Inhibition of SGLT2 in the renal proximal tubule results in increased urinary glucose excretion and modest improvements of hemoglobin A1C. Treatment with any of the three currently FDA-approved SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin) results in sustained systolic and diastolic blood pressure reduction, in part via minimal natriuresis and possible reductions in sympathetic tone. Recent randomized clinical trials in high cardiovascular risk patients with type 2 diabetes suggest that the unique effects of SGLT2 inhibitors on blood pressure and body weight may translate into reduced cardiovascular events and slowed kidney disease progression. However, concerns about volume depletion and acute kidney injury have been raised. SGLT2 inhibitors are viable second-line glucose-lowering agents for people with type 2 diabetes with high cardiovascular risk.

Diabetic kidney disease (DKD) is the major cause of kidney failure in the world and the combination of DKD and diabetes mellitus contributes to an additive incidence of worsening cardiovascular mortality rates. Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) remain the mainstay of therapy and have reduced kidney function decline in DKD from 8 to 10 to~4 mL/min/y. Sodium-glucose co-transporter-2 (SGLT2) inhibitors, in the presence of ACE inhibitors or ARB agents, further slowdown DKD progression by an additional 58% to 1.8 mL/min/y. Moreover, SGLT2 inhibitors reduce heart failure risk. However, the normal rate of kidney function decline in humans is between 0.7 and 0.9 mL/min/y, hence, there is still room for improvement. Mineralocorticoid receptor antagonists (MRAs) already have a track record of benefit in heart failure risk reduction, and efficacy in reducing albuminuria and treating resistant hypertension; however hyperkalaemia and other adverse effects preclude their routine use in DKD. Novel non-steroidal MRAs offer a reduced risk of hyperkalaemia, and yet have many benefits that they share with their steroidal cousins. This paper reviews the data for both steroidal and non-steroidal MRAs in DKD and presents some data from soon-to-becompleted ongoing renal and cardiovascular outcome trials in DKD.

MRAs have a clear role in further reducing very high albuminuria when used with other renin-angiotensin system blockers; however, hyperkalemia is a limiting factor for the use of MRAs. Use of the new potassium binder patiromer has facilitated the use of MRAs in CKD, and novel nonsteroidal MRAs are currently being tested in advanced CKD outcome trials.