site-specific cancers in a large For the case–control study, we will carry out a logistic database containing the electronic primary care records regression model adjusted for the potential confounders of approximately 6 million people in Catalonia during described in the covariables section to analyse the risk of the 2006–2017 period. MS on cancer and the risk of cancer comparing the effect Recent studies have suggested that MS might be a risk of MS versus the individual components of MS. A descrip- factor for different cancer sites. However, to date, the tive analysis will determine the time elapsed between role of MS in cancer development is still uncertain. The exposure to MS to cancer event. Kaplan-Meier curve will possible link between MS and cancer has been scarcely be computed by each sex and logrank, and Breslow tests studied in our setting. will be applied to compare curves. MS can be modulated by adopting healthy lifestyles The analysis will be stratified by type of cancer. that reduce obesity, cholesterol and blood pressure. Since Sensitivity analysis: cancer is one of the main causes of mortality worldwide, 1. Two measures will be necessary to consider a value of the possible association with MS could have a significant specific factor as pathological. clinical and financial impact on health services. If the 2. We will conduct an analysis in those cases that waist results of the study show that there is a statistically signif- circumference is registered. icant association, these results will be added to existing 4 Puente D, et al. BMJ Open 2019;9:e025365. doi:10.1136/bmjopen-2018-025365 Open access recommendations on cancer, the risk of MS as a whole Open access This is an open access article distributed in accordance with the rather than only the risk originating from individual MS Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, components. The training of primary care physicians and and license their derivative works on different terms, provided the original work is nurses will be enhanced by the results of this study, specif- properly cited, appropriate credit is given, any changes made indicated, and the use ically with regard to cancer risk factors and the reduction is non-commercial. See: http://​creativecommons.​org/​licenses/​by-​nc/​4.​0/. of MS by means of healthy lifestyles. We foresee the following potential limitations in this study: the possible underestimation of the prevalence of References some diseases and a left truncation, that is, the onset of 1. Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic some diseases and risk factors will remain unknown since syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National the database starts in 2005, when in reality the diagnosis Heart, Lung, and Blood Institute; American Heart Association; of MS or some of its components might precede this date. World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation In addition, we need to take into account the possible 2009;120:1640–5. under-recording and quality of variables in the primary 2. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome care setting and the lack of data on diet, a lifestyle item among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002;287:356–9. that can affect MS components and cancer risk. Data 3. Fernández-Bergés D, Cabrera de León A, Sanz H, et al. 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The metabolic mises this potential bias. syndrome and cancer: Is the metabolic syndrome useful for predicting cancer risk above and beyond its individual components? Diabetes Metab 2015;41:463–9. Author affiliations 7. Chen Y, Zhang L, Liu W, et al. Case-control study of metabolic 1 Fundació Institut Universitari per a la recerca a l'Atenció Primària de Salut Jordi syndrome and ovarian cancer in Chinese population. Nutr Metab Gol i Gurina (IDIAPJGol), Barcelona, Spain 2017;14:21. 2 Foundation Network of Study Groups of Diabetes in Primary Care (redGDPS), 8. Esposito K, Chiodini P, Colao A, et al. Metabolic syndrome and risk Sabadell, Spain of cancer: a systematic review and meta-analysis. Diabetes Care 3 2012;35:2402–11. Primary Care Centre Sant Martí de Provençals. Primary Care Management 9. Fiori E, Lamazza A, De Masi E, et al. Association of liver steatosis Barcelona Ciutat, Catalan Institute of Health, Barcelona, Spain with colorectal cancer and adenoma in patients with metabolic 4 CAP Salou, Institut Català de la Salut, Tarragona, Spain syndrome. Anticancer Res 2015;35:2211–4. 5 Universitat Autònoma de Barcelona, Bellaterra, Cerdanyola del Vallès, Spain 10. Montella M, Di Maso M, Crispo A, et al. Metabolic syndrome and the risk of urothelial carcinoma of the bladder: a case-control study. BMC Cancer 2015;15:720. Acknowledgements We would like to thank the Catalan Institute of Health and 11. Esposito K, Chiodini P, Capuano A, et al. Effect of metabolic SIDIAP, which provided the database for the study. We would also like to thank syndrome and its components on prostate cancer risk: meta- Dr Núria Malats (Centro Nacional de Investigaciones Oncológicas, Madrid, Spain) analysis. J Endocrinol Invest 2013;36:132–9. and Dr Heinz Freisling (International Agency for Research on Cancer, Lyon, France) 12. Gacci M, Russo GI, De Nunzio C, et al. Meta-analysis of metabolic for their contribution in the study design. We would like to thank Eulàlia Farré for syndrome and prostate cancer. Prostate Cancer Prostatic Dis English proofreading. 2017;20:146–55. 13. Gatta G, van der Zwan JM, Casali PG, et al. Rare cancers are Contributors All authors contributed to the design, revised the study protocol not so rare: the rare cancer burden in Europe. Eur J Cancer and approved the final version. DP, TL-J and TD-S drafted the study protocol. DP 2011;47:2493–511. obtained the funding as team leader. All authors have read and approved the final 14. Li C, Liu P, Liu L, et al. Metabolic syndrome in hematologic manuscript. malignancies survivors: a meta-analysis. Med Oncol 2015;32:422. 15. Bhaskaran K, Douglas I, Forbes H, et al. Body-mass index and risk of Funding The project received a research grant from the Carlos III Institute of Health, 22 specific cancers: a population-based cohort study of 5·24 million Ministry of Economy and Competitiveness (Spain), awarded on the 2017 call under UK adults. Lancet 2014;384:755–65. the Health Strategy Action 2013–2016 of the National Research Program oriented to 16. Stocks T, Lukanova A, Johansson M, et al. Components of the Societal Challenges, within the Technical, Scientific and Innovation Research National metabolic syndrome and colorectal cancer risk; a prospective study. Int J Obes (Lond. 2008;32:304–14. Plan 2013–2016 (reference PI17/00914), cofunded with European Union ERDF funds 17. Stocks T, Van Hemelrijck M, Manjer J, et al. Blood pressure and risk (European Regional Development Fund). TD-S is funded by the Department of Health of cancer incidence and mortality in the Metabolic Syndrome and of the Generalitat de Catalunya, awarded on the 2016 call under the Strategic Plan Cancer Project. Hypertension 2012;59:802–10. for Research and Innovation in Health (PERIS) 2016-2020, modality incorporation of 18. Mendonça FM, de Sousa FR, Barbosa AL, et al. Metabolic syndrome scientists and technologists, with reference SLT002/16/00308. and risk of cancer: which link? Metabolism 2015;64:182–9. 19. Abbasi F, Brown BW, Lamendola C, et al. Relationship between Competing interests None declared. obesity, insulin resistance, and coronary heart disease risk. J Am Coll Ethics approval The protocol of the study was approved by IDIAP’s clinical Cardiol 2002;40:937–43. research ethics committee. 20. Jafri H, Alsheikh-Ali AA, Karas RH. Baseline and on-treatment high- density lipoprotein cholesterol and the risk of cancer in randomized Provenance and peer review Not commissioned; externally peer reviewed. controlled trials of lipid-altering therapy. J Am Coll Cardiol 2010;55:2846–54. Author note The data and variables of study are included in the electronic primary 21. Esposito K, Chiodini P, Capuano A, et al. Metabolic syndrome and care records included in the Information System for Research in Primary Care endometrial cancer: a meta-analysis. Endocrine 2014;45:28–36. (SIDIAP) (​www.​sidiap.​org) and registered in the Catalan Authority of Data Protection 22. Kriegmair MC, Mandel P, Porubsky S, et al. Metabolic Syndrome (APDCAT). This anonymous database, described in the methodology section, is used Negatively Impacts the Outcome of Localized Renal Cell Carcinoma. for research projects. Horm Cancer 2017;8:127–34. Puente D, et al. BMJ Open 2019;9:e025365. doi:10.1136/bmjopen-2018-025365 5 Open access 23. 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Felícitas Domínguez-Berjón M, Borrell C, Cano-Serral G, et al. Prim Care 2011;19:135–45. Construcción de un índice de privación a partir de datos censales 26. Expert Panel on Detection, Evaluation, and Treatment of High Blood en grandes ciudades españolas (Proyecto MEDEA). Gac Sanit Cholesterol in Adults. Executive Summary of The Third Report of The 2008;22:179–87. 6 Puente D, et al. BMJ Open 2019;9:e025365. doi:10.1136/bmjopen-2018-025365