Non-Time Varying and Cumulative Effects of Long-Term Use of Renin-Angiotensin System Inhibitor on All-Site Cancers and Mortality in the Hong Kong Diabetes Surveillance Database (2002-2019)

Abstract

Background: In many countries, cancer is replacing cardiovascular disease as a leading causes of death. Type 2 diabetes (T2D) is associated with increased risk of cancer. Patients with T2D have activated renin-angiotensin-system (RAS) although the association of RAS inhibitors (RASi) and cancer risk remains inconclusive in T2D. Methods: We conducted a prospective cohort study with new-user design in 253,491 Chinese patients with T2D in 2002-2019. We used longitudinal real-world-data from a territory-wide electronic medical record system and evaluated the associations of time-varying RASi use (angiotensin-converting-enzyme-inhibitor [ACEi] and angiotensin-receptor-blocker [ARBs]) with all-site cancer, diabetes-related cancers, and cancer-specific mortality with or without comparison with new-users of calcium-channel-blockers (CCBs). Findings: After excluding prevalent RASi users, amongst the eligible patients (n=253,491), 133,730 (52·8%) were new-RASi and 119,761 (47·2%) were non-RASi users during 6·5 years follow-up period. Time-varying RASi use was associated with lower risk of all-site cancer (HR=0·76, 95%CI: 0·74-0·79), diabetes-related cancer (HR=0·79, 0·75-0·84), cancer-specific mortality (HR=0·50, 0·47-0·53), and diabetes-related cancer mortality (HR=0·49, 0·45-0·54) versus non-RASi. ARBs use was associated with lower risk of cancer-specific mortality versus ACEi (HR=0·77, 0·66-0·91). Use of RASi was non-time-varying with an estimated prevention of 2·6 (95% CI: 2·3-3·0) all-site cancer events per-1000-person-years and 2·2 (95%CI: 2·0-2·5) cancer-related mortality per-1000-person-years. The reduced risk associations of RASi with all-cause and cancer-specific mortality were most evident in young adults versus new-CCBs users. Interpretation: Long-term RASi use was independently associated with lower cancer risk in T2D, including diabetes-related cancers and cancer-specific mortality, with stronger associations in users of ARBs than ACEi. Funding Information: Dr. Aimin Yang was supported by a CUHK Impact-Research-Fellowship Scheme. Declaration of Interests: JCNC has received research grants and/or honoraria for consultancy or giving lectures, from AstraZeneca, Bayer, Boehringer Ingelheim, Eli-Lilly, Hua Medicine, Lee Powder, Merck Serono, Merck Sharp & Dohme, Pfizer and Sanofi. APSK has received research grants and/or speaker honoraria from Abbott, Astra Zeneca, Bayer, Boehringer Ingelheim, Eli-Lilly, Merck Serono, Nestle, Novo Nordisk, Pfizer and Sanofi. AOYL has served as a member of advisory panel for Amgen, AstraZeneca, Boehringer Ingelheim and Sanofi and received research support from Amgen, Asia Diabetes Foundation, Bayer, Boehringer Ingelheim, Lee’s Pharmaceutical, MSD, Novo Nordisk, Roche, Sanofi, Sugardown Ltd, Takeda. None of these relationships had any influence on the content of the present manuscript. RCWM has received research funding from AstraZeneca, Bayer, Merck Sharp & Dohme, Novo Nordisk, Pfizer and Tricida Inc. for carrying out clinical trials, and has received speaker honorarium or consultancy in advisory boards from AstraZeneca, Bayer and Boehringer Ingelheim. All proceeds have been donated to the Chinese University of Hong Kong to support diabetes research. Other authors have no conflicts of interest to disclose. Ethics Approval Statement: Ethical approval was obtained from the Joint Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee for analysis and reporting of anonymized data.