Effects of SGLT2 inhibitors in patients with CKD with or without frailty: A Systematic Review

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Barbara Wong1, C Aldenhoven1, E Copland1,2, N Jones1, T Cai1, PA Bateman1, FDR Hobbs1,3, JP Sheppard1

1 Nuffield Department of Primary Care Health Sciences, University of Oxford 2 Wolfson Institute of Population Health, Barts and The London School of Medicine and Dentistry, Queen Mary University of London 3 Oxford Institute of Digital Health, Oxford

Scientific Research

SP - Pharmacology

Frailty

View DOI

Abstract

Introduction

Frailty is common in patients with chronic kidney disease (CKD), and their coexistence increases the risk of cardiorenal complications. Whether the cardiorenal benefits of sodium-glucose co-transporter-2 (SGLT2) inhibitors extend to patients with CKD and frailty remains unclear. This review summarised the evidence in this population.

Methods

We searched MEDLINE, Embase, and the Cochrane Library from inception to February 10, 2025, without language restrictions. Eligible studies were randomised controlled trials (RCTs) or observational studies of adults with CKD receiving SGLT2 inhibitors versus placebo, standard care, or active comparators, with outcomes stratified by a study-defined frailty measure. Primary outcomes were individual renal endpoints, including estimated glomerular filtration rate decline ≥ 40%, end-stage kidney disease, or death from renal causes. Co-primary outcomes were hospitalisation for heart failure or cardiovascular death, death from cardiovascular cause or all-cause mortality. Review was registration with PROSERPO (CRD420251000967).

Results

Among 8,421 records, two RCTs met inclusion criteria (DAPA-CKD and EMPA-KIDNEY; n=10,912), with no eligible observational studies. None reported our pre-specified primary renal outcome. In DAPA-CKD, dapagliflozin versus placebo reduced composite renal outcomes across all frailty groups. The hazard ratios (HRs) ranged from 0.42 (95% CI [confidence interval] 0.27–0.67) to 0.57 (95% CI 0.41–0.90) in not-to-mildly frail and severely frail patients, respectively (p-interaction=0.44). In EMPA-KIDNEY, empagliflozin reduced the risk in moderately (HR 0.65, 95%CI 0.52-0.80; HR 0.66 95%CI 0.48-0.91) and severely frail patients (HR 0.74, 95%CI 0.57-0.97). Heart failure hospitalisation or cardiovascular death was reduced in severely frail patients in DAPA-CKD (HR 0.67, 95%CI 0.49–0.92) (p-interaction=0.63) and moderately frail patients in EMPA-KIDNEY (HR 0.53, 95%CI 0.29–0.96). In DAPA-CKD, all-cause mortality was reduced in moderate and severely frail patients.

Conclusions

There was no evidence that the benefits and harms of SGLT2 inhibitors vary by frailty in CKD; frailty alone should not preclude prescribing. Interpretation warrants caution given limited evidence.