The SGLT2 Inhibitor Empagliflozin Might Be a New Approach for the Prevention of Acute Kidney Injury

Abstract

Three randomized control trials (Canagliflozin Cardiovascular Assessment Study, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients [EMPA-REG OUTCOME], and Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 [DECLARE-TIMI 58]) showed that the sodium-glucose co-transporter 2 (SGLT2) inhibitors, originally developed as glucose-lowering drugs, are associated with a lower rate of adverse renal outcomes, such as need for renal replacement therapy, doubling of serum creatinine, and loss of glomerular filtration rate (GFR) compared to those in placebo groups. Besides, canagliflozin and empagliflozin also showed a lower risk of progression to macroalbuminuria. The EMPA-REG OUTCOME trial and DECLARE-TIMI 58 trial also indicated that these SGLT2 inhibitors might have beneficial effects on the prevention of acute kidney injury. The United States Food and Drug Administration (FDA) warned of the risk of acute kidney injury for canagliflozin and dapagliflozin. We compared canagliflozin, empagliflozin, and dapagliflozin with respect to chemical structure and pharmacological properties, to explain the observed differences in preventing acute kidney injury, and put forward the hypotheses of the potential mechanisms of different effects of SGLT2 inhibitors on acute kidney injury. Given the raising clinical use of SGLT2 inhibitors, our review should stimulate further basic science and clinical studies in order to definitively understand the role of SGLT2 inhibitors in acute kidney injury. A weakness of the clinical data obtained so far is the fact that the statements concerning acute kidney injury are just based on safety data – mainly creatine measurements. However, given the mode of action of SGLT2 blockers, initiation of a therapy with a SGLT2 blocker will cause an increase of creatine because of its effects on the tubuloglomerular feedback mechanisms/glomerular hemodynamics like RAAS blocking agents do. To really understand the potential effects of SGLT2 inhibitors, we need preclinical and clinical SGLT2 inhibitor studies focusing on all aspects of acute kidney injury – not just changes in GFR biomarkers.

Sodium–glucose cotransporter type 2 inhibitors for the treatment of type 2 diabetes mellitus

“…These results were confirmed in real-life conditions where the risk of AKI associated with SGLT2i use was consistently reported to be lower rather than higher compared with other glucose-lowering agents [223][224][225] . All together, these data led to the intriguing proposal that the SGLT2i empagliflozin might be considered as a new approach for the prevention of AKI 226 .…”

Pharmacokinetics, pharmacodynamics and tolerability of single and multiple doses of janagliflozin, a sodium‐glucose co‐transporter‐2 inhibitor, in Chinese people with type 2 diabetes mellitus

“…When used alone, SGLT2 inhibitors do not increase the risk of hypoglycaemia, and have a protective effect on heart and kidney function by reducing body weight and blood pressure. 1,[5][6][7] inhibitors were included in the 2015 American Diabetes Association/European Association for the Study of Diabetes position statement on the management of hyperglycaemia and the American Association of Clinical Endocrinologists/American College of Endocrinology diabetes management guidelines and algorithm. 8,9 Four SGLT2 inhibitors have been approved by the US Food and Drug Administration and the European Medicine Agency, including dapagliflozin, empagliflozin, ertugliflozin and canagliflozin, and six SGLT2 inhibitors have been approved in Japan, including ipragliflozin, tofogliflozin, luseogliflozin dapagliflozin, empagliflozin and canagliflozin.…”

“…Orally administered dapagliflozin achieves C max at 2 hours (T max ), and the half-life is 12.9 hours. 6,13,14 Dapagliflozin has two dosing options, 5 or 10 mg once daily. 15,16 Dapagliflozin 10 mg provides continuous inhibition of urinary glucose reabsorption for 24 hours post-dose, improves glycaemic control, and has a favourable tolerability profile.…”

“…Clinical trials have confirmed the anti‐hyperglycaemic effect of SGLT2 inhibitors in individuals with type 2 diabetes mellitus (T2DM). When used alone, SGLT2 inhibitors do not increase the risk of hypoglycaemia, and have a protective effect on heart and kidney function by reducing body weight and blood pressure 1,5–7 . SGLT2 inhibitors were included in the 2015 American Diabetes Association/European Association for the Study of Diabetes position statement on the management of hyperglycaemia and the American Association of Clinical Endocrinologists/American College of Endocrinology diabetes management guidelines and algorithm 8,9 …”

“…Among these, dapagliflozin is a highly selective, orally active, reversible inhibitor of SGLT2 used to treat T2DM. Orally administered dapagliflozin achieves C max at 2 hours (T max ), and the half‐life is 12.9 hours 6,13,14 . Dapagliflozin has two dosing options, 5 or 10 mg once daily 15,16 .…”