Probucol Suppresses Initiation of Chronic Hemodialysis Therapy and Renal Dysfunction-Related Death in Diabetic Nephropathy Patients: Sakura Study

Abstract

Aim: Probucol has antioxidant as well as cholesterol-lowering effects. We examined the effect of probucol on the progression of diabetic nephropathy. We named this study 'Sakura Study' after our hospital and city. Methods: We performed a randomized, open trial on 162 type 2 diabetic patients with clinical albuminuria (urinary albumin excretion ＞300 mg/g creatinine). Eighty patients were assigned to probucol treatment (500 mg/day) and 82 patients to no probucol treatment. All patients were followed for five years. The primary outcome was the time to renal dysfunction events, defined as the initiation of chronic hemodialysis therapy and renal dysfunction-related death. Results: Probucol decreased total cholesterol, HDL-cholesterol, and LDL-cholesterol compared to the control group. The serum creatinine increase rate was significantly lower (p = 0.015) in the probucol group (0.066 mg/dL/month) than in the non-probucol group (0.116 mg/dL/month). Renal dysfunction events occurred in 72 patients during this study. The 69 patients who were initiated on chronic hemodialysis comprised 42 in the non-probucol group and 27 in the probucol group. Three patients in the non-probucol group, but no patients in the probucol group died of renal dysfunction. The renal dysfunction event-free survival rate was significantly higher (log-rank: p = 0.02) in the probucol group than in the non-probucol group. Conclusion: Probucol suppressed the progression of diabetic nephropathy and renal dysfunction events.

Probucol in Albuminuric Type 2 Diabetes Mellitus Patients on Renin–Angiotensin System Blockade

“…10,11 However, a significant additional LDL-C-lowering effect of probucol was observed in this study. As probucol upregulates the fractional catabolic rate of LDL-C via an LDL receptor-independent pathway and increasing bile acid synthesis, 18,19 its effect on LDL-C lowering might be complementary to that of statins.…”

“…Although lower levels of total and LDL-C were achieved in subjects allocated to the probucol 250 and 500 mg/d groups, there The results of this multicenter, double-blind, placebo-controlled study are in contrast with previous open-label studies in which probucol suppressed the progression of proteinuria and decline in renal function. 10,11 In addition to the open-label study design of the previous studies, the different proportions of subjects who used ACEIs/ARBs could explain the discrepancy. In a previous study, 17.6% of subjects in probucol group and 21.6% in the control group used ACEIs/ARBs, 10 and a significant reduction in urinary protein excretion in the probucol group was observed.…”

“…10 No significant change in UACR was observed in another study, in which 86% of the subjects in the probucol group and 83% in the control group used ACEIs/ ARBs. 11 Because all subjects in the current study used ACEIs/ ARBs with no change in dose for at least 3 months before screening, the use of ACEIs/ARBs could have masked the benefit of probucol in terms of UACR. The study period of 4 months in the current study could have been too short to evaluate the long-term benefits of probucol, such as the delay in chronic hemodialysis therapy initiation seen in previous studies.…”

“…10 A larger scale (n=162), single-center, open-label study showed that probucol treatment delayed the initiation of chronic dialysis and renal dysfunction-related death in diabetes mellitus patients with urinary albumin excretion of >300 mg/g creatinine, with no significant difference in the extent of proteinuria between groups. 11 However, only a minority (<30%) of the study subjects in these clinical trials used 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins), 10 and use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II type I receptor antagonist (ARBs) was not included in the eligibility criteria. Therefore, the benefit of probucol in patients with diabetic kidney disease has not been examined by a multicenter, double-blind, placebo-controlled trial in a population in which most subjects use both renin-angiotensin-aldosterone system blockade and statins.…”

Role of the TGFβ/p65 pathway in tanshinone IIA-treated HBZY-1 cells

“…One study revealed that treatment with vildagliptin + telmisartan controlled blood pressure, renovascular structural and biochemical parameters in diabetic neuropathy rats (4). Endo et al (8) performed a randomized, open trial on 162 type 2 diabetic patients and found that probucol suppressed the progression of DN and renal dysfunction events.…”