Dapagliflozin for the treatment of chronic kidney disease

ABSTRACT

Introduction

Sodium-dependent glucose cotransporter 2 (SGLT2) is a glucose transporter expressed on the proximal tubular cells, where it reabsorbs glucose from the glomerular filtrate. SGLT2 inhibitors (SGLT2is), initially developed as an antidiabetic drug, have recently attracted considerable attention because they have cardiorenal protective effects. Among SGLT2is, dapagliflozin was the first to demonstrate the renoprotective effect in patients with and without diabetes and has been approved for chronic kidney disease (CKD) treatment.

Areas covered

This review covers the pharmacological characteristics and the clinical efficacy and safety profiles of dapagliflozin, including comparison with other SGLT2is and risk modification strategies.

Expert opinion

In DAPA-CKD, dapagliflozin reduced the primary outcome (≥50% estimated glomerular filtration rate [eGFR] decline, end-stage kidney disease [ESKD], or renal or cardiovascular [CV] death) by 39% in CKD patients. This beneficial effect was consistent across prespecified subgroups, including those based on the presence of diabetes. Dapagliflozin also decreased the CV composite outcome and all-cause death by 29% and 31%, respectively. Although an increased risk of adverse events such as ketoacidosis and volume depletion has been reported, the robust renal and CV benefits of dapagliflozin are expected to outweigh potential risks. SGLT2is, including dapagliflozin, will constitute the mainstay of CKD treatment.

KEYWORDS:

• Chronic kidney disease
• sodium-dependent glucose cotransporter 2 (SGLT2)
• SGLT2 inhibitor
• dapagliflozin
• diabetes

Article highlights

• SGLT2 is a glucose transporter expressed on the proximal tubular cells in the kidney, where it reabsorbs glucose from the glomerular filtrate.

• Dapagliflozin is a highly selective SGLT2i, and oral administration of dapagliflozin induces urinary glucose excretion dose-dependently.

• DECLARE-TIMI 58, a global phase 3 trial in patients with type 2 diabetes, was designed to evaluate the CV safety in accordance with the FDA guidance and demonstrated the renoprotective effect of dapagliflozin as a secondary outcome.

• DAPA-CKD, a global phase 3 RCT in CKD patients with and without type 2 diabetes, showed that dapagliflozin reduced the primary composite outcome (≥50% eGFR decline, ESKD, or renal or CV death) by 39%.

• Based on the DAPA-CKD trial, dapagliflozin was approved for CKD treatment, regardless of diabetes status.

• Although an increased risk of AEs such as ketoacidosis and volume depletion has been reported, the robust renal and CV benefits of dapagliflozin are expected to outweigh potential risks.

• SGLT2 inhibitors, including dapagliflozin, will constitute the mainstay of CKD treatment.

Declaration of interest

M Nangaku has received lecture fees from Kyowa Kirin, Astellas, GSK K.K., Daiichi Sankyo, Mitsubishi Tanabe, Chugai, Torii, JT, Alexion, Akebia, MSD K.K. and Boehringer lngelheim; and research support from JT, Kyowa Kirin, Astellas, Ono, Takeda, Daiichi Sankyo, Mitsubishi Tanabe, Chugai, Torii, Kissei and Boehringer lngelheim.

Information resources

Recent review articles [150–155] and guidelines [148,149,156] will provide additional information on SGLT2is including dapagliflozin.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.