title: The albuminuria-lowering response to dapagliflozin is variable and reproducible among individual patients.
abstract: Albuminuria reduction is essential for renal and cardiovascular protection. We characterized the efficacy of dapagliflozin, a sodium-glucose co-transporter 2 inhibitor, on albuminuria. Secondly, we assessed whether the albuminuria-lowering effect varies among patients, and whether this variability in response is reproducible.
  
  
  
  A double-blind, randomized, placebo controlled crossover trial was conducted. Patients with type 2 diabetes and albumin:creatinine ratio > 100 mg/g on a stable dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) were enrolled. Patients were assigned to 6-week treatment periods with dapagliflozin 10 mg/d or placebo in random order, separated by 6-weeks wash-out periods. After the 2 treatment periods, half of the patients were re-exposed for 6 weeks to dapagliflozin 10 mg/d. Primary outcome was change in 24-hour urinary albumin excretion rate (24 h UAE). To assess reproducibility in individual albuminuria response, responses from the first and second exposure to dapagliflozin were correlated.
  
  
  
  A total of 33 patients (age, 61 years; female gender, 24.2%; median 24 h UAE, 470 mg/24 h) completed the study. Dapagliflozin, as compared to placebo, reduced 24 h UAE by 36.2% (95% CI, 22.9-47.2; P  < .001). Systolic blood pressure fell by 5.2 mm Hg (95% CI, 0.5-10.0) and eGFR by 5.3 (95% CI, 2.7-8.0). All effects were reversible directly after treatment discontinuation. In a subgroup of 15 patients who were exposed twice to dapagliflozin, 24 h UAE responses showed a large variation among individuals: first exposure (range, -76% to +52%) and second exposure (-90% to +95%) and first and second individual response were significantly correlated (r = 0.69 [95% CI, 0.27-0.89]; P  < .004).
  
  
  
  Dapagliflozin significantly reduces albuminuria when given as adjunct to ACEi or ARB. The albuminuria response to dapagliflozin markedly varies among patients. This variation is not a random phenomenon, but is reproducible upon re-exposure. These data support personalized therapy approaches to optimize diabetic kidney disease.
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Sergei I
authors.initials: SI
authors.lastname: Petrykiv
authors.affiliation: Department of Nephrology, Ziekenhuisgroep Twente, Almelo and Hengelo, the Netherlands.
authors.forename: Gozewijn D
authors.initials: GD
authors.lastname: Laverman
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: de Zeeuw
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Hiddo J L
authors.identifier: 0000-0002-3126-3730
authors.initials: HJL
authors.lastname: Heerspink
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000419:Albuminuria / Q000188:drug therapy* / Q000209:etiology; D001559:Benzhydryl Compounds / Q000627:therapeutic use*; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D005960:Glucosides / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010919:Placebos; D015203:Reproducibility of Results; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D001559:Benzhydryl Compounds; D005960:Glucosides; D010919:Placebos; C529054:dapagliflozin
keywords: 
  SGLT2
  ; albuminuria; dapagliflozin; response variability; type 2 diabetes