The renal protective effect of angiotensin receptor blockers depends on intra-individual response variation in multiple risk markers

Abstract

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, 5(th) to 95(th) 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.

Keywords: angiotensin receptor blockers; personalized medicine; renal disease; type 2 diabetes.

Figure 1

Discordance between ARB-induced responses in multiple parameters within individual patients. A) Overview of the variation in risk marker response in the total population (inter-individual variability). The thick short line in the boxplots indicates the median and the dot the mean change. Box and whiskers represent interquartile range and 5^th to 95^th percentile, respectively. B) Radar plot showing the overall response (bold black outer line with numbers indicating mean values) for each risk marker in RENAAL. Dashed grey lines indicate 95% confidence interval. C) Radar plots showing discordance of the different responses within individuals. For example, the red lines and numbers indicate the risk marker responses in blood pressure responders. The black outer line represents the response in the overall population as explained in B. The overlap between each of the responder populations (colored line) vs. the overall population (black line) indicates that responses within an individual are discordant. N underneath radar plots indicate number of responders in each figure. SBP, systolic blood pressure; ACR, albuminuria; K, potassium; Hb, haemoglobin; chol, cholesterol; UA, uric acid