HOUSTON — The benefits of SGLT2 inhibitors in slowing kidney disease progression are similar regardless of patients’ type 2 diabetes (T2D) or albuminuria status, the results of a recent meta-analysis showed.

“These data support removal of stratification by level of albuminuria from guideline recommendations for use of SGLT2 inhibitors in chronic kidney disease (CKD) and also support more widespread use of these treatments,” said first author Natalie Staplin, PhD, of the Nuffield Department of Population Health, Medical Sciences Division, University of Oxford, Oxford, England, who presented the findings at Kidney Week 2025: the American Society of Nephrology Annual Meeting. The research was simultaneously published in JAMA.

International recommendations from the Kidney Disease Improving Global Outcomes CKD Work Group call for the use of SGLT2 inhibitors in CKD, with the highest recommendations (1A) for patients with T2D and an estimated glomerular filtration rate (eGFR) of ≥ 20 mL/min/1.73 m².

The recommendation, however, is weaker (2B) for patients without T2D and a urine albumin-to-creatinine ratio (UACR) of < 200 mg/g, indicative of lower risk, based largely on data from heart failure trial populations and a subgroup of participants with CKD in the EMPA-Kidney trial, the authors of the current study explained.

As many as two thirds of individuals with decreased eGFR fall into the category of having normal-to-mild increases in albuminuria, and therefore remain at risk for adverse health outcomes, including cardiovascular death, heart failure, and acute kidney injury, that could be modifiable with SGLT1 inhibitors; however, these patients may not be prescribed the drugs based primarily on their lower UACR, they added.

“Guidelines focusing on only one potential benefit of SGLT2 inhibition (eg, kidney disease progression outcomes alone) will overlook the major absolute benefits on other important clinical outcomes among this large group of individuals, including reduction in hospitalizations and mortality,” they noted.

An SGLT2 Inhibitor Meta-Analysis Cardio-Renal Trialists’ Consortium (SMART-C) Meta-Analysis

To better assess the evidence on the relative and absolute effects of SGLT2 inhibitors across albuminuria levels and diabetes status, Staplin and the SMART-C conducted the current meta-analysis which included eight randomized clinical trials with a total of 59,354 patients comparing SGLT2 inhibitors with placebo.

A total of 34,322 patients were in trials specifically for T2D and included those at high risk for atherosclerotic cardiovascular disease; 9718 were in trials of heart failure; and 15,314 were in trials of CKD.

Of the 58,816 participants included in the meta-analysis, 48,946 (83.2%) had T2D. Overall, 17,088 trial participants (29.1%) had a baseline UACR of ≥ 200 mg/g.

In terms of relative benefits, the analysis found that treatment with SGLT2 inhibitors was associated with a lower rate of kidney disease progression (defined as a decline in eGFR of ≥ 40%, kidney failure, or death due to kidney failure), to be greater compared with placebo among those with diabetes (hazard ratio [HR], 0.65) and without diabetes (HR, 0.74). The rates were also similar based on UACR status of ≥ 200 mg/g or < 200 mg/g.

CKD progression occurred in 5.9% of patients with diabetes and 7.2% for those without diabetes.

The mean follow-up for the groups was about 3 years for those with diabetes and 1.7 years for those without diabetes.

The use of SGLT2 inhibitors was also associated with improvements in all patients in acute kidney injury (HR, 0.77 with diabetes and 0.72 without diabetes), a lower rate of any hospitalization (HR, 0.90 with diabetes vs 0.89 without diabetes), and a lower rate of any death (HR, 0.86 with diabetes and 0.91 without diabetes) compared with placebo. The mean times of follow-up in those groups ranged from 1.5 to 3.3 years.

The similar rate of hospitalization seen among patients with a UACR < 200 mg/g was notably observed even after exclusion of participants from the heart failure trials.

In terms of absolute benefits, those with a UACR ≥ 200 mg/g treated had higher reductions in kidney disease progression with SGLT2 inhibitors compared with those whose UACR was < 200 mg/g.

Patients with diabetes and a UACR of < 200 mg/g had a lower estimated absolute benefit from SGLT2 inhibitors in terms of disease progression, with a number needed to treat (NNT) to prevent one case of CKD progression of 120, compared with an NNT of only 16 for those with a UACR ≥ 200 mg/g.

Furthermore, the NNT was 358 for those without diabetes and UACR of < 200 mg/g vs only 25 for those with UACR ≥ 200 mg/g.

