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

Abstract

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 m2, 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 12 weeks. 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 mm Hg; -8 to -1), hemoglobin A1c (-0.3%; -0.5 to -0.03), and serum cholesterol (-10 mg/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.

Clinical trial registry name and registration number: A Study to Evaluate the Soluble Guanylate Cyclase (sGC) Stimulator IW-1973 in Diabetic Nephropathy/Diabetic Kidney Disease as Measured by Albuminuria, NCT03217591.

Keywords: albuminuria; chronic kidney disease; diabetes; hypertension.

Copyright © 2021 by the American Society of Nephrology.

Figures

Graphical abstract

Figure 1.

Summary of participant disposition. ITT, intent to treat.

Figure 2.

Changes in urine albumin-creatinine ratio in trial participants over 12 weeks. Geometric mean (90% confidence interval) change from baseline in urine albumin-creatinine ratio over 12 weeks.

Figure 3.

Changes in 24 hour BP and heart rate (ABPM) in trial participants over 12 weeks. Least square mean difference from placebo in change from baseline in hemodynamic parameters. Forest plots for individual and pooled praliciguat dose group versus placebo. DBP, diastolic BP; MAP, mean arterial pressure; SBP, systolic BP.

Figure 4.

Changes in hemoglobin A1c in trial participants over 12 weeks. Least square mean change from baseline in hemoglobin A1c over 12 weeks.