Understanding the protective effects of SGLT2 inhibitors in type 2 diabetes patients with chronic kidney disease

ABSTRACT

Introduction

Sodium-glucose co-transporter type 2 inhibitors (SGLT2is) were developed as glucose-lowering agents for the management of type 2 diabetes (T2D). Unexpectedly, they showed a significant reduction in hospitalization for heart failure and hard renal outcomes in patients with and without T2D. Underlying mechanisms remain a matter of debate.

Areas covered

We summarize the protective renal effects of SGLT2is in patients with cardiovascular disease, chronic kidney disease (CKD, especially with albuminuria) or heart failure; a description of the safety of SGLT2is, with a special focus on the risk/benefit balance in people with stage 3 CKD; a comprehensive discussion of mechanisms that could explain nephro-protection; a reappraisal of the positioning of SGLT2is in recent international guidelines.

Expert opinion

Several mechanisms could contribute to improved renal prognosis with SGLT2is, among which a reduction in intraglomerular pressure by restoring the tubuloglomerular feedback, a diuretic effect that contributes to lower albuminuria and renal decongestion, especially if fluid overload is present, a reduction in renal oxygen consumption, an improvement of heart failure status with less cardiorenal syndrome and a lower risk of acute renal injury. All these effects may be mutually not exclusive, and their respective contribution may differ according to patient characteristics.

KEYWORDS:

• Acute kidney injury
• Albuminuria
• Chronic kidney disease
• Gliflozin
• Heart failure
• Nephroprotection
• Mechanism
• Renal outcome
• SGLT2 inhibitor

Article highlights

• Chronic kidney disease, which may progress to end-stage renal disease, is a common and feared complication among patients with type 2 diabetes

• SGLT2 inhibitors are recent glucose-lowering agents that proved cardiovascular and renal protection in at risk individuals, with or without type 2 diabetes

• Besides a major reduction in hospitalization for heart failure, a reduction in renal composite outcome was consistently demonstrated in large prospective trials in patients with (or at risk of) atheromatous cardiovascular disease, renal disease with albuminuria, and heart failure.

• The potential impact of baseline albuminuria and/or glomerular filtration rate has been investigated showing a positive effect across different categories, yet further studies and analyses are still required.

• Underlying mechanisms that could explain renal protection are multiple: intra-renal hemodynamic changes due to restoration of tubuloglomerular feedback, diuretic effects that may contribute to reduce albuminuria and renal congestion (especially in case of heart failure: cardiorenal syndrome), improved renal oxygenation, combination of positive effects

• SGLT2 inhibitors occupy a privileged place in recent international guidelines published not only by diabetes associations but also by nephrology and cardiology scientific societies.

Declaration of interest

AJ Scheen has received lecturer/advisor fees from AstraZeneca, Boehringer Ingelheim, Janssen, Merck Sharp & Dohme. He also worked as a clinical investigator in three cardiovascular outcome trials with SGLT2is (EMPA-REG OUTCOME, CANVAS-R, DECLARE-TIMI 58). P Delanaye has received lecturer/advisor fees from AstraZeneca. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

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

Additional information

Funding

The authors have no funding to report.