A new study led by researchers at Oxford Population Health has found that sodium-glucose co-transporter-2 (SGLT2) inhibitors provide major kidney and heart benefits for people with chronic kidney disease (CKD), regardless of whether they have diabetes or raised levels of albumin in their urine. The study is published in JAMA (The Journal of the American Medical Association) and was presented today at the American Society of Nephrology Kidney Week 2025 in Houston, Texas.
CKD affects an estimated 850 million people worldwide. Many of those at early stages of the disease, especially those without diabetes, remain untreated with SGLT2 inhibitors despite their proven benefits. Prior to this study, there has been uncertainty about the effects of SGLT2 inhibitors in certain types of patients with CKD, with international guidelines recommending different treatments based on diabetes status and urine albumin:creatinine ratio (uACR) of ≥200 mg/g or <200 mg/g.
The researchers combined data from more than 58,816 participants enrolled in eight large randomised trials of SGLT2 inhibitors, including empagliflozin, dapagliflozin, and canagliflozin, versus placebo. The study was conducted by the SGLT2 Inhibitor Meta-Analysis Cardio-Renal Trialists’ Consortium (SMART-C).
Key findings:
- SGLT2 inhibitors substantially reduced the risks of kidney disease progression, acute kidney injury, hospitalisation, and death in people with and without diabetes, and across all levels of albuminuria (a measure of kidney damage);
- Compared to placebo, allocation to SGLT2 inhibition reduced the hazard of kidney disease progression by 35% among participants with diabetes and 26% among participants without diabetes;
- Allocation to SGLT2 inhibition reduced the risk of acute kidney injury to a similar extent in participants with and without diabetes by 23% and 28% respectively;
- The risk of hospitalisation for heart failure was 32% (in people with diabetes) and 25% (in people without diabetes) lower in people who were allocated an SGLT2 inhibitor, and risk of any hospitalisation was reduced by 10% and 11%, in participants with and without diabetes respectively;
- People with lower albumin levels, who are often at lower risk of kidney failure, experienced benefit as a result of taking an SGLT2 inhibitor, particularly through reduced hospital admissions for heart failure and any other cause;
- Participants with higher albuminuria (≥200 mg/g) had larger absolute reductions in kidney disease progression;
- Serious adverse events were rare and mainly confined to patients with diabetes, where there was a small increase in ketoacidosis.
The findings suggest that guideline recommendations distinguishing between patients based on diabetes status or albuminuria level may no longer be necessary. Current international kidney disease guidelines give stronger recommendations for using SGLT2 inhibitors in patients with high albumin levels, but the new results indicate that all patients with chronic kidney disease can benefit.
Natalie Staplin, first author and Senior Statistician at Oxford Population Health, said: ‘People with early kidney disease are often managed in primary care and are at risk of hospitalisation as well as kidney and heart problems. Our study provides evidence that broader use of SGLT2 inhibitors could reduce these risks and lessen the burden on healthcare systems globally.’
Will Herrington, co-lead of the Renal Studies Group and Professor of Trials and Kidney Disease Epidemiology, from Oxford Population Health, said: ‘Our analysis shows that the kidney and heart protection provided by SGLT2 inhibitors clearly outweigh the risks, even in those without diabetes or with only small amounts of protein in their urine. This evidence supports simplifying treatment guidance to ensure more patients can benefit.’
The study authors note that with the availability of generic SGLT2 inhibitors, extending treatment to all eligible patients could make a major contribution to the World Health Organization’s goal of improving kidney health worldwide.