Mid-term renal impact of SGLT2 inhibitors in heart failure: a systematic review and meta-analysis

Background Decline in renal function is a major concern in patients with heart failure (HF), necessitating a comprehensive evaluation of estimated glomerular filtration rate (eGFR) slopes to assess impact of sodium-glucose co-transporter-2 (SGLT2) inhibitors. Purpose This meta-analysis examined data from thirteen randomised controlled trials, encompassing 90,412 participants, to compare renal function decline in patients treated with SGLT2 inhibitors versus placebo. Methods The study was conducted in accordance with PRISMA guidelines, with searches performed in MEDLINE,Embase, PubMed, CINAHL-Ebsco, and CENTRAL from inception till October 31, 2024. Eligible studies involving any class of SGLT2 inhibitors, included double-blinded, placebo-controlled RCTs in adults with Heart failure; with either reduced ejection faction (HFrEF, <40%), mid-range (HFmrEF, 40-50%) and preserved ejection fraction (HFpEF≥50%) assessing renal outcomes including eGFR changes, acute kidney injury, and albuminuria. Hard endpoints such as need for renal replacement therapy were excluded. Changes in eGFR were assessed across three distinct slope measurements: acute, total, and chronic. The acute slope represented the early phase following treatment initiation, the total slope measured eGFR decline over the entire study duration, while the chronic slope excluded the initial weeks of acute eGFR reduction. Results In five studies encompassing 17,759 patients with HF, SGLT2 inhibitors were associated with a greater initial acute eGFR decline compared to placebo, as reflected in a Hedges' g value of -0.16 (95% CI -0.21 to -0.10; p=0.0011). However, analysis of the total eGFR slope across six trials involving 20,170 participants demonstrated a significantly slower annual decline in eGFR among those receiving SGLT2 inhibitors, with a mean difference of 1.03 ml/min/1.73m² per year (95% CI 0.39 to 1.66, p=0.0087). Further assessment of the chronic slope, based on four trials with 14,212 participants, showed greater preservation of renal function in the SGLT2 inhibitor group, with mean difference of 1.37 ml/min/1.73m² per year (95% CI 0.63 to 2.10, p=0.0096). A subgroup analysis was performed by combining six total slope trials and four chronic slope trials, including a total of 34,382 participants. SGLT2 inhibitors attenuated rate of eGFR decline, with mean difference of 1.18 ml/min/1.73m² per year (95% CI 0.80 to 1.57, p<0.0001). When comparing patients between the HFmrEF and HFpEF groups, the effects of SGLT2 inhibitors on eGFR decline did not differ significantly between the two groups. However, those in the HFrEF group exhibited the greatest renal benefits. Conclusion SGLT2 inhibitors initially cause a small acute decline in eGFR, but over time, they significantly slow the rate of kidney function decline in patients with HF. This protective effect is consistent across different patient groups, with the greatest benefit seen in those with HFrEF.