Associate Professor Brendon Neuen

Research continues to emphasise the benefits of SGLT2 inhibitors in patients with CKD across the full spectrum of eGFR and UACR, and regardless of diabetes status, according to a meta-analysis of SGLT2 inhibitor trials.

The findings, presented at the ASN Kidney Week meeting and concurrently published in JAMA [link here], reinforce recommendations from major cardiovascular, endocrinology, and nephrology clinical practice guidelines to initiate SGLT2 inhibitors in patients with CKD and an eGFR greater than or equal to 20 mL/min/1.73 m², regardless of diabetes status.

The meta-analysis, led by Associate Professor Brendon Neuen from The George Institute for Global Health, comprised 70,361 participants from ten SGLT2 inhibitor trials including kidney outcomes trials such as CREDENCE, DAPA-CKD, and EMPA-KIDNEY, along with heart failure and type 2 diabetes trials.

Participants included those in baseline categories of eGFR <30, 30-<45, 45-<60, and ≥60 mL/min/1.73 m²; UACR <30, 30-300, and >300 mg/g; and KDIGO classification of low, moderate, high, and very high-risk.

The meta-analysis found the incidence of the primary outcome of CKD progression was lower with SGLT2 inhibitors compared with placebo (25.4 vs 40.3 events per 1000 patient-years; HR, 0.62 [95% CI, 0.57-0.68]).

SGLT2 inhibitors also lowered the risks of all secondary kidney outcomes studied, including CKD progression or cardiovascular death (HR, 0.75 [95% CI, 0.72- 0.80]), kidney failure alone (HR, 0.66 [95% CI, 0.58-0.75]), kidney failure or all-cause mortality (HR, 0.85 [95% CI, 0.81-0.89]), and serious AKI (HR, 0.74 [95% CI, 0.66-0.82]).

The HR for the effect of SGLT2 inhibitors on CKD progression was similar across eGFR categories.

In analyses further stratified by diabetes status, there was no evidence that the effect of SGLT2 inhibitors on CKD progression was modified by eGFR in participants with or without diabetes.

SGLT2 inhibitors also reduced risk of CKD progression regardless of baseline UACR.

“In analyses treating participants with and without diabetes separately, there was also no evidence of effect modification by baseline UACR in either population (P for trend = .96 and .07 for diabetes and no diabetes, respectively), although there were very few events in participants without diabetes and UACR less than or equal to 30 mg/g,” it said.

SGLT2 inhibitors also reduced the risk of CKD progression irrespective of KDIGO risk categories overall and in participants with and without diabetes.

“These findings, representing the totality of the large-scale randomised evidence for SGLT2 inhibitors approved for reducing CKD progression, provide the clearest support to date for routine use of SGLT2 inhibitors across the full spectrum of CKD, including in patients with stage 4 CKD, who are at the highest risk of kidney failure, and in those with little to no albuminuria.”

In a statement from the George Institute, Associate Professor Neuen reiterated that the findings provide the strongest evidence yet to support widespread use of SGLT2 inhibitors in people with CKD.

“SGLT2 inhibitors are a powerful tool to reduce the burden of kidney failure, hospitalisation and premature death in patients with diabetes, CKD, or heart failure. These findings indicate that many more individuals than are currently being treated stand to benefit, highlighting a major opportunity to improve population health.” he said.

He said simplifying treatment guidelines would encourage broader use of the SGLT2 inhibitors.

“As these medicines become more affordable and widely available in generic form over the next few years, we have a once-in-a-generation opportunity to transform care for millions of people living with or at risk of developing kidney disease around the world.

Meanwhile, a second paper from the SGLT2 Inhibitor Meta-Analysis Cardio-Renal Trialists’ Consortium (SMART-C) was also published in JAMA [link here] and presented at ASN Kidney Week by the University of Oxford’s Associate Professor Natalie Staplin.

SMART-C simultaneous publication in @JAMA_current!

Bottom line: Absolute benefits of SGLT2i far exceed any potential harms in people with & without diabetes, and UACR < & >200mg

Time to accelerate implementation to improve population health: https://t.co/YLUnA9EJm3#kidneywk pic.twitter.com/RTvO7xnEAD

— Brendon Neuen (@brendonneuen) November 7, 2025

The meta-analysis of data representing 58,816 participants from eight trials of SGLT2 inhibitors vs placebo found SGLT2 inhibitor use reduced the risk of AKI by 23% (HR, 0.77 [95% CI, 0.69-0.87]) in participants with diabetes and 28% (HR, 0.72 [95% CI, 0.56-0.92]) in participants without diabetes.

“Similarly, use of an SGLT2 inhibitor reduced the risk of hospitalisation for heart failure by 32% (HR, 0.68 [95% CI, 0.62-0.74]) in participants with diabetes vs 25% (HR, 0.75 [95% CI, 0.63-0.88]) in participants without diabetes and reduced the risk of any hospitalisation by 10% (HR, 0.90 [95% CI, 0.87-0.92]) in participants with diabetes vs 11% (HR, 0.89 [95% CI, 0.83-0.95]) in participants without diabetes…” the study said.

“The effects of SGLT2 inhibition on cardiovascular and noncardiovascular death separately and combined were also not modified by diabetes status.”

It found no evidence that the diabetes-specific HRs were modified by baseline UACR category for acute kidney injury, hospitalisation for heart failure, any hospitalisation, cardiovascular death, or noncardiovascular death.

“When considering death from any cause among participants with diabetes, there was some evidence that the magnitude of the relative effect of SGLT2 inhibition was greater among participants with a UACR of 200 mg/g or greater (HR, 0.78 [95% CI, 0.70-0.87]) vs a UACR less than 200 mg/g (HR, 0.90 [95% CI, 0.83-0.98]) (P = .03 for heterogeneity).”

Regarding safety, SGLT2 inhibition doubled the risk of ketoacidosis (HR, 2.29 [95% CI, 1.42-3.71]) among participants with diabetes but the risk was substantially outweighed by the cardiorenal, hospitalisation, and mortality benefits, it said.

“The presented evidence offers an opportunity for the guidelines to be simplified to reduce arguably unnecessary stratification of recommendations by diabetes status and by UACR and consequently maximize implementation of appropriate use of SGLT2 inhibitors,” the investigators said.

An accompanying editorial in JAMA [link here] agreed that the evidence warranted consideration of expanding the eligibility criteria for SGLT2 inhibitor in future guidelines. 

“Despite the lower absolute benefits, some people with lower overall risk, such as those with UACR less than 200 mg/g, may still prefer to reduce their risk as much as possible, and the guidelines should reflect the benefit of SGLT2 inhibitors for achieving this goal,” it said.

“Such a change in eligibility criteria would increase the number of people eligible to receive these treatments and, when scaled to the population level, this could have a substantial potential benefit for improving total kidney outcomes.”

Meanwhile, clinical implementation efforts should address the underutilisation of SGLT2 inhibitors in the higher risk patients for whom they were currently indicated.