However substantial absolute benefits with SGLT2 inhibitors were observed regardless of albuminuria status in other measures, including in the risk for hospitalization, heart failure, or other causes, across all subgroups.

The net absolute benefits remained consistent among patients from nonheart failure populations who had an eGFR of < 60 mL/min/1.73 m².

Safety Outcomes ‘Reassuring’

In terms of safety, among those with diabetes, SGLT2 inhibitor use was associated with approximately double the risk for ketoacidosis (HR, 2.29) regardless of UACR status; however, the rates of the adverse events were too infrequent among those without diabetes to estimate an HR based on UACR.

The risks for lower limb amputation and bone fracture did not differ significantly among those with and without diabetes or based on UACR differences.

“The absolute risks of serious harm were largely limited to participants with diabetes and were substantially outweighed by the cardiorenal, hospitalization, and mortality benefits,” the authors noted.

Meg Jardine, MBBS, PhD, who was a co-author on the study and comoderated the session at Kidney Week, noted that the safety findings were encouraging.

“The safety, if anything, is more reassuring in people without diabetes — you don’t see ketoacidosis in people without diabetes, but the benefits are just as strong,” Jardine, who is director of the NHMRC Clinical Trials Centre and a professor of medicine, both at The University of Sydney, Sydney, Australia, told Medscape Medical News.

SGLT2 Inhibitors Underutilized in CKD

The findings are especially notable considering that the underutilization of SGLT2 inhibitors in CDK, with recent data from 2022 to 2023 showing that only 11.9% of those with diabetes who had a class 1A indication for SGLT2 inhibitors were prescribed the drugs.

Utilization rates are reportedly even lower among Medicare beneficiaries, at just 7.3% for those with CKD and 13.7% for those with both CKD and T2D. Treatment discontinuation rates are also high.

Jardine noted that with most new therapies “you usually see lower uptake in general practice than you would expect from the guidelines or the indications.”

“However, it’s probably a more critical issue for the SGLT2 inhibitors because their benefits are so proven,” she noted.

Cost Effectiveness

In addition to a lack of awareness of the drugs’ benefits in various risk groups, an important factor in underutilization is the high cost of SGLT2 inhibitors. With that in mind, some of the absolute values and higher numbers needed to treat observed in the lower risk groups may give pause.

Those results “have important implications for the cost-effectiveness of broadening indications to include individuals at lower risk for CKD progression,” said Sankar D. Navaneethan, MD, MPH, of Baylor College of Medicine, Houston, and coauthors in an editorial published along with the study.

He noted, however, that “despite the lower absolute benefits, some people with lower overall risk, such as those with UACR < 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.”

“While the absolute might be lower compared to those with higher level of albuminuria, SGLT2 inhibitors still would offer benefits for an individual patient,” Navaneethan told Medscape Medical News.

“In real world practice, adoption of these agents remains suboptimal even in high-risk population and efforts are needed to increase their uptake,” he said.

Of the notable absolute benefits of SGLT2 inhibitors observed in the lower albuminuria-risk patients were the large effects on hospitalization, which have been shown in large trials to result in cost-effectiveness in participants with CKD regardless of their diabetes status and level of albuminuria.

“The widespread use of SGLT2 inhibitors for individuals with CKD could lead to major reductions in kidney failure and hospitalization globally, thus improving efficiency for healthcare services,” the authors noted in the study.

Generic Availability?

Importantly, a key event that should significantly improve the utilization of SGLT2 inhibitors will be the upcoming availability of generic options of SGLT2 inhibitors.

“High cost is one of the multiple barriers and we anticipate generic version of dapagliflozin will be available very soon,” Navaneethan said.

While this offers some help, continued education to identify high-risk populations who would benefit from these medications and to help clinicians initiate them, is critical, he added.

Staplin reported receiving institutional grant support from Boehringer Ingelheim, Eli Lilly, and Novo Nordisk. Jardine’s disclosures included advisory or other relationships with Astra Zeneca, Bayer, Baxter, Boehringer Ingelheim, Chinook, CSL, Janssen, Novartis, OccuRx, Vifor. Navaneethan reported receiving grants from National Institutes of Health and Veterans Affairs and personal fees from Alnylam, Intercept, ProKidney, Vertex, AstraZeneca, Bayer, Boehringer Ingelheim, and Novartis, outside the editorial.