Impact of Empagliflozin on Glomerular Hyperfiltration and Albuminuria in Youth with Type 2 Diabetes

Key Points We investigated the effects of empagliflozin on hyperfiltration and albuminuria in youth with type 2 diabetes. Hyperfiltration and albuminuria were significantly attenuated compared with placebo in adolescents aged 10–17 years with type 2 diabetes on empagliflozin. Additional studies are required to evaluate the effect of sodium-glucose cotransporter-2 inhibition on diabetic kidney disease risk in youth. Background Hyperfiltration, common in youth with type 2 diabetes (T2D), may increase the risk of early diabetic kidney disease. The Diabetes Study of Linagliptin and Empagliflozin in Children and Adolescents and Diabetes Study of Linagliptin and Empagliflozin in Children and Adolescents MONO trials showed that compared with placebo, empagliflozin improved glycemic control in youth with T2D. This post hoc analysis evaluated empagliflozin versus placebo on selected parameters in participants from both trials according to their baseline (BL) hyperfiltration/normofiltration status. Methods We calculated eGFR using the Zappitelli equation (combined serum creatinine and cystatin C), with hyperfiltration defined as 2 SDs above average for healthy youth per National Health and Nutrition Examination Survey (>126.8 ml/min per 1.73 m 2 ). After randomization, 116 participants received empagliflozin (10 mg or 25 mg) or placebo. We compared responses to therapy for eGFR and urine albumin-creatinine ratio (UACR) at week 26 by BL hyperfiltration and normofiltration (≤126.8 ml/min per 1.73 m 2 ), with empagliflozin groups pooled. Results Empagliflozin treatment led to more significant reductions in eGFR among participants with BL hyperfiltration compared with normofiltration ( P interaction = 0.01). At week 26, eGFR decreased significantly with empagliflozin versus placebo in those with hyperfiltration (adjusted mean difference [95% confidence interval], −11.67 ml/min per 1.73 m 2 [−19.90 to −3.43]; P = 0.006); 15% of those with hyperfiltration on empagliflozin shifted to normofiltration at week 26 versus 6% for placebo. At week 26, the geometric mean ratio of UACR was 55% lower with empagliflozin versus placebo in participants with UACR ≥30 mg/g at BL (0.45 [0.22 to 0.93]; P = 0.03). In the normofiltration subgroup, eGFR and UACR changes over time were similar between treatment groups. Conclusions Empagliflozin was associated with attenuated hyperfiltration and albuminuria in youth with T2D. Future longitudinal evaluations can assess potential long-term benefits of treatment. Clinical Trial registry name and registration number: ClinicalTrials.gov, NCT03429543.