SGLT2 Inhibition for CKD and Cardiovascular Disease in Type 2 Diabetes: Report of a Scientific Workshop Sponsored by the National Kidney Foundation

Abstract

Diabetes is the most frequent cause of chronic kidney disease (CKD), leading to nearly half of all cases of kidney failure requiring replacement therapy. The principal cause of death among patients with diabetes and CKD is cardiovascular disease (CVD). Sodium/glucose cotransporter 2 (SGLT2) inhibitors were developed to lower blood glucose levels by inhibiting glucose reabsorption in the proximal tubule. In clinical trials designed to demonstrate the CVD safety of SGLT2 inhibitors in type 2 diabetes mellitus (T2DM), consistent reductions in risks for secondary kidney disease end points (albuminuria and a composite of serum creatinine doubling or 40% estimated glomerular filtration rate decline, kidney failure, or death), along with reductions in CVD events, were observed. In patients with CKD, the kidney and CVD benefits of canagliflozin were established by the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial in patients with T2DM, urinary albumin-creatinine ratio > 300 mg/g, and estimated glomerular filtration rate of 30 to <90 mL/min/1.73 m 2. To clarify and support the role of SGLT2 inhibitors for treatment of T2DM and CKD, the National Kidney Foundation convened a scientific workshop with an international panel of more than 80 experts. They discussed the current state of knowledge and unanswered questions to propose therapeutic approaches and delineate future research. SGLT2 inhibitors improve glomerular hemodynamic function and are thought to ameliorate other local and systemic mechanisms involved in the pathogenesis of CKD and CVD. SGLT2 inhibitors should be used when possible by people with T2DM to reduce risks for CKD and CVD in alignment with the clinical trial entry criteria. Important risks of SGLT2 inhibitors include euglycemic ketoacidosis, genital mycotic infections, and volume depletion. Careful consideration should be given to the balance of benefits and harms of SGLT2 inhibitors and risk mitigation strategies. Effective implementation strategies are needed to achieve widespread use of these life-saving medications. Complete author and article information provided before references.

Sodium‐glucose cotransporter‐2 inhibition reduces cellular senescence in the diabetic kidney by promoting ketone body‐induced NRF2 activation

“…Sensitivity analyses of CREDENCE and DAPA‐CKD showed that the renoprotective effect was evident in subjects with eGFR less than 45 mL/min/1.73 m 2 to a similar extent to that observed in those with eGFR >45 mL/min/1.73 m 2 16,17 . The mechanism of the renoprotective effect of SGLT2 inhibition could be multifactorial, 4,24‐26 which may include an antisenescent effect induced by β‐HB.…”

Crosstalk between Sodium–Glucose Cotransporter Inhibitors and Sodium–Hydrogen Exchanger 1 and 3 in Cardiometabolic Diseases

“…Thus, ketogenesis is postulated to contribute to the development of diabetic nephropathy. It is more favorable to say that SGLT-2i works by mimicking the starvation state by stimulating the activity of AMPK and suppressing Akt/mTOR signaling to reduce oxidative stress, reduce inflammation, normalize mitochondrial function and structure, prevent IRI, and prevent the development of cardiomyopathy [ 158 , 159 ].…”

Activin A and Cell-Surface GRP78 Are Novel Targetable RhoA Activators for Diabetic Kidney Disease

“…Current treatment options, including glucose and blood pressure control, use of renin-angiotensin system blockers and, more recently, use of SGLT2 (sodium-glucose cotransporter-2) inhibitors in those with type 2 diabetes, slow disease progression. However, DKD remains the leading cause of kidney failure globally, accounting for almost half of those with end-stage kidney disease requiring dialysis or transplantation [ 1 , 2 ]. A continued improvement in our understanding of the molecular mechanisms underlying its pathogenesis will enable the development of additional complementary therapeutics that will impact DKD progression.…”