TY - JOUR
T1 - Effects of pyridoxamine in combined phase 2 studies of patients with type 1 and type 2 diabetes and overt nephropathy
AU - Williams, Mark E.
AU - Bolton, W. Kline
AU - Khalifah, Raja G.
AU - Degenhardt, Thorsten P.
AU - Schotzinger, Robert J.
AU - McGill, Janet B.
PY - 2007/10
Y1 - 2007/10
N2 - 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.
AB - 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.
KW - Advanced glycation end products
KW - Diabetic nephropathy
KW - Phase 2 clinical studies, pyridoxamine
KW - Pyridoxamine
KW - Serum creatinine
KW - Urinary transforming growth factor-beta 1
UR - http://www.scopus.com/inward/record.url?scp=35548975242&partnerID=8YFLogxK
U2 - 10.1159/000108104
DO - 10.1159/000108104
M3 - Article
C2 - 17823506
AN - SCOPUS:35548975242
SN - 0250-8095
VL - 27
SP - 605
EP - 614
JO - American Journal of Nephrology
JF - American Journal of Nephrology
IS - 6
ER -