A placebo-adjusted effect of the initial eGFR decline following SGLT-2 inhibitor initia-tion: a systematic review and meta-analysis

INTRODUCTION: Sodium‑glucose cotransporter 2 inhibitors (SGLT‑2is) are pivotal in managing heart failure, chronic kidney disease, and type 2 diabetes mellitus. While their beneficial impact is well established, the effects of the initial decline in estimated glomerular filtration rate (eGFR) at the start of SGLT‑2i therapy are poorly understood. OBJECTIVES: The study aimed to assess the impact of the initial eGFR dip on prognosis in the abovementioned conditions. PATIENTS AND METHODS: We systematically searched several databases to identify studies analyzing the effect of the initial eGFR dip following the initiation of an SGLT‑2i on selected outcomes. Randomized controlled trials (RCTs) were included, and a backward snowballing method was applied. The analysis was conducted according to the PRISMA guidelines and registered in PROSPERO (CRD42024527609). RESULTS: Out of 2422 papers screened, 14 passed the initial screening, and 5 were included in the quantitative analysis. The dip status was reported for all participants (n = 23 890), with the dip occurring in 13 575 patients (56.82%; 8245 [34.51%] in the intervention arm and 5330 [22.31%] in the placebo arm). In the patients allocated to receive SGLT2is, the initial eGFR dip, regardless of its magnitude, was not linked to an increased risk of adverse kidney outcomes, cardiovascular composite end point, cardiovascular mortality (hazard ratio [HR], 0.85; 95% CI, 0.65-1.11; P = 0.24), or all‑cause mortality (HR, 0.9; 95% CI, 0.7-1.15; P = 0.4). In contrast, in the placebo group, the dip was associated with a worse prognosis for the cardiovascular composite end point (HR, 1.35; 95% CI, 1.19-1.52; P <0.001). The use of an SGLT-2i, as compared with placebo, was associated with a positive effect on the cardiovascular composite end point in the dip range of 0%-1.1% to 10%-11.8% (risk difference [RD], -0.04; 95% CI, -0.07 to -0.01; P = 0.006) and greater than 10%-11.8% (RD, -0.04; 95% CI, -0.06 to -0.02; P <0.001), but not if the dip exceeded 25%-30% (RD, -0.06; 95% CI, -0.13 to 0.02; P = 0.12). CONCLUSIONS: Unlike in the placebo arms of RCTs, where an eGFR dip was associated with unfavorable outcomes, the early eGFR dip in the patients receiving SGLT‑2is was either neutral or beneficial. The SGLT-2i-related eGFR dip appears to confer a particularly favorable effect in the population with heart failure with reduced ejection fraction. Mild SGLT-2i-related eGFR dip (reduction by ≤11.8%) correlated with improved cardiovascular outcomes, while larger reductions did not negatively impact patient prognosis.