Abstract

BACKGROUND: Diabetes confers a two times excess risk of cardiovascular disease, yet predicting individual risk remains challenging. The effect of total microvascular disease burden on cardiovascular disease risk among individuals with diabetes is unknown. METHODS: A population-based cohort of patients with type 2 diabetes from the UK Clinical Practice Research Datalink was studied (n=49 027). We used multivariable Cox models to estimate hazard ratios (HRs) for the primary outcome (the time to first major cardiovascular event, which was a composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal ischaemic stroke) associated with cumulative burden of retinopathy, nephropathy, and peripheral neuropathy among individuals with no history of cardiovascular disease at baseline. FINDINGS: During a median follow-up of 5·5 years, 2822 (5·8%) individuals experienced a primary outcome. After adjustment for established risk factors, significant associations were observed for the primary outcome individually for retinopathy (HR 1·39, 95% CI 1·09-1·76), peripheral neuropathy (1·40, 1·19-1·66), and nephropathy (1·35, 1·15-1·58). For individuals with one, two, or three microvascular disease states versus none, the multivariable-adjusted HRs for the primary outcome were 1·32 (95% CI 1·16-1·50), 1·62 (1·42-1·85), and 1·99 (1·70-2·34), respectively. For the primary outcome, measures of risk discrimination showed significant improvement when microvascular disease burden was added to models. In the overall cohort, the net reclassification index for USA and UK guideline risk strata were 0·036 (95% CI 0·017-0·055, p<0·0001) and 0·038 (0·013-0·060, p<0·0001), respectively. INTERPRETATION: The cumulative burden of microvascular disease significantly affects the risk of future cardiovascular disease among individuals with type 2 diabetes. Given the prevalence of diabetes globally, further work to understand the mechanisms behind this association and strategies to mitigate this excess risk are warranted. FUNDING: Circulation Foundation.