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.

Keywords: BP; Cyclic guanosine monophosphate; Endothelial function; Hyperlipidaemia; Hypertension; Insulin resistance; Soluble guanylate cyclase stimulator; Type 2 diabetes.

Conflict of interest statement

LM is an employee of ProSciento, Inc., the contract research organisation that conducted the study. ALF and ADM are the principal investigators on a research grant to Boston Children’s Hospital from Ironwood Pharmaceuticals. All other authors are employed by and may own stock/stock options in Cyclerion Therapeutics. No other potential conflicts of interest relevant to this article are reported.

Figures

Fig. 1

Changes in metabolic variables from baseline to week 2. Data are presented as LS mean change from baseline with 95% CIs. LS mean differences (95% CI) between praliciguat (n = 19) and placebo-treated (n = 6) participants were as follows: (a) plasma glucose, −0.7 (−1.8, 0.4) mmol/l; (b) total cholesterol, −0.7 (−1.1, −0.2) mmol/l; (c) LDL-cholesterol, −0.5 (−1.0, −0.1) mmol/l; and (d) triacylglycerol, −0.2 (−0.5, 0.2) mmol/l

Fig. 2

Changes in haemodynamic variables from baseline to week 2 measured by 24 h ABPM. Data are presented as LS mean change from baseline with 95% CIs. LS mean differences (95% CI) between praliciguat-treated (n = 19) and placebo-treated (n = 6) participants were as follows: (a) systolic BP, −2 (−10, 5) mmHg; (b) diastolic BP, −4 (−9, 1) mmHg; (c) MAP, −5 (−10, 1) mmHg; and (d) heart rate, 3 (−1, 6) bpm