Preclinical evidence supports superior efficacy of sotagliflozin in attenuating salt-induced renal injury

Sodium-glucose co-transporter 2 (SGLT2) inhibitors, originally developed to treat type 2 diabetes, have significant protective effects on the heart and kidneys. In the kidney, SGLT2 reabsorbs approximately 97% of the filtered glucose in the S1 and S2 segments of the proximal tubule, while SGLT1 reabsorbs the remainder in the S3 segment.

In a study conducted in rats, researchers found that dual inhibition of SGLT1 and SGLT2 reduced salt-sensitive hypertension and kidney injury more effectively than SGLT2 inhibition alone. The findings will be presented at ASN Kidney Week 2025, November 5–9.

Salt-sensitive hypertension, elevated blood pressure due to excessive salt consumption – affects almost half of people with high blood pressure and is a major contributor to kidney disease, cardiovascular complications and progression to kidney failure. When researchers compared selective SGLT2 inhibition (via dapagliflozin treatment) with dual SGLT1/2 inhibition (via sotagliflozin treatment) in a well-established rat model of salt-induced hypertension and chronic kidney disease, they found that both drugs had profound effects in slowing the progression of hypertension.

Compared with selective SGLT2 inhibition, dual SGLT1/2 inhibition produced a greater reduction in mean arterial pressure and more effective attenuation of renal injury, although it had no effect on arterial pressure under normal salt conditions. Sotagliflozin also reduced body weight, enhanced urinary sodium and chloride excretion, and almost doubled fractional glucose excretion compared with dapagliflozin. Neither treatment changed kidney function. Inhibition of SGLT2 modulates several metabolic pathways in a site-specific manner in the kidney, with pronounced effects on lipid metabolism and inflammatory signaling.

Our study provides preclinical evidence supporting the expanded use of dualSGLT1/2 inhibitors beyond heart failure and diabetes, expanding their potential in the management of hypertension, particularly in salt-sensitive patients.”

Olha Kravtsova, University of South Florida

“These findings also lay a foundation for further research into peripheral renal metabolism. Furthermore, they highlight lipid and inflammatory pathways as promising therapeutic targets in the treatment of hypertension.”