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

Diabetic complications are linked to oxidative stress, which hampers the cyclic guanosine monophosphate production by inhibiting nitric oxide/soluble guanylate cyclase (sGC) signaling. This study aimed to determine whether the administration of a novel sGC activator avenciguat alone or in combination with an SGLT2 inhibitor could slow the progression of renal and liver fibrosis in the type 2 diabetic and uninephrectomized <i>db/db</i> mouse model. Experiment groups included normal controls, untreated <i>db/db</i> mice terminated at 12 and 18 wk of age, and <i>db/db</i> mice treated with either one of two doses of avenciguat alone, empagliflozin (Empa) alone, or a combination of both from <i>weeks 12</i> to <i>18</i> of age. Untreated <i>db/db</i> mice exhibited obesity, hyperglycemia, elevated levels of HbA1c and triglycerides (TG), and developed progressive albuminuria, glomerulosclerosis, fatty liver, and liver fibrosis between <i>weeks 12</i> and <i>18</i> 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, whereas Empa reduced HbA1c but not TG levels as compared with untreated <i>db/db</i>. Both avenciguat and Empa alone effectively slowed the progression of diabetes-associated glomerulosclerosis and liver fibrosis. Importantly, avenciguat, especially at high doses in combination with Empa, further lowered these progression markers compared with 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.<b>NEW & NOTEWORTHY</b> Whether combining an sGC activator with an SGLT2 inhibitor could better control diabetes-associated oxidative stress and NO-cGMP signal deficiency has not yet been explored. Using the type 2 diabetic <i>db/db</i> mouse model, this study underscores the sGC activator avenciguat as a novel therapy for diabetic nephropathy and liver injury beyond sGLT2 inhibitors. It also highlights the need for further investigation into the combined effects of these two treatments in managing diabetic complications.