A Randomised Controlled Trial of Tripterygium wilfordii polyglycoside in the Treatment of Stage IV Diabetic Nephropathy

Diabetic Nephropathy(DN) imposes a substantial burden on both individual health and healthcare systems. Proteinuria is both a hallmark manifestation and a critical driver of DN progression. In particular, 24-hour urinary protein excretion has been established as a robust marker of renal damage severity and an independent predictor of ESRD risk. Tripterygium wilfordii polyglycosides (TWP), extracted from the root bark of Tripterygium wilfordii Hook F (TwHF) , a traditional Chinese medicinal herb, demonstrate a multi-target, multi-activity, and multi-pathway pharmacological profile. Existing randomized controlled trials of TWP in DN have been limited to treatment durations of ≤24 weeks, which precludes robust evaluation of its long-term therapeutic benefits and potential effects on ESRD progression. The present study was designed to address these gaps by incorporating extended treatment periods and prolonged follow-up, aiming to systematically evaluate the long-term efficacy and safety of TWP in patients with DKD.

In this single-center, prospective, randomized controlled trial (ChiCTR-IOR-17010623), patients with DN receiving stable angiotensin II receptor blocker (ARB) therapy were enrolled. Participants were randomly assigned to ARB alone or ARB plus TWP, titrated to 30–90 mg/day. The primary endpoint was a ≥30% reduction in proteinuria at 48 weeks. Secondary endpoints included: (1) all-cause and cardiovascular mortality; (2) progression to end-stage renal disease (ESRD, defined as serum creatinine >530.4 μmol/L or eGFR <15 mL/min/1.73 m²) or need for renal replacement therapy; (3) doubling of serum creatinine or increase ≥442 μmol/L, confirmed 4 weeks later. Analyses were conducted according to the intention-to-treat principle. 

A total of 49 patients were randomized (26 to TWP+ARB, 23 to ARB), and 41 completed 48 weeks of follow-up. Baseline characteristics were comparable between groups. At week 48, the TWP+ARB group achieved significantly greater proteinuria reduction (median -1.76 g/24h, -51.8%; 76.9% responders) than the ARB group (-0.41 g/24h, -12.8%; 34.8% responders; P<0.001). Median eGFR remained stable in the TWP+ARB group (59.8 vs. 54.2 ml/min/1.73 m²), whereas it declined in the ARB group (44.4 vs. 52.4 ml/min/1.73 m²; P=0.005 within-group). No deaths occurred during the 48-week treatment. Two patients in the ARB group experienced creatinine doubling or ESRD, compared with none in the TWP+ARB group. During extended follow-up (median 206 weeks), ESRD or need for renal replacement therapy occurred in 38.1% of TWP+ARB patients versus 65.0% of ARB patients (HR 0.53, 95% CI 0.23–1.21; P=0.132). 

In this randomized controlled trial, the addition of TWP to ARB therapy in patients with type 2 DN significantly reduced proteinuria and preserved renal function over 48 weeks. Extended follow-up (median 206 weeks) suggested a lower risk of progression to end-stage renal disease or need for renal replacement therapy with TWP+ARB compared with ARB alone, while maintaining a comparable safety profile. These findings support TWP as an effective adjunctive therapy with both short- and potential long-term renal benefits in DN management.