IDF21-0454 Time-varying associations of long-term use of RASi use and all-site Cancers and mortality in type 2 diabetes (2002-2019)

Background: Cancer has replaced cardiovascular disease (CVD) as the leading cause of death in many countries. Type 2 diabetes (T2D) is associated with increased risk of cancer. Renin-angiotensin system inhibitors (RASi) are prescribed for hypertension and organ-protection, but may have pluripotent, anti-cancer effects. Evidence for a link between RASi and cancer remains inconclusive and prior studies did not account for time-varying and cumulative treatment effects. Aim: To evaluate the time-varying associations of RASi use with incidence of all-site cancer, diabetes-related cancers, and cancer-specific mortality in patients with T2D. Method: We conducted a prospective cohort study with new-user design in the territory-wide Hong Kong Diabetes Surveillance Database including 558,177 Chinese patients with comprehensive baseline data in the Risk Assessment and Management Programme for Diabetes Mellitus (RAMP-DM) module between 2002 and 2018, with follow-up till 31 December 2019. We used principal discharge diagnoses International Classification of Diseases, Ninth Revision (ICD-9) codes to define all-site, diabetes-related and top site-specific cancers (liver, lung, colorectal, breast, prostate and pancreas). Causes of death was defined by ICD-10 codes. Using propensity score with overlap weighting, we compared risk of cancer events and related mortality in new-users of RASi (angiotensin-converting-enzyme-inhibitor [ACEi] and angiotensin-receptor-blocker [ARBs]) with non-RASi users. We further compared against new-users of calcium-channel-blockers (CCBs) as active comparator. Results: Amongst 253,491 patients with T2D eligible for this analysis, 133,730 (52.8%) were incident-RASi users (73,596 ACEi-only users, 21,103 ARBs-only users, and 39,031 ACEi/ARBs users), and 119,761 (47.2%) were non-RASi users. There were 8,246 (6.2%) and 6,784 (5.7%) all-site cancers in RASi and non-RASi users over a mean follow-up of 6.5 years with respective crude-incidence rate of 9.2 and 9.1 events per-1000-person-years. Compared with non-RASi users, time-varying RASi exposure was associated with lower risk of all-site cancer (HR=0.76, 95% CI: 0.74-0.79), diabetes-related cancer (HR=0.79, 95% CI: 0.75-0.84). All-cause mortality (HR=0.52, 95% CI: 0.50-0.53), cancer-specific mortality (HR=0.50, 95% CI: 0.47-0.53), and diabetes-related cancer mortality (HR=0.49, 95% CI: 0.45-0.54). Use of ARBs was associated with lower risk of cancer-specific mortality as compared with ACEi (HR=0.77, 95% CI: 0.66-0.91). The reduced risk associations of RASi with all-site cancer and cancer-related mortality was non-time dependent and remained stable throughout the whole follow-up period with prevention of 2.6 (95% CI: 2.3-3.0) and 2.2 (95% CI: 2.0-2.5) events per-1000-person-years, respectively. Compared with incident users of CCBs, the reduced risk association of RASi with all-cause and cancer-specific mortality were most evident in young adults with T2D. Discussion: Long-term use of RASi was independently associated with reduced risk of cancer, including diabetes-related cancers and cancer-specific mortality in T2D. These associations appeared to be more robust with ARBs when compared directly with ACEi.