Effects of pyridoxamine in combined phase 2 studies of patients with type 1 and type 2 diabetes and overt nephropathy

Mark E. Williams, W. Kline Bolton, Raja G. Khalifah, Thorsten P. Degenhardt, Robert J. Schotzinger, Janet B. McGill

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196 Scopus citations

Abstract

Background/Aims: 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) ≤2.0 mg/dl. In PYR-205/207, randomization was 2:1 and bSCr was ≤2.0 for PYR-205 and ≥2.0 but ≤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 ≥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-β1 also tended to decrease with pyridoxamine (p = 0.049) as did the CML and CEL AGEs. Conclusion: These data provide a foundation for further evaluation of this AGE inhibitor in DN.

Original languageEnglish
Pages (from-to)605-614
Number of pages10
JournalAmerican Journal of Nephrology
Volume27
Issue number6
DOIs
StatePublished - Oct 2007

Keywords

  • Advanced glycation end products
  • Diabetic nephropathy
  • Phase 2 clinical studies, pyridoxamine
  • Pyridoxamine
  • Serum creatinine
  • Urinary transforming growth factor-beta 1

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