Effects of the Soluble Guanylate Cyclase Stimulator Praliciguat in Diabetic Kidney Disease A Randomized Placebo-Controlled Clinical Trial

Background and objectives Impaired nitric oxide signaling through soluble guanylate cyclase has been implicated in the pathophysiology of diabetic kidney disease. Praliciguat, a soluble guanylate cyclase stimulator that amplifies nitric oxide signaling, inhibited kidney inflammation and fibrosis in animal models. Design, setting, participants, & measurements In a phase 2 trial, 156 adults with type 2 diabetes, eGFR 30-75 ml/min per 1.73 m(2), and urine albumin-creatinine ratio 200-5000 mg/g treated with renin-angiotensin system inhibitors were randomly allocated 1:1: 1 to placebo, 20 mg praliciguat, or 40 mg praliciguat daily for 12weeks. The primary efficacy and safety outcomes were change from baseline to weeks 8 and 12 in urine albumin creatinine ratio and treatment-emergent adverse events, respectively. Other outcomes assessed were 24-hour ambulatory BP and metabolic parameters. Results Of 156 participants randomized, 140 (90%) completed the study. The primary efficacy analysis demonstrated a mean change from baseline in urine albumin-creatinine ratio of -28% (90% confidence interval, -36 to -18) in the pooled praliciguat group and -15% (-28 to 0.4) in the placebo group(difference -15%; -31 to 4; P = 0.17). Between-group decreases from baseline to week 12 for praliciguat versus placebo were seen in mean 24-hour systolic BP (-4 mmHg; -8 to -1), hemoglobin A1c (-0.3%; -0.5 to -0.03), and serum cholesterol (-10mg/dl; -19 to -1). The incidence of treatment-emergent adverse events was similar in the pooled praliciguat and placebo groups (42% and 44%, respectively). Serious adverse events, events leading to study drug discontinuation, and events potentially related to BP lowering were reported at higher frequency in the 40-mg group but were similar in 20-mg and placebo groups. Conclusions Praliciguat treatment for 12 weeks did not significantly reduce albuminuria compared with placebo in the primary efficacy analysis. Nonetheless, the observed changes in urine albumin-creatinine ratio, BP, and metabolic variables may support further investigation of praliciguat in diabetic kidney disease.

Automated summary

In this study, treatment with praliciguat for 12 weeks did not significantly reduce albuminuria compared with placebo in the primary efficacy analysis. However, observed changes in urine albumin-creatinine ratio, blood pressure, and metabolic parameters may encourage further investigation of praliciguat in the treatment of diabetic kidney disease.