Associations between Allopurinol and Cardiovascular and Renal Outcomes in Diabetes

Diabetes is a leading cause of cardiovascular and kidney disease, and novel therapies to reduce these adverse diabetes outcomes are urgently required. Allopurinol, a uric acid-lowering therapy traditionally used for the treatment of gout, may reduce mortality and cardiovascular and kidney disease through reductions in oxidative stress and improved endothelial function, but this has not been well-studied in diabetes. Through three related projects, this thesis examines the associations between allopurinol and all-cause mortality, cardiovascular and renal outcomes in individuals with diabetes using population-based administrative health care data in Ontario, Canada. The first project examined patterns of allopurinol use and their predictors, to inform the design of subsequent studies. In 38,416 individuals with diabetes newly prescribed allopurinol, discontinuation and interruption of allopurinol were common. Female sex and greater severity of gout were associated with worse adherence. The second project evaluated the association between allopurinol-exposed time and all-cause mortality and cardiovascular outcomes in 38,416 new allopurinol users with diabetes. Allopurinol-exposed time was associated with a reduced risk of the primary composite outcome of all-cause mortality, atherothrombotic cardiovascular events (myocardial infarction, revascularization, stroke), or heart failure, which was primarily driven by a reduction in all-cause mortality. However, healthy user bias could not be completely excluded. The third project evaluated the association between allopurinol use and progression of chronic kidney disease (CKD) or development of end-stage renal disease (ESRD). In 5937 individuals with a gout flare and Stages 1 to 3 CKD at baseline (1911 with diabetes), renal outcomes did not differ between allopurinol users and non-users after weighting by the inverse probability of treatment. Based on the thesis results, allopurinol may reduce mortality and atherothrombotic cardiovascular events in individuals with diabetes, but does not appear to reduce heart failure, CKD progression, or development of ESRD. Defining allopurinol exposure in pharmacoepidemiology studies is challenging due to frequent interruptions and discontinuation. Thus, study designs incorporating time-varying exposure and time-varying confounders may be more robust. A clinical trial designed to evaluate the effect of allopurinol on atherothrombotic cardiovascular events in individuals with diabetes and hyperuricemia is strongly justified.Ph.D