Association between Allopurinol and Cardiovascular Events and All-Cause Mortality in Diabetes—A Population-Based Cohort Study

Abstract

Higher uric acid (UA) is associated with cardiovascular events and mortality. Allopurinol, a UA-lowering therapy, may reduce risk of these outcomes. Despite the high prevalence of elevated UA in diabetes, the association between allopurinol and cardiovascular events and mortality in diabetes is unclear. A population-based cohort was constructed using administrative data in Ontario, Canada. Subjects with diabetes entered on receipt of a new prescription for allopurinol after age 66 (April 1/2002-March 31/2012) and were followed until a composite of all-cause mortality, stroke, myocardial infarction or revascularization. A Cox proportional hazards model was used for each sex, with time-varying allopurinol exposure modeled as yes/no, dose categories and cumulative dose. Over a median [IQR] follow-up time of 4.7[1.8-7.8] years, the composite outcome occurred in 16,262/23,103 males and 10,566/15,313 females. Allopurinol exposure was associated with a reduction in the composite outcome in a dose-response manner but there was no cumulative dose effect (Table 1). Any allopurinol exposure and higher allopurinol doses were associated with reduced cardiovascular events and mortality in a large diabetes cohort. Potential mechanisms include an acute reduction of oxidative stress and endothelial dysfunction. Table 1: Hazard Ratios by Sex.Males (n=23,103)Females (n=15,313)Allopurinol ExposureUnadjusted HRAdjusted HRUnadjusted HRAdjusted HRExposed time v. unexposed time0.82 (0.79, 0.84)0.77 (0.75, 0.80)0.88 (0.85, 0.92)0.81 (0.78, 0.84)Dose categories0mg---->0 and ≤100mg1.03 (0.99, 1.08)0.84 (0.80, 0.88)1.(1.01, 1.12)0.86 (0.81, 0.90)>100 and ≤200mg0.82 (0.78, 0.85)0.75 (0.72, 0.78)0.83 (0.79, 0.87)0.76 (0.72, 0.80)>200mg0.71 (0.68, 0.74)0.75 (0.72, 0.78)0.78 (0.73, 0.82)0.81 (0.77, 0.86)Cumulative Dose (per 100g increase)0.99 (0.98, 1.00)1.00 (0.99, 1.01)0.99 (0.98, 1.01)0.99 (0.98, 1.00) Disclosure A. Weisman: None. G.A. Tomlinson: None. L. Lipscombe: None. B.A. Perkins: Advisory Panel; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH, Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc., Abbott. Speaker's Bureau; Self; Abbott, Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Insulet Corporation. Speaker's Bureau; Self; Insulet Corporation, Dexcom, Inc.. G.A. Hawker: None.