Effects of the Soluble Guanylate Cyclase Stimulator Praliciguat in Diabetic Kidney Disease

Abstract

Background and objectivesImpaired 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, & measurementsIn 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.ResultsOf 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.ConclusionsPraliciguat 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

Renal effects of guideline‐directed medical therapies in heart failure: a consensus document from the Heart Failure Association of the European Society of Cardiology

“…sGC is a ubiquitously distributed intracellular enzyme which mediates nitric oxide biological effects by the conversion of guanosine triphosphate into cGMP 113 . In the kidney, sGC is expressed in various types of renal cell (glomerular arterioles, granular cells, descending vasa recta, fibroblasts, podocytes) and its activation is able to modulate renal blood flow, to regulate the function of glomerular and tubular compartments and to reduce inflammation and renal fibrosis 114 …”

Nitric oxide signalling in kidney regulation and cardiometabolic health

“…A randomized, double-blind, placebo-controlled, phase II study (NCT03217591) evaluated the safety and efficacy of the sGC stimulator praliciguat (IW-1973) in 140 patients with T2DM and albuminuria treated with RAAS inhibitors 142 . Treatment with praliciguat was not significantly associated with a reduction in albuminuria from baseline to week 8 and week 12 (the primary efficacy outcome) compared with placebo ( P = 0.17).…”

Neues zu Hypertonie und Diabetes

“…Bei 174 Probanden der CREDENCE-Studie lag die eGFR zum Zeitpunkt des Screenings bei ≥ 30 ml/min, zum Zeitpunkt der Randomisierung jedoch bei < 30 ml/min, weswegen sie von der Hauptstudie ausgeschlossen wurden. Diese Klientel wurde in einer Post-hoc-Analyse noch einmal gesondert betrachtet [ 30 ]. Von Wochen 1–130 imponierte eine 66 %ige Differenz des mittleren eGFR-Abfalls mit Canagliflozin vs. Plazebo (−1,30 vs. −3,83 ml/min/Jahr; Differenz −2,54 [0,90–4,17] ml/min/Jahr).…”