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

Autor: Hanrahan JP; Cyclerion Therapeutics, Inc., 301 Binney Street, Cambridge, MA, 02142, USA. JHanrahan@Cyclerion.com., Seferovic JP; Cyclerion Therapeutics, Inc., 301 Binney Street, Cambridge, MA, 02142, USA., Wakefield JD; Cyclerion Therapeutics, Inc., 301 Binney Street, Cambridge, MA, 02142, USA., Wilson PJ; Cyclerion Therapeutics, Inc., 301 Binney Street, Cambridge, MA, 02142, USA., Chickering JG; Cyclerion Therapeutics, Inc., 301 Binney Street, Cambridge, MA, 02142, USA., Jung J; Cyclerion Therapeutics, Inc., 301 Binney Street, Cambridge, MA, 02142, USA., Carlson KE; Cyclerion Therapeutics, Inc., 301 Binney Street, Cambridge, MA, 02142, USA., Zimmer DP; Cyclerion Therapeutics, Inc., 301 Binney Street, Cambridge, MA, 02142, USA., Frelinger AL 3rd; Center for Platelet Research Studies, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA., Michelson AD; Center for Platelet Research Studies, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA., Morrow L; ProSciento, Inc., Chula Vista, CA, USA., Hall M; Ironwood Pharmaceuticals, Inc., Cambridge, MA, USA., Currie MG; Cyclerion Therapeutics, Inc., 301 Binney Street, Cambridge, MA, 02142, USA., Milne GT; Cyclerion Therapeutics, Inc., 301 Binney Street, Cambridge, MA, 02142, USA., Profy AT; Cyclerion Therapeutics, Inc., 301 Binney Street, Cambridge, MA, 02142, USA.
Jazyk: angličtina
Zdroj: Diabetologia [Diabetologia] 2020 Apr; Vol. 63 (4), pp. 733-743. Date of Electronic Publication: 2019 Dec 19.
DOI: 10.1007/s00125-019-05062-x
Abstrakt: 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.
Databáze: MEDLINE
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