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 m² 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 in order 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.

Figure 1

Sodium/glucose cotransporter 2 (SGLT-2) inhibition and glomerular hemodynamics in diabetes. ADP, adenosine diphosphate; ATP, adenosine triphosphate; P, phosphate. Reproduced from Alicic et al. (18) with permission of the copyright holder; original graphic © 2018 by the National Kidney Foundation.

Figure 2

Effects of canagliflozin on cardiovascular outcomes in the overall population. A: Cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. B: Fatal or nonfatal myocardial infarction. C: Fatal or nonfatal stroke. D: Hospitalization for heart failure. Reproduced from Mahaffey et al. (49) with permission of Wolters Kluwer Health, Inc; original graphic © 2019 by Mahaffey et al.

Figure 3

The kidney-heart connection for organ protection. LV, left ventricular; NHE3, sodium–hydrogen exchanger 3. Reproduced courtesy of Emily J. Cox, PhD; original graphic © 2020 E.J. Cox.

Figure 4

CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) primary outcome: kidney failure, serum creatinine doubling, kidney or cardiovascular disease death. Adapted with permission from Perkovic et al. (14) with permission of the copyright holder; original graphic © 2019 Massachusetts Medical Society.

Figure 5

CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation): summary forest plot. *Post hoc analysis. CV, cardiovascular; eGFR, estimated glomerular filtration rate; Scr, serum creatinine. Developed with data from Perkovic et al. (14)

Figure 6

Effects of sodium/glucose cotransporter 2 (SGLT2) inhibitors on chronic kidney disease end points in the cardiovascular disease outcome trials and CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation). Random effects meta-analysis. ESKD, end-stage kidney disease; RR, relative risk. Reproduced from Neuen et al. (69) with permission of the copyright holder; original graphic © 2019 Elsevier Ltd.