title: Estimated GFR decline as a surrogate end point for kidney failure: a post hoc analysis from the Reduction of End Points in Non-Insulin-Dependent Diabetes With the Angiotensin II Antagonist Losartan (RENAAL) study and Irbesartan Diabetic Nephropathy Trial (IDNT).
abstract: BACKGROUND
  A doubling of serum creatinine value, corresponding to a 57% decline in estimated glomerular filtration rate (eGFR), is used frequently as a component of a composite kidney end point in clinical trials in type 2 diabetes. The aim of this study was to determine whether alternative end points defined by smaller declines in eGFR would improve the statistical power of these clinical trials.
  
  
  METHODS
  Post hoc analyses of 2 multinational randomized controlled trials (Reduction of End Points in Non-Insulin-Dependent Diabetes With the Angiotensin II Antagonist Losartan [RENAAL] and Irbesartan Diabetic Nephropathy Trial [IDNT]) that assessed the treatment effect of the angiotensin receptor blockers (ARBs) losartan and irbesartan.
  
  
  METHODS
  1,513 (RENAAL) and 1,715 (IDNT) adult patients with type 2 diabetes and nephropathy.
  
  
  METHODS
  Established versus alternative end points defined as a confirmed doubling of serum creatinine level versus confirmed eGFR decline of 57%, 40%, 30%, or 20% as a component of a composite end point of end-stage renal disease or eGFR < 15mL/min/1.73m(2).
  
  
  RESULTS
  Numbers of patients reaching end points, precision (standard error), and significance (z score) of ARB treatment effect (HR) during follow-up.
  
  
  RESULTS
  Lesser eGFR declines resulted in a greater number of patients reaching end points in both treatment groups and lower standard error of the HR, but the effect on z score was counterbalanced by attenuation of the HR. When calculating the eGFR decline from month 3, attenuation of the HR was less pronounced.
  
  
  CONCLUSIONS
  Post hoc analysis.
  
  
  CONCLUSIONS
  Despite increases in precision of the treatment effect, eGFR declines less than a doubling of serum creatinine value did not consistently improve statistical power of the clinical trials due to attenuation of the treatment effect. Attenuation of the treatment effect appears to be due in part to acute effects of ARBs on eGFR. These findings should be taken into account when using lesser eGFR declines as alternative end points for clinical trials.
authors.affiliation: Department of Clinical Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. Electronic address: h.j.lambers.heerspink@umcg.nl.
authors.forename: Hiddo J
authors.initials: HJ
authors.lastname: Lambers Heerspink
authors.affiliation: Department of Clinical Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Misghina
authors.initials: M
authors.lastname: Weldegiorgis
authors.affiliation: Division of Nephrology, Tufts Medical Center, Boston, MA.
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Inker
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Ron
authors.initials: R
authors.lastname: Gansevoort
authors.affiliation: Department of Medical Endocrinology, Rigshospitalet, University of Copenhagen, and the Faculty of Health Sciences, Aarhus University, Aarhus, Denmark.
authors.forename: Hans-Henrik
authors.initials: HH
authors.lastname: Parving
authors.affiliation: Department of Nephrology, Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Jamie P
authors.initials: JP
authors.lastname: Dwyer
authors.affiliation: Division of Nephrology, Tufts Medical Center, Boston, MA.
authors.forename: Hasi
authors.initials: H
authors.lastname: Mondal
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
authors.forename: Josef
authors.initials: J
authors.lastname: Coresh
authors.affiliation: University of Utah, Salt Lake City, UT.
authors.forename: Tom
authors.initials: T
authors.lastname: Greene
authors.affiliation: Division of Nephrology, Tufts Medical Center, Boston, MA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Levey
authors.affiliation: Department of Clinical Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: de Zeeuw
mesh_terms: D000368:Aged; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D004311:Double-Blind Method; D005260:Female; D005919:Glomerular Filtration Rate / Q000502:physiology*; D006801:Humans; D000077405:Irbesartan; D007676:Kidney Failure, Chronic / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D019808:Losartan / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D015415:Biomarkers; D001713:Biphenyl Compounds; D013777:Tetrazoles; D000077405:Irbesartan; D019808:Losartan
keywords: Type 2 diabetes; angiotensin receptor blocker; clinical trial; disease progression; end-stage renal disease; kidney disease trajectory; kidney end point; nephropathy; renal function