One large clinical trial investigated renal primary endpoints and demonstrated that SGLT2 inhibitors slowed the progression of diabetic kidney disease (DKD).
Message: The present review proposes a novel theory; unlike other hypoglycemic agents or diuretics, SGLT2 inhibitor could protect DKD from failing by improving latent renal congestion even without symptomatic HF.
Recently, sodium-glucose co-transporter 2 (SGLT2) inhibitors have been demonstrated to reduce cardiovascular complications and slow diabetic kidney disease progression in patients with type 2 diabetes.
There may be a growing role for sodium-glucose co-transporter 2 (SGLT-2) inhibitors in diabetic renal disease and for glucagon-like peptide (GLP)-1 therapy in renal and liver disease (nonalcoholic steatohepatitis).
This Perspective summarizes proposed mechanisms of action for SGLT2 inhibitors, integrates these data with results of recent cardiovascular outcomes trials, and discusses clinical applications for patients with DKD.
Even with recent studies employing SGLT2 inhibitors demonstrating protection against cardiovascular and kidney diseases, kidney function continues to decline in people with established diabetic kidney disease (DKD).
Preclinical studies performed in animal models of DKD support the renoprotective action of SGLT-2 inhibitors showing that these agents exert albuminuria-lowering effects and reverse glomerulosclerosis.
Inhibition of Sglt2 is accepted as a viable therapeutic treatment option for patients with type 2 diabetes and has been shown to delay development of diabetic kidney disease.
Empagliflozin and SGLT2 inhibitors may have a favorable impact on the progression of DKD in nonalbuminuric diabetic people, a hypothesis to be tested in specific clinical trials.
Recent studies suggest that SGLT-2 inhibitors affect phosphate homeostasis, but their effects on phosphate-regulating hormones in patients with diabetic kidney disease are still unclear.
Through various proposed mechanisms, among which diuretic and natriuretic effects, SGLT-2 inhibitors decrease heart failure hospitalization, reduce cardiovascular mortality, and mitigate progression of diabetic kidney disease.
For major cardiovascular events (MACE), there is no class effect for SGLT-2 inhibitors, as the 7% reduction of MACE risk observed with dapagliflozin in the DECLARE trial was not significant; on the other hand, a class effect is evident for both heart failure and diabetic kidney disease, as in all four trials so far completed (EMPAREG-OUTCOME, CANVAS, DECLARE, CREDENCE) the risk of hospitalization for heart failure and progression of diabetic kidney disease was significantly reduced by all SGLT-2 inhibitors.
Therefore, we can reasonably suggest that normalized Pin1 expression and AMPK activation contribute to the molecular mechanisms underlying SGLT2 inhibitor-induced suppression of diabetic nephropathy, possibly at least in part by reducing inflammation and fibrotic change.
The effects of dapagliflozin (Dapa) on the activation of the Nlrp3 inflammasome and the combined effect of SGLT2 and DPP4 on T2DM-induced inflammasome activation and progression of DN have not been previously studied.
In the EMPA-REG OUTCOME trial, SGLT2 inhibition with empagliflozin reduced the primary outcome of major adverse cardiovascular events (MACE), while also reducing mortality, hospitalization for heart failure, and progression of diabetic kidney disease.
SGLT2 inhibitors display renoprotective effects in diabetic kidney disease, which creates a rationale for testing the therapeutic potential of this drug class in nondiabetic chronic kidney disease.
Results of ongoing clinical trials in patients with DKD are eagerly awaited to expand knowledge of how SGLT2 inhibitors might be used for prevention and treatment.