ESPE Yearbook of Paediatric Endocrinology

Diabetes Care. 2024 Sep 1;47(9):1617-1621. doi: 10.2337/dc24-0322

Brief Summary: Thispaper reports a post hoc analysis of the AWARD-PEDS study, evaluating the effects of dulaglutide on kidney function in youth aged 10–18 years with T2D. AWARD-PEDS enrolled 154 youth aged 10 to <18 years with T2D andBMI >85th percentile. Participants were either on metformin, with or without basal insulin, or following lifestyle modification alone, and were randomized to receive dulaglutide (0.75 mg or 1.5 mg once weekly) or placebo. The cohort was ~50% female and included individuals of diverse ancestry, reflecting the epidemiology of pediatric T2D in the United States. The primary outcome was the change in HbA1c at 26 weeks. Dulaglutide reduced HbA1c by 0.6–0.9 percentage points compared to a 0.6 percentage point increase with placebo. More dulaglutide-treated participants achieved HbA1c <7.0% (51% vs. 14% with placebo). There was no difference in BMI change between the groups.

In this post hoc analysis over 26 weeks, dulaglutide was associated with a reduction in estimated glomerular filtration rate (eGFR) compared to placebo, particularly in those with baseline glomerular hyperfiltration. Additionally, the prevalence of both glomerular hyperfiltration and proteinuria decreased in the dulaglutide group, whereas these measures increased in the placebo group. The study did not establish whether these changes translate into a reduced long-term risk of diabetic kidney disease in this population.

Comment: In adults with obesity, renal hyperfiltration (increased glomerular filtration rate (GFR) relative to body weight) is associated with early kidney injury, as evidenced by increased albuminuria. The pathophysiology involves increased renal plasma flow and intraglomerular hypertension, driven by afferent arteriolar vasodilation, insulin resistance, and activation of the renin-angiotensin-aldosterone system. This leads to glomerular and tubular hypertrophy, increased Bowman’s space, and, over time, proteinuria, microalbuminuria, and progression to focal segmental glomerulosclerosis and chronic kidney disease. In adolescents with obesity, renal hyperfiltration is highly prevalent, depending on the definition and GFR estimation method used. In adolescents, hyperfiltration is associated with insulin resistance, hypertriglyceridemia, and hyperuricemia, and may be an early marker of obesity-related glomerulopathy. Adolescents with hyperfiltration often have a worse cardiometabolic profile and are at increased risk for future CKD. Therefore, early identification and interventions are critical to prevent progression to irreversible kidney damage and associated metabolic complications in youth with obesity and T2D. This secondary analysis supports the principle that pharmacologic intervention to improve glucose metabolism and/or promote weight loss may be an important component of management of risk for kidney disease in adolescents with obesity and T2D.

Key Message: In adolescents, obesity and T2D are associated with glomerular hyperfiltration, which is a risk for early development of CKD. Therefore, comprehensive management of these adolescents requires early identification and management of hyperfiltration. In addition to current efforts at improving lifestyle and weight, this manuscript provides support for pharmacologic interventions to improve glucose control, insulin resistance, and adiposity.

References: 1. Ahmed N, Dalmasso C, Turner MB, et al. From Fat to Filter: The Effect of Adipose Tissue-Derived Signals on Kidney Function. Nature Reviews. Nephrology. 2025;21(6):417-434. doi: 10.1038/s41581-025-00950-5.2. Mackowiak-Lewandowicz K, Ostalska-Nowicka D, Zaorska K, et al. Chronic Kidney Disease Predictors in Obese Adolescents. Pediatric Nephrology (Berlin, Germany). 2022;37(10):2479-2488. doi: 10.1007/s00467-021-05403-2.3. Ricotti R, Genoni G, Giglione E, et al. High-Normal Estimated Glomerular Filtration Rate and Hyperuricemia Positively Correlate With Metabolic Impairment in Pediatric Obese Patients. PloS One. 2018;13(3):e0193755. doi: 10.1371/journal.pone.0193755.