Author Manuscript Published OnlineFirst on July 10, 2020; DOI: 10.1158/1055-9965.EPI-19-1051 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 TITLE PAGE 2 Full title: Chondroitin sulphate and glucosamine use depend on non-steroidal anti- 3 inflammatory drugs use to modify the risk for colorectal cancer. 4 Running title: Colorectal cancer and chondroitin sulphate and glucosamine 5 Authors: Gemma Ibáñez-Sanz1,2,3,4; Elisabet Guinó 1,3,4; Rosa Morros 5,6,7; María Ángeles 6 Quijada-Manuitt8,9; Luisa Carmen de la Peña-Negro1,2,10; Victor Moreno1,3,4,11* 7 Affiliations 8 1Oncology Data Analytics Program, Institut Català d’Oncologia, Hospitalet de Llobregat, Spain. 9 2 Servei d’Aparell Digestiu, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Spain. 10 3Colorectal Cancer Group, programa ONCOBELL, Institut d'Investigació Biomèdica de Bellvitge 11 (IDIBELL), Hospitalet de Llobregat, Spain 12 4Consorcio de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), 13 Madrid, Spain. 14 5Departament de Farmacologia, Terapèutica i Toxicologia, Universitat Autònoma de Barcelona, 15 Barcelona, Spain 16 6Institut Català de la Salut (ICS), Spain 17 7Fundació Institut Universitari per a la Recerca en Atenció Primària de Salut Jordi Gol i Gurina 18 (IDIAP Jordi Gol) 19 8Servei de Farmacologia Clínica, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. 20 9Departament de Patologia i Terapèutica Experimental, Unitat Docent Campus de Bellvitge, 21 Universitat de Barcelona, L’Hospitalet de Llobregat, Spain 22 10Servei d’Aparell Digestiu, Hospital de Viladecans, Viladecans, Spain. 23 11Department de Ciències clíniques, Facultat de medicina i Ciències de la salut, Universitat de 24 Barcelona, Barcelona, Spain. 25 26 Abbreviations: ATC: Anatomical Therapeutic Chemical code; ASA: acetylsalicylic acid; BMI: 27 body mass index; CRC: colorectal cancer; CS: chondroitin sulphate; G: glucosamine; NSAID: 28 non-steroidal anti-inflammatory drugs. 29 30 Correspondence to: 31 Victor Moreno 32 Cancer Prevention and Control Unit, Catalan Institute of Oncology 33 Av. Gran Via, 199-203 34 08908 L’Hospitalet de Llobregat, Barcelona, SPAIN 35 Email: [email protected] 36 Telephone: +932607186 37 Fax: +932607956 38 39 40 CONFLICT OF INTEREST STATEMENT 41 The authors received funding from Bioibérica, S.A.U. to study epidemiological evidence of 42 drugs associated to CRC. The authors acted with complete independence of this company and 43 it has not been involved in the preparation of the manuscript. 44 1 Downloaded from cebp.aacrjournals.org on September 25, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 10, 2020; DOI: 10.1158/1055-9965.EPI-19-1051 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 45 ABSTRACT 46 Background: A safe and effective colorectal cancer (CRC) chemoprevention agent remains to 47 be discovered. There is little evidence regarding the protective effect of chondroitin sulphate 48 and glucosamine on CRC. We aimed to assess the association between CRC risk and the use of 49 chondroitin sulphate and glucosamine using a large cohort with dispensed data. 50 Methods: We performed population-based case-control study in Catalonia using primary care 51 reimbursed medication records (SIDIAP database). The study included 25,811 cases with an 52 incident diagnosis of CRC and 129,117 matched controls between 2010 and 2015. 53 Results: The prevalence of ever use was 9.0% (n=13,878) for chondroitin sulphate, 7.3% 54 (n=11,374) for glucosamine and 35% for regular use of NSAID (n=45,774). A decreased risk of 55 CRC was observed among chondroitin sulphate (OR: 0.96, 95%CI 0.91-1.01), glucosamine users 56 (OR: 0.92, 95%CI 0.87-0.97), and concurrent use of chondroitin sulphate and glucosamine (OR: 57 0.83, 95% CI: 0.70-0.98). Especially for glucosamine, there was a dose-response association 58 regarding duration and cumulative dose. The analysis stratified by simultaneous use with 59 NSAIDs showed that these drugs used without NSAIDs do not reduce risk (OR: 1.06, 95%CI 60 0.74-1.51). However, they may have a synergistic protective effect when used with other 61 NSAIDs (OR=0.80, 95%CI: 0.72-0.88). 62 Conclusion: This study does not provide strong support for an independent protective 63 association of chondroitin sulphate or glucosamine on CRC risk in our population. However, 64 these drugs may have a synergistic beneficial effect among NSAIDs users. 65 Impact: chondroitin sulphate or glucosamine may contribute to the protective effect of NSAID 66 use in CRC. 67 68 KEY WORDS: Colorectal cancer; Chemoprevention; Glucosamine; Chondroitin sulphate; 69 Nonsteroidal anti-inflammatory drugs. 