Mediation analysis for estimating cardioprotection of longitudinal RAS inhibition beyond lowering blood pressure and albuminuria in type 1 diabetes

Abstract

PurposeWe assessed the extent of cardiovascular benefit of renin–angiotensin system (RAS) inhibition beyond lowering blood pressure (BP) and albuminuria in type 1 diabetes (T1D). MethodsThis cohort study included 605 T1D participants from the Pittsburgh Epidemiology of Diabetes Complications study without baseline coronary artery disease (CAD). Participant follow-up extended through 25 years. We implemented marginal structural models to estimate total effect of and controlled direct effect by isolating the role of BP or albuminuria in mediating the relation between RAS inhibitors and CAD. ResultsTotal effect of longitudinal RAS inhibition treatment was associated with 38% decreased CAD risk (HR [95% CI]: 0.62 [0.23, 1.77]). The controlled direct effect of RAS inhibition was a 27% risk reduction (HR: 0.73 [0.20, 2.59]) when isolating the role of BP and 26% risk reduction (HR: 0.74 [0.16, 3.35]) when isolating the role of albuminuria. The mediation proportion for each 10 mm Hg systolic BP and each 1 log unit of albumin excretion rate were 34% and 37%, respectively. ConclusionOur findings suggest that BP regulation and albuminuria reduction can only partially explain cardiovascular benefit of RAS inhibition on CAD in T1D, supporting the assertion that RAS inhibitors provide additional cardioprotection beyond lowering BP and albuminuria.