TABLE 1.

Pathogenic Factors in the Development of DKD and Potential Renal Protective Mechanisms by Which SGLT2 Inhibitors Can Slow the Progressive Decline in GFR in Patients With Established DKD

Etiological Factor	Potential SGLT2 Inhibitor Benefit?
Hyperglycemia	Yes*
Hypertension	Yes
Deranged tubuloglomerular feedback	Yes
Tubular hypertrophy/growth factors	Unknown
Renal hypoxia	Possible†
Podocyte injury/albumin toxicity	Possible†
Lipotoxicity	Possible†
Inflammation/reactive oxygen species	Possible†
Mitochondrial dysfunction	Unknown
Genetics	No

^*Strict glycemic control (A1C <6.5%) represents primary prevention of DKD. However, the prevention of worsening of established DKD by SGLT2 inhibition is unrelated to the reduction in plasma glucose concentration and can be best appreciated in patients with diabetes with a GFR <45 mL/min/1.73 m², in whom the decline in A1C is quite small.

^†Some supporting evidence is present in humans or in experimental models of DKD.