RAS intervention early in the course of proteinuric DKD is more beneficial than late intervention in delaying ESRD.

Aims Angiotensin receptor blockers (ARBs) are renoprotective and targeted to blood pressure. However, ARBs have multiple other (off‐target) effects which may affect renal outcome. It is unknown whether on‐target and off‐target effects are congruent within individuals. If not, this variation in short term effects may have important implications for the prediction of individual long term renal outcomes. Our aim was to assess intra‐individual variability in multiple parameters in response to ARBs in type 2 diabetes. Methods Changes in systolic blood pressure (SBP), albuminuria, potassium, haemoglobin, cholesterol and uric acid after 6 months of losartan treatment were assessed in the RENAAL database. Improvement in predictive performance of renal outcomes (ESRD or doubling serum creatinine) for each individual using ARB‐induced changes in all risk markers was assessed by the relative integrative discrimination index (RIDI). Results SBP response showed high variability (mean –5.7 mmHg, 5th to 95th percentile –36.5 to +24.0 mmHg) between individuals. Changes in off‐target parameters also showed high variability between individuals. No congruency was observed between responses to losartan in multiple parameters within individuals. Using individual responses in all risk markers significantly improved renal risk prediction (RIDI 30.4%, P < 0.01) compared with using only SBP changes. Results were successfully replicated in two independent trials with irbesartan, IDNT and IRMA‐2. Conclusions In this post hoc analysis we showed that ARBs have multiple off‐target effects which vary between and within individuals. Combining all ARB‐induced responses beyond SBP provides a more accurate prediction of who will benefit from ARB therapy. Prospective trials are required to validate these findings.

Based on the RADAR/JAPAN study, with short-term changes in risk markers, atrasentan is expected to decrease renal risk without increased risk of heart failure. Within this population albuminuria responders appear to contribute to the predicted improvements, whereas non-responders showed no benefit. The ongoing hard outcome trial (SONAR) in type 2 diabetic patients with >30% albuminuria reduction to atrasentan will allow us to assess the validity of these predictions.