70 71 2 Downloaded from cebp.aacrjournals.org on September 25, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 10, 2020; DOI: 10.1158/1055-9965.EPI-19-1051 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 72 INTRODUCTION 73 A large body of evidence has shown that nonsteroidal anti-inflammatory drugs (NSAIDs), 74 particularly acetylsalicylic acid (ASA), reduce the risk of colorectal cancer (CRC) and 75 adenomas.(1-4) Though the exact mechanism of action of NSAIDs in cancer prevention is 76 unclear, the inhibition of production of prostaglandins by supressing cyclooxygenase-2 (COX-2) 77 might be at least partly responsible for their chemopreventive effects. This COX-2 inactivation, 78 which is irreversible with ASA and reversible with NSAIDs, has been shown to decrease tumour 79 growth and angiogenesis.(5-8) However, NSAIDs are not generally recommended in average- 80 risk population to prevent CRC since COX-1 and 2 inhibitions increase the risk of 81 gastrointestinal complications and cardiovascular disease.(2,9) 82 Glucosamine (G) and chondroitin sulphate (CS), sometimes consumed in combination, are 83 commonly used in osteoarthritis to alleviate pain and inflammation.(10) Recent evidence 84 suggests that G and CS supplements could reduce CRC risk.(11-15) These drugs have been 85 shown to reduce the nuclear factor κβ (NF-kβ) translocation which has a clear role in the 86 coordination of immune responses, cell-cycle regulation and, in tumorigenesis.(16,17) This 87 mechanism may explain the possible chemopreventive effect, while the evidence also suggests 88 that these drugs have a long-term safe profile with few side effects.(18,19) 89 There have been many randomised controlled trials assessing drugs and nutritional agents for 90 the chemoprevention of CRC and adenomatous polyps. To this day there is no solid evidence 91 that other nutrients such as folic acid, calcium, vitamin D, and antioxidants are effective in the 92 chemoprevention of colorectal neoplasia in the general population.(20,21) 93 The United States Preventive Services Task Force (USPSTF), after a careful review of ASA 94 evidence for the prevention of CRC, recommends low-dose ASA use in a specific scenario 95 where not only would prevent the risk of CRC but also cardiovascular disease.(1) The USPSTF’s 96 recommendation for ASA use is in adults from 50 to 69 years who have a life expectancy of at 97 least 10 years, a 10% or greater 10-year cardiovascular risk, are not at increased risk for 98 bleeding, and are willing to take low-dose aspirin daily for at least 10 years.(22) In line with this 99 recommendation, Seaton et al.(23) reported that the subgroup of women who would benefit 100 the most of ASA’s chemoprevention effect would be those with any cardiovascular disease 101 risk, no family history of CRC, or a history of colonoscopy with polypectomy. Though ASA is the 102 agent with more evidence, a general use is not recommended because of its adverse 3 Downloaded from cebp.aacrjournals.org on September 25, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 10, 2020; DOI: 10.1158/1055-9965.EPI-19-1051 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 103 events.(21,24) Safety is particularly important in chemoprevention, as the intake of the drug 104 will be prolonged, thus increasing the possibility of side effects. 105 In this national register-based case-control study, we aimed to examine the association 106 between CRC risk and CS and G since one of the main advantages of G and CS is their safety 107 profile. 108 109 MATERIALS AND METHODS 110 Data source 111 The selection of the subjects was performed using the Information System for Development of 112 Primary Care Research (SIDIAP) database (www.sidiap.org).(25) Study design has been already 113 published.(26,27) Briefly, SIDIAP database comprises clinical information routinely collected by 114 primary care professionals, hospital admissions and dispensed prescriptions since 2005. 115 Exposure to medications is obtained from pharmacies’ claims for reimbursement to the 116 Catalan Institute of Health which is the public system in Catalonia. It provides health care to 117 74% of the population (5.8 million people). The data was obtained on the specific drug 118 prescribed, date and units of the drug withdrawn. Previous studies have evaluated the quality 119 of SIDIAP data to study the epidemiology of health outcomes.(28) 120 Research was performed in accordance with the ethical standards of the institution, and with 121 the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The 122 Ethics Committee for Clinical Research of IDIAP Jordi Gol approved the study protocol. Written 123 informed consent was not obtained from the participating individuals, as the study was based 124 on anonymized data routinely collected and the Ethics Committee cleared that requirement.