Renal functional reserve predicts GFR response to empagliflozin in RENALIS and RACELINES clinical trials

Background: Glomerular hyperfiltration is common in type 2 diabetes (T2D) and may reflect reduced nephron number and/or perturbed intrarenal hemodynamics. Renal functional reserve (RFR), the capacity to increase glomerular filtration rate (GFR) with physiological stimuli (e.g. a meal), may help reveal single-nephron hyperfiltration in patients with preserved baseline whole-kidney GFR. We hypothesized that reduced postprandial RFR predicts the acute hemodynamic GFR response in T2D to the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin, but not to the dipeptidyl-peptidase-4 inhibitor linagliptin or a sulfonylurea. Methods: This analysis pooled data from two 8-week randomized, double-blind, parallel-group mechanistic trials, encompassing 71 T2D patients with preserved whole-kidney GFR [mean ± standard deviation age 65 ± 7 years, boby mass index 30.4 ± 3.9 kg/m², glycated hemoglobin A1c 7.8 ± 1.0% (61.6 ± 11.0 mmol/mol), GFR 86.5 ± 17.6 mL/min/1.73 m²]. Patients received empagliflozin (10 mg; N = 20), linagliptin (5 mg; N = 27) or sulfonylurea (glimepiride 1 mg or gliclazide 30 mg; N = 24), in addition to metformin. Measured (m)GFR and effective renal plasma flow (ERPF) were determined by inulin/iohexol and para-aminohippurate clearance, respectively, based on timed urine sampling in fasting and post-protein-rich meal conditions. Intrarenal hemodynamics were calculated using Gomez equations; fractional sodium excretion (FE_Na) and systemic hemodynamics were evaluated. Results: The meal increased mGFR (+7.3 ± 1.7 mL/min/1.73 m²; P < .001) and ERPF (+44.3 ± 14.9 mL/min/1.73 m²; P = .005), with concomitant decrease in renal vascular resistance (RVR; −0.02 ± 0.01 mmHg/L/min; P < .001), driven by reduced afferent arteriolar resistance (−1068 ± 241dyne/s/cm⁵; P < .001) and lower FE_Na (−0.21 ± 0.05; P < .001). Postprandial mGFR changes did not correlate with baseline mGFR, but did correlate with postprandial RVR change (r: −0.57; P < .001). After 8 weeks, mGFR tended to decrease with sulfonylurea (P = .054) and decreased with empagliflozin (−9.1 ± 3.2 mL/min/1.73 m²; P = .016), but not with linagliptin. Baseline meal-induced mGFR changes correlated with 8-week treatment-induced mGFR changes with empagliflozin (r: 0.88; P < .001), but not with linagliptin or sulfonylurea. Conclusion: Baseline postprandial RFR predicts GFR-dipping with empagliflozin after 8 weeks, but not with GFR changes following linagliptin or sulfonylurea. As initial GFR dipping is associated with long-term kidney benefit, RFR warrants evaluation as a potential additional tool to personalize SGLT2 inhibitor therapy. Trial registration: ClinicalTrials.gov: NCT02106104 (RENALIS) and NCT03433248 (RACELINES).