Meta-Analyses Confirm Broad Kidney Protection From SGLT2 Inhibitors

Sodium-glucose cotransporter-2 (SGLT2) inhibitors have rapidly reshaped the management of kidney and cardiovascular disease. Initially developed as glucose-lowering agents for type 2 diabetes, they have since demonstrated consistent benefits in slowing chronic kidney disease (CKD) progression, reducing cardiovascular events, and lowering the risk of hospitalization across broad patient groups. As a result, they have been incorporated into major clinical practice guidelines for diabetes, CKD, and heart failure. Yet real-world practice still lags behind the evidence, and uncertainty has persisted regarding how these therapies perform among people at the margins of prior trials—particularly those with very low estimated glomerular filtration rate (eGFR) or with normal or near-normal albuminuria.

Two companion meta-analyses from the SGLT2 Inhibitor Meta-Analysis Cardio-Renal Trialists’ Consortium (SMART-C) were designed to address these uncertainties. The results, presented at the American Society of Nephrology Kidney Week and published in JAMA, pool data from large randomized, double-blind, placebo-controlled trials that met SMART-C’s inclusion criteria (≥500 participants per arm and ≥6 months’ follow-up).

Brendon Neuen, MBBS, MSc, PhD, renal and metabolic program lead at the George Institute for Global Health and an associate professor at the University of New South Wales, Sydney, Australia, was an investigator on both studies. He explained, “SGLT2 inhibitors are a powerful tool to reduce the burden of kidney failure, hospitalization, 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.”

Effects by Glomerular Filtration Rate and Albuminuria

In the first meta-analysis, Dr. Neuen and colleagues examined whether the kidney-protective effects of SGLT2 inhibitors were consistent across the spectrum of kidney function and albuminuria. They included 10 large, randomized trials comprising 70,361 participants, drawing from studies in type 2 diabetes, CKD, and heart failure with preserved or reduced ejection fraction. Patients in lower eGFR categories tended to have an albumin-to-creatinine ratio (UACR) greater than 300 mg/g and were less likely to have atherosclerotic cardiovascular disease or diabetes. Groups with higher UACRs had higher proportions of participants with eGFR less than 45 mL/min/1.73 m² and lower proportions with atherosclerotic cardiovascular disease or diabetes. All trials included had a low risk of bias.

The primary outcome, progression of CKD (defined as kidney failure, at least a 50% decline in eGFR, or death due to kidney failure) occurred among 2,314 participants. Rates of CKD progression were substantially lower among those receiving an SGLT2 inhibitor compared with placebo (25.4 vs 40.3 events per 1,000 patient-years; hazard ratio [HR], 0.62; 95% CI, 0.57-0.68). Secondary analyses demonstrated reductions in risks for CKD progression or cardiovascular death (HR, 0.75), kidney failure alone (HR, 0.66), kidney failure or all-cause mortality (HR, 0.85), and serious acute kidney injury (HR, 0.74).

Notably, effect sizes did not vary across eGFR categories, including participants with stage 4 CKD. Benefits were similarly consistent across UACR categories, including for participants with UACR of 30 mg/g or lower, who experienced robust protection (HR, 0.58; 95% CI, 0.44-0.76). These findings address an evidence gap, showing that the benefits of SGLT2 inhibitors are consistent across eGFR categories—including stage 4 CKD—and across all levels of albuminuria, including participants with minimal albuminuria.

The authors concluded that SGLT2 inhibitors “were found to lower the risk of CKD progression regardless of baseline eGFR or albuminuria, including among patients with stage 4 CKD or minimal albuminuria, supporting their routine use to improve kidney outcomes across the full spectrum of kidney function among patients with type 2 diabetes, CKD, or heart failure.”

Effects by Diabetes Status and Albuminuria

The second meta-analysis, conducted by Natalie Staplin, PhD, Dr. Neuen, and colleagues, examined whether the relative and absolute benefits of SGLT2 inhibitors differ by diabetes status and across levels of albuminuria. Eight randomized controlled trials met inclusion criteria, spanning 59,354 participants. Nearly all had baseline UACR measurements, allowing for more granular subgroup meta-analyses.

Participants with diabetes—who comprised roughly 83% of the pooled study population—had higher baseline eGFR than participants without diabetes. Both groups had UACR of less than 200 mg/g on average. Progression of kidney disease occurred among 5.9% of participants with diabetes and 7.2% of those without.

Across both groups, SGLT2 inhibitors substantially reduced the risk for kidney disease progression, with benefits observed irrespective of diabetes status or baseline albuminuria. Among participants with diabetes, SGLT2 inhibitors reduced CKD progression by 35% (HR, 0.65; 95% CI, 0.60-0.70). Among those without diabetes, risk was reduced by 26% (HR, 0.74; 95% CI, 0.63-0.85).

Similarly, rates of acute kidney injury and hospitalization for any cause were lower with SGLT2 inhibitors compared with placebo, regardless of whether the patient had diabetes. All-cause mortality was significantly lower with SGLT2 inhibitor use for patients with diabetes.

The authors wrote that “there were clear absolute benefits of SGLT2 inhibitors on kidney, hospitalization, and mortality outcomes irrespective of diabetes status and level of UACR,” underscoring that diabetic status alone should not gatekeep therapy.

The consistency of benefits among people without diabetes further strengthens the positioning of SGLT2 inhibitors as kidney medications, not merely glucose-lowering drugs. Dr. Neuen emphasized that the findings of both meta-analyses point toward broader adoption of SGLT2 inhibitors. “Our findings support simplifying treatment guidelines to encourage broader use of these medicines,” he said.

“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.”