Background: Praliciguat (IW-1973) is an sGC stimulator in clinical development as a potential treatment for diabetic kidney disease. In animal models, praliciguat distributes broadly to tissues and elicits hemodynamic, anti-inflammatory, anti-fibrotic, and metabolic effects. Here, we assessed the metabolic effects of praliciguat in diabetic TALLYHO mice housed at thermoneutrality in order to minimize any confounding contribution of brown fat thermogenesis on metabolism, which is rare in humans but common in mice.
Methods: Six- to eight-week-old male TALLYHO/JngJ mice were maintained on low-fat diet (10% kcal from fat, LFD). Due to incomplete penetrance of the diabetic phenotype in this model, diabetic mice were identified prior to study initiation using HbA1c and urinary glucose/creatinine ratio as criteria. At 10-12 weeks of age, a diabetic control group (n=6) was maintained on LFD, while another group (n=6) was switched to LFD formulated with praliciguat to achieve a Cmax drug exposure similar to a 20 mg oral clinical dose. Plasma was collected at baseline and after 4 weeks of treatment. Oral glucose tolerance tests (OGTT) and oral lipid tolerance tests (LTT) were performed after 5 and 6 weeks of treatment, respectively.
Results: At week 4, praliciguat treatment attenuated the HbA1c increase in TALLYHO diabetic mice (+0.40 vs. +0.95%, in praliciguat and control groups, respectively P<0.05). At week 5, fasting glucose (561 ± 33 vs. 650 ± 46 mg/dl; -14%, P<0.01) and OGTT glucose AUC (-12%, P<0.01) were lower in praliciguat-treated mice than in untreated controls. At week 6, fasting plasma triglycerides (721 ± 97 vs. 1134 ± 190 mg/dl; -36%, P<0.05) and LTT triglyceride AUC (-23%, P<0.01) were lower in praliciguat-treated mice than in untreated controls. Body weight loss and food intake were lower in praliciguat-treated mice than in untreated mice.
Conclusion: Praliciguat improved nutrient handling in diabetic TALLYHO mice.
C. Schwartzkopf: None. A. Carvalho: Stock/Shareholder; Self; Cyclerion Therapeutics. J. Hadcock: None. M. Currie: Employee; Self; Cyclerion Therapeutics. Stock/Shareholder; Self; Cyclerion Therapeutics. J.E. Jones: None.