title: Effects of pyridoxamine in combined phase 2 studies of patients with type 1 and type 2 diabetes and overt nephropathy.
abstract: OBJECTIVE
  Treatments of diabetic nephropathy (DN) delay the onset of end-stage renal disease. We report the results of safety/tolerability studies in patients with overt nephropathy and type 1/type 2 diabetes treated with pyridoxamine, a broad inhibitor of advanced glycation.
  
  
  METHODS
  The two 24-week studies were multicenter Phase 2 trials in patients under standard-of-care. In PYR-206, patients were randomized 1:1 and had baseline serum creatinine (bSCr) <or=2.0 mg/dl. In PYR-205/207, randomization was 2:1 and bSCr was <or=2.0 for PYR-205 and >or=2.0 but <or=3.5 mg/dl for PYR-207. Treated patients (122 active, 90 placebo) received 50 mg pyridoxamine twice daily in PYR-206; PYR-205/207 patients were escalated to 250 mg twice daily.
  
  
  RESULTS
  Adverse events were balanced between the groups (p = NS). Slight imbalances, mainly in the PYR-205/207 groups, were noted in deaths (from diverse causes, p = NS) and serious adverse events (p = 0.05) that were attributed to pre-existing conditions. In a merged data set, pyridoxamine significantly reduced the change from baseline in serum creatinine (p < 0.03). In patients similar to the RENAAL/IDNT studies (bSCr >or=1.3 mg/dl, type 2 diabetes), a treatment effect was observed on the rise in serum creatinine (p = 0.007). No differences in urinary albumin excretion were seen. Urinary TGF-beta1 also tended to decrease with pyridoxamine (p = 0.049) as did the CML and CEL AGEs.
  
  
  CONCLUSIONS
  These data provide a foundation for further evaluation of this AGE inhibitor in DN.
authors.affiliation: Harvard Medical School, Joslin Diabetes Center, Boston, MA 02215, USA. mark.williams@joslin.harvard.edu
authors.forename: Mark E
authors.initials: ME
authors.lastname: Williams
authors.forename: W Kline
authors.initials: WK
authors.lastname: Bolton
authors.forename: Raja G
authors.initials: RG
authors.lastname: Khalifah
authors.forename: Thorsten P
authors.initials: TP
authors.lastname: Degenhardt
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schotzinger
authors.forename: Janet B
authors.initials: JB
authors.lastname: McGill
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D003401:Creatine / Q000097:blood; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D003928:Diabetic Nephropathies / Q000097:blood / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors; D006801:Humans; D007676:Kidney Failure, Chronic / Q000517:prevention & control; D008297:Male; D008875:Middle Aged; D011733:Pyridoxamine / Q000494:pharmacology*; D016896:Treatment Outcome; D014803:Vitamin B Complex / Q000494:pharmacology*