A novel soluble guanylate cyclase activator, avenciguat, in combination with empagliflozin, protects against renal and hepatic injury in diabetic db/db mice.

Abstract

Diabetic complications are linked to oxidative stress, which hampers the cyclic guanosine monophosphate production by inhibiting nitric oxide /soluble guanylate cyclase (sGC) signalling. This study aimed to determine whether administration of a novel sGC activator avenciguat alone or in combination with a SGLT2 inhibitor could slow the progression of renal and liver fibrosis in the type 2 diabetic and uninephrectomized db/db mouse model. Experiment groups included normal controls, untreated db/db mice terminated at 12 and 18 weeks of age, and db/db mice treated with either one of two doses of avenciguat alone, empagliflozin (Empa) alone, or a combination of both from weeks 12 to 18 of age. Untreated db/db mice exhibited obesity, hyperglycemia, elevated levels of HbA1c and triglycerides (TG) and developed progressive albuminuria, glomerulosclerosis, fatty liver and liver fibrosis between weeks 12 and 18 of age, accompanied by increased renal and liver production of fibronectin, type-IV collagen, laminin, and increased oxidative stress markers. Avenciguat had no effect on body weight but reduced both blood HbA1c and TG levels, while Empa reduced HbA1c but not TG levels as compared to untreated db/db. Both avenciguat and Empa alone effectively slowed the progression of diabetes-associated glomerulosclerosis and liver fibrosis. Importantly, avenciguat, especially at high dose in combination with Empa, further lowered these progression markers compared to baseline measurements. These results suggested that either avenciguat alone or in combination with Empa is therapeutic. Avenciguat in combination with Empa shows promise in halting the progression of diabetic complications.