An exploratory, randomised, placebo-controlled, 14 day trial of the soluble guanylate cyclase stimulator praliciguat in participants with type 2 diabetes and hypertension

Abstract

Aims/hypothesis Praliciguat (IW-1973), a soluble guanylate cyclase stimulator, amplifies nitric oxide signalling. This exploratory trial investigated the safety, tolerability, pharmacokinetic profile and pharmacodynamic effects of praliciguat in individuals with type 2 diabetes and hypertension. Methods This Phase IIA, double-blind, placebo-controlled trial investigated praliciguat in 26 participants with type 2 diabetes and hypertension on stable glucose-and BP-lowering therapies. Participants were randomly allocated in a 3:5:5 ratio to three groups: placebo (n = 6), praliciguat 40 mg once daily for days 1-14 (n = 10), or praliciguat 20 mg twice daily for days 1-7 then 40 mg once daily for days 8-14 (n = 10). Assessments were made in clinic and included treatment-emergent adverse events, pharmacokinetics, metabolic variables, 24 h BP and heart rate, platelet function, reactive hyperaemia index (RHI) and plasma biomarkers. Participants, the sponsor, the investigator and clinic study staff (except designated pharmacy personnel) were blinded to group assignment. Results Participants treated for 14 days with praliciguat had least-square mean change-from-baseline differences vs placebo (95% CI) of −0.7 (−1.8, 0.4) mmol/l for fasting plasma glucose, −0.7 (−1.1, −0.2) mmol/l for total cholesterol, −0.5 (−1.0, −0.1) mmol/l for LDL-cholesterol, −23 (−56, 9) for HOMA-IR in those not being treated with insulin, and −5 (−10, 1) mmHg and 3 (−1, 6) beats/min for average 24 h mean arterial pressure and heart rate, respectively. Apart from one serious adverse event (SAE; upper gastrointestinal haemorrhage), praliciguat was well tolerated. Praliciguat did not affect platelet function or RHI. Among exploratory biomarkers, plasma levels of asymmetric dimethylarginine decreased in praliciguat vs placebo recipients. Conclusions/interpretation In participants with type 2 diabetes and hypertension on standard therapies, over 14 days praliciguat was well tolerated, except for a single SAE, and showed positive trends in metabolic and BP variables. These results support further clinical investigation of praliciguat. Trial registration ClinicalTrials.gov NCT03091920. Funding This trial was funded by Cyclerion Therapeutics.

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

“…In this study, praliciguat treatment was also associated with modest reductions in certain metabolic measures, including HbA1c and total and LDL cholesterol levels. This is consistent with clinical data on praliciguat in people with type 2 diabetes and hypertension (36), as well as findings from nonclinical studies (36,45,46). Possible mechanisms of Intent-to-treat population.…”

“…As in previous clinical studies (36,37), praliciguat treatment was associated with modest decreases in systemic BP and changes in heart rate, presumably compensatory. These hemodynamic effects are consistent with the known pharmacology of sGC stimulators (23).…”

“…Praliciguat inhibited proinflammatory and profibrotic responses in isolated human kidney proximal tubular cells (33) and ameliorated proteinuria and kidney damage in animal models of nephropathy, including at doses that had minimal effects on systemic BP in multiple rat models (34,35). In clinical studies of praliciguat in healthy adults and individuals with type 2 diabetes and hypertension (36,37), oral doses up to 40 mg were generally well tolerated and showed increases in plasma cGMP levels and modest decreases in systemic BP consistent with the expected vascular effects of NO signaling (23). Furthermore, in nonclinical studies (38) and in people with type 2 diabetes and hypertension (36), praliciguat showed promising effects on metabolic variables.…”

“…In clinical studies of praliciguat in healthy adults and individuals with type 2 diabetes and hypertension (36,37), oral doses up to 40 mg were generally well tolerated and showed increases in plasma cGMP levels and modest decreases in systemic BP consistent with the expected vascular effects of NO signaling (23). Furthermore, in nonclinical studies (38) and in people with type 2 diabetes and hypertension (36), praliciguat showed promising effects on metabolic variables.…”

Olinciguat, an Oral sGC Stimulator, Exhibits Diverse Pharmacology Across Preclinical Models of Cardiovascular, Metabolic, Renal, and Inflammatory Disease

“…Although the mechanism is not completely understood, our data add to a growing body of evidence that pharmacological stimulation of sGC may have favorable effects on metabolism in obesity and metabolic syndrome. In 2015, it was reported that the sGC stimulator BAY 41-8543 protected against weight gain and improved the diabetic phenotype in a diet-induced obesity mouse model (Hoffmann et al, 2015), and in a study in 26 patients with diabetes and hypertension, 14 days of treatment with the sGC stimulator praliciguat reduced fasting glucose level and total and LDL cholesterol levels (Hanrahan et al, 2020).…”