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

Autor:	Hanrahan JP; Cyclerion Therapeutics, Inc., Cambridge, Massachusetts., de Boer IH; Department of Medicine, Kidney Research Institute, University of Washington, Seattle, Washington., Bakris GL; Department of Medicine, Comprehensive Hypertension Center, The University of Chicago Medicine, Chicago, Illinois., Wilson PJ; Cyclerion Therapeutics, Inc., Cambridge, Massachusetts., Wakefield JD; Cyclerion Therapeutics, Inc., Cambridge, Massachusetts., Seferovic JP; Cyclerion Therapeutics, Inc., Cambridge, Massachusetts., Chickering JG; Cyclerion Therapeutics, Inc., Cambridge, Massachusetts., Chien YT; Cyclerion Therapeutics, Inc., Cambridge, Massachusetts., Carlson K; Cyclerion Therapeutics, Inc., Cambridge, Massachusetts., Cressman MD; Cardiovascular/Metabolic Unit, Covance Inc., Princeton, New Jersey., Currie MG; Cyclerion Therapeutics, Inc., Cambridge, Massachusetts., Milne GT; Cyclerion Therapeutics, Inc., Cambridge, Massachusetts., Profy AT; Cyclerion Therapeutics, Inc., Cambridge, Massachusetts.
Jazyk:	angličtina
Zdroj:	Clinical journal of the American Society of Nephrology : CJASN [Clin J Am Soc Nephrol] 2020 Dec 31; Vol. 16 (1), pp. 59-69. Date of Electronic Publication: 2020 Dec 16.
DOI:	10.2215/CJN.08410520
Abstrakt:	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 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. (Copyright © 2021 by the American Society of Nephrology.)
Databáze:	MEDLINE
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