SGLT2 inhibitors: Salty or Just Sweet? Protection of Heart and Kidney Failure in Monotherapy and Combination Therapy with RAS inhibitors

• Dapagliflozin lowers blood pressure without clear effects on sodium excretion in people with T2D and preserved kidney function

• Dapagliflozin did not induce prolonged changes in plasma volume, extracellular volume, and intracellular volume

• Other nondiuretic-related effects cannot be ruled out in the CV protective effects conferred by SGLT2 inhibitors, including reductions in arterial stiffness, inhibition of the sympathetic nervous system, or restoration of endothelial function.

• Multiple intra-kidney compensatory mechanisms are activated to counteract dapagliflozin-induced osmotic diuresis, including
1) an increase in co-peptin
2) decrease in free water clearance that facilitate maintenance of normal urinary volumes
3) a decrease in fractional urea excretion and
4) activation of RAS.

• Dapagliflozin decreased blood pressure despite no clear changes in 24-hr sodium and volume excretion in patients with CKD without T2D.

• Dapagliflozin activates kidney specific adaptive mechanisms to maintain body fluid and sodium balance to prevent volume depletion, including activation of RAS and stimulation of ADH release, in patients with CKD without T2D.

• Kidney-active drugs do not seem to alter the effect of SGLT2 inhibitors on hard kidney endpoints in large outcome trials.

• Dapagliflozin over 24 weeks provides similar clinically relevant improvements in urinary albumin- creatinine ratio (UACR), eGFR, HbA1c, and hematocrit, irrespective of treatment with RAS inhibitors at baseline, in people with T2D and increased albuminuria.

• The use of RAS inhibitors in combination with SGLT2 inhibitors does not impact the biomarkers associated with CV and kidney function.

• Empagliflozin+losartan combination therapy induced a greater placebo-controlled reduction in mGFR and estimated glomerular pressure compared to either of the agents alone.

• This reduction in mGFR was accompanied by a trend towards a reduction in renal vascular resistance (RVR), suggesting that the clinically observed mGFR decline may be explained by postglomerular vasodilation.

• These data support combined beneficial effects of RAS and SGLT2 inhibitors.• Empagliflozin+losartan combination therapy has a larger blood pressure-lowering effect than either of the agents alone when compared to placebo.

• Both drugs lower blood pressure by reductions in arterial stiffness and sympathetic nervous system (SNS) activity

• The mechanisms underlying the blood pressure reductions at least partially differ between empagliflozin and losartan, since empagliflozin additionally seems to induce volume contraction.