title: The renal protective effect of angiotensin receptor blockers depends on intra-individual response variation in multiple risk markers.
abstract: OBJECTIVE
  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.
authors: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors: Bauke
authors: http://orcid.org/0000-0002-2577-4876
authors: B
authors: Schievink
authors: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors: Dick
authors: D
authors: de Zeeuw
authors: Department of Medical Endocrinology, Rigshospitalet, University of Copenhagen, Copenhagen.|Department of Medical Endocrinology, Rigshospitalet, HEALTH, Aarhus University, Aarhus, Denmark.
authors: Hans-Henrik
authors: HH
authors: Parving
authors: Steno Diabetes Center, Gentofte, NNF Center for Basic Metabolic Research University of Copenhagen, Copenhagen, HEALTH, Aarhus University, Aarhus.
authors: Peter
authors: P
authors: Rossing
authors: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors: Hiddo Jan
authors: HJ
authors: Lambers Heerspink
mesh_terms: D000328:Adult; D000368:Aged; D000419:Albuminuria / Q000188:drug therapy; D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D015415:Biomarkers; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D003404:Creatinine / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000503:physiopathology; D005260:Female; D006454:Hemoglobins / Q000187:drug effects; D006801:Humans; D007206:Individuality; D000077405:Irbesartan; D007668:Kidney / Q000187:drug effects*; D007676:Kidney Failure, Chronic / Q000517:prevention & control*; D019808:Losartan / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D011188:Potassium / Q000097:blood*; D011446:Prospective Studies; D012307:Risk Factors; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use; D014527:Uric Acid / Q000097:blood
chemical_list: D057911:Angiotensin Receptor Antagonists; D015415:Biomarkers; D001713:Biphenyl Compounds; D006454:Hemoglobins; D013777:Tetrazoles; D014527:Uric Acid; D002784:Cholesterol; D003404:Creatinine; D000077405:Irbesartan; D019808:Losartan; D011188:Potassium
keywords: angiotensin receptor blockers; personalized medicine; renal disease; type 2 diabetes