Empagliflozin and Linagliptin Administered in Combination or as Serial Add-On Therapy Decreases Macrovascular and Microvascular Stiffening and Microalbuminuria in a Mouse Model of Diabetic Nephropathy

Diabetic individuals are at increased risk for progression of proteinuria and renal fibrosis. There is an urgent need for more effective therapeutic strategies since conventional anti-hyperglycemic therapies may not sufficiently reduce renal injury. Combinations of newer anti-hyperglycemia therapies, such as, DPP-4 and SGLT2 inhibitors, which improve glycemia by differing mechanisms and exhibit cardiovascular and renal protections may show promise in this regard. We tested the hypothesis that targeting SGLT2 and DPP-4 improves aortic and renal vascular stiffening as well as suppression of renal tissue injury. Eleven week old female db/db mice were fed a diet containing LINA (2mg/kg/day) or EMPA (10mg/kg/day) monotherapy for 10 weeks. Additional groups received add-on therapy after 5 weeks on monotherapy (LINA added to EMPA or EMPA added to LINA. One group received LINA and EMPA combination therapy for the entire 10 week test period. A control group received no therapy. Both EMPA and LINA monotherapies decreased diabetes associated aortic and renal vascular stiffening and albuminuria. Improvement by LINA was observed without any significant improvement in glycemic control whereas EMPA significantly reduced both fasting glucose and HbA1c levels accompanied by decrease vascular stiffening and albuminuria. Like the monotherapies, combination therapy or serial add-on therapies afforded cardiovascular and reno-protection, however, these dual therapies had marginal advantage over monotherapy. Taken together, suppression of macrovascular and microvascular stiffening by DPP-4 and SGLT2 inhibitors contribute significantly to vascular health in diabetic patients by both glycemic-dependent and -independent mechanisms.