SGLT2i and GLP1-RA exert additive cardiorenal protection with a RAS blocker in uninephrectomized db/db mice

Area of Science:

• Nephrology
• Cardiology
• Endocrinology

Background:

• Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease.
• Current renin-angiotensin system (RAS) blockade treatments do not fully prevent DKD progression.
• Sodium-glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like-1 receptor agonists (GLP-1RA) show promise in delaying DKD progression.

Purpose of the Study:

• To investigate the synergistic cardiorenal protective effects of combining RAS blockade with SGLT2i (empagliflozin) and/or GLP-1RA (semaglutide).
• To evaluate the add-on benefits of this combination therapy in a type 2 diabetic mouse model.

Main Methods:

• Type 2 diabetic db/db mice underwent uninephrectomy and were treated for 8 weeks.
• Treatments included ramipril (RAS blocker) with empagliflozin (SGLT2i) and/or semaglutide (GLP-1RA).
• Parameters monitored included body weight, food/water intake, glycemia, albuminuria, and glomerular filtration rate (GFR); kidney and heart tissues were analyzed post-mortem.

Main Results:

• The triple therapy (empagliflozin, semaglutide, ramipril) significantly reduced albuminuria, blood glucose, and glomerular mesangial matrix expansion.
• This combination therapy also decreased the expression of proinflammatory and profibrotic genes (CCL2, TGF-β1) in the kidney.
• The combination of empagliflozin and semaglutide with ramipril demonstrated superior reduction in cardiomyocyte hypertrophy and heart fibrosis.

Conclusions:

• Combination therapy with SGLT2i and GLP-1RA on top of RAS blockade provides enhanced cardiorenal protection in DKD.
• This multi-drug approach is more effective than individual agents in mitigating DKD-associated kidney and heart damage.