pressure differences (275). The beneficial effects of ARBs on the kidney seem to extend to individuals with diabetes without overt proteinuria, as shown in the MARVAL (Microalbuminuria Reduction with Valsartan) trial (276), which showed a significant protein-lowering effect of valsartan, again independent of blood pressure effects. Because ARBs curtailed CKD progression to some degree via mechanisms apart from significant blood pressure-lowering, they were integrated into the standard of care (277). Although these ARB trials reduced DKD progression to about a 4–5 mL/min/year loss, we still did not have a way to normalize the rate of decline to normality (i.e., 0.8 mL/min/year), as shown in Figure 1 (3,4,9,53,236,278–281). Thus, the significant residual risk that remained in DKD patients drove the development of a spectrum of agents, all of which unfortunately failed to further slow nephropathy progression (Figure 2) (237,282–287). The subsequent renal outcomes trials examined agents addressing mechanisms such protein kinase C (PKC)-ß inhibition, dual ACE inhibition/ARB blockade, transforming growth factor (TGF)-ß production inhibition, renin inhibition, and activation of the nuclear factor erythroid 2–related factor 2 (Nrf2) pathway while inhibiting the nuclear factor-κB pathway; however, none of them successfully further slowed DKD progression, and FIGURE 1 Historical perspective on slowing CKD progression associated with type 2 diabetes (3,4,9,53,236,278–281). -12 -10 -8 -6 -4 -2 0 1980 1987 1994 2001 2008 2015 2022 Average decline in kidney function (mL/min/year) Normal annual decline rate CREDENCE19 DAPA-CKD20 FIDELIO21 mL/min/year No specific therapy for CKD Captopril trial15 Enalapril trial16 Bakris et al.17 Bakris et al.18 RENAAL10 IDNT11 CHRONIC KIDNEY DISEASE AND TYPE 2 DIABETES 29 some were associated with even higher morbidity and mortality (237,285,288). The development of sodium–glucose cotransporter 2 (SGLT2) inhibitors for hyperglycemia management and the subsequent results of their cardiovascular outcomes trials (CVOTs) led to a marked paradigm shift in DKD management from a cardiorenal perspective. SGLT2 Inhibitors Although initially designed to manage hyperglycemia, SGLT2 inhibitors proved to possess pleiotropic effects that extend well beyond their glucose-lowering effects. They have been clearly shown to be cardiorenal risk–reducing agents irrespective of glycemic control and level of kidney function down to an eGFR of 25 mL/min/1.73 m2 (53,281,289). In people with relatively healthy kidneys (i.e., an eGFR >60 mL/min/1.73 m2 ), they aid in glycemic control by blocking SGLT2 receptors in the proximal tubule. Hence, renal absorption of glucose is withheld independent of insulin action. This mechanism results in osmotic diuresis, natriuresis, and reduction in intraglomerular pressure, often observed as a rapid decline in eGFR during the first weeks of treatment, followed by a slight increase toward baseline, then stabilization reflecting long-term renoprotection (290,291). Also, note that this initial reduction in eGFR does not occur among individuals with an eGFR well below 40 mL/min/1.73 m2 , yet renal and cardiovascular benefits are still seen (281,292). Moreover, the magnitude of blood pressure reduction is independent of glucose-lowering and eGFR, as similar levels of reduction are seen throughout the eGFR range of 25–80 mL/min/1.73 m2 (293). There is no unifying mechanism for how SGLT2 inhibitors reduce cardiovascular risk and preserve kidney and cardiac function; however, potential mechanisms have been reviewed (294–296). For example, blood pressure reduction occurs irrespective of sodium loss with glucose or eGFR level (293) and may relate to sympathetic inhibition of this class, as SGLT2 inhibition has been nicely shown to have effects such as renal denervation in an animal model (297). Extrarenal metabolic effects include reductions in body weight (specifically, in visceral fat); lower systolic and diastolic blood pressure, serum uric acid, and albuminuria; and either neutral or favorable effects on lipid fractions (292,298,299). Figure 3 summarizes the panoply of mechanisms found to relate to changes seen with SGLT2 inhibitors. There are currently four U.S. Food and Drug Administration (FDA)–approved SGLT2 inhibitors that have been studied in large and appropriately statistically powered CVOTs and two renal outcomes trials. All have converged on favorable cardiovascular and renal outcomes. The most recent meta-analysis, by McGuire et al. (156) included the six trials that, despite heterogeneity across the different SGLT2 inhibitor agents concerning cardiovascular outcomes, found consistent reduction of hospitalization for heart failure (HHF) and progression of kidney disease. On closer examination of the individual trials included in this meta-analysis, patients in four of the six trials had baseline eGFRs between 60 and 90 mL/min/1.73 m2 , with high or moderately increased albuminuria (50% and possible associated sodium-hydrogen exchanger inhibition • Reduction in NLRP3 inflammasome activity • Inhibition of sympathetic tone-like denervation • Attenuation of obesity-associated inflammation (i.e., reduced adipocyte cytokine production) • Improvement in anemia through effects on erythropoietin and possibly HIF-1 •