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Background and Hypothesis: This post-hoc analysis explored the semaglutide effects on eGFR slope by baseline glycemic control, blood pressure (BP), body mass index (BMI), and albuminuria status in people with type 2 diabetes and high cardiovascular risk., Methods: Pooled SUSTAIN 6 and PIONEER 6 data were analyzed for change in estimated glomerular filtration (eGFR) slope by baseline HbA1c (<8%/≥8%; <64 mmol/mol/≥64 mmol/mol), systolic BP (<140/90 mmHg/≥140/90 mmHg), and BMI (<30 kg/m2/≥30 kg/m2). SUSTAIN 6 data were analyzed by baseline urinary albumin: creatinine ratio (UACR; <30/30 - 300/>300 mg/g)., Results: The estimated absolute treatment differences (ETD) overall in eGFR slope [95% confidence intervals] favored semaglutide versus placebo in the pooled analysis (0.59 [0.29;0.89] mL/min/1.73m2/year) and in SUSTAIN 6 (0.60 [0.24;0.96] mL/min/1.73m2/year); the absolute benefit was consistent across all HbA1c, BP, BMI, and UACR subgroups (all p-interaction > 0.5)., Conclusion: A clinically meaningful reduction in risk of chronic kidney disease progression was observed with semaglutide versus placebo regardless of HbA1c, BP, BMI, and UACR levels., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Nedosiran is an N-acetyl-D-galactosamine (GalNAc)-conjugated RNA interference agent targeting hepatic lactate dehydrogenase (encoded by the LDHA gene), the putative enzyme mediating the final step of oxalate production in all three genetic subtypes of primary hyperoxaluria (PH). This phase I study assessed the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of subcutaneous nedosiran in patients with PH subtype 3 (PH3) and an estimated glomerular filtration rate  ≥ 30 mL/min/1.73 m 2 . Single-dose nedosiran 3 mg/kg or placebo was administered in a randomized (2:1), double-blinded manner. Safety/tolerability, 24-h urinary oxalate (Uox) concentrations, and plasma nedosiran concentrations were assessed. The main PD endpoint was the proportion of participants achieving a > 30% decrease from baseline in 24-h Uox at two consecutive visits. Six participants enrolled in and completed the study (nedosiran, n = 4; placebo, n = 2). Nedosiran was well-tolerated and lacked safety concerns. Although the PD response was not met, 24-h Uox excretion declined 24.5% in the nedosiran group and increased 10.5% in the placebo group at Day 85. Three of four nedosiran recipients had a > 30% reduction in 24-h Uox excretion during at least one visit, and one attained near-normal (i.e., ≥ 0.46 to < 0.60 mmol/24 h; ≥ 1.0 to < 1.3 × upper limit of the normal reference range) 24-h Uox excretion from Day 29 to Day 85. Nedosiran displayed predictable plasma PK. The acceptable safety and trend toward Uox-lowering after single-dose nedosiran treatment enables further clinical development of nedosiran in patients with PH3 who currently have no viable therapeutic options. A plain language summary is available in the supplementary information., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective treatments for reducing hemoglobin A1c (HbA1c) in people with type 2 diabetes (T2D), including those with reduced kidney function., Methods: This post hoc analysis assessed the HbA1c-lowering efficacy of semaglutide, a GLP-1RA, in participants with a range of kidney functions in the SUSTAIN 4-6 and 10 (subcutaneous semaglutide) and PIONEER 5 and 6 (oral semaglutide) clinical trials. Trial-level changes from baseline to end of treatment (EOT) in HbA1c and body weight (BW) were assessed in participants with estimated glomerular filtration rate (eGFR) >15 ml/min per 1.73 m 2 by subgroups categorized according to baseline eGFR. Adverse events were also evaluated., Results: The analysis included 8859 participants. The mean comparator-adjusted reduction in HbA1c from baseline to EOT with semaglutide ranged from 0.6% to 1.6% points across trials, with similar reductions across the eGFR subgroups (interaction P -value ≥ 0.33 for difference between eGFR subgroups within each trial). Greater weight loss from baseline to EOT with semaglutide versus comparator was observed across almost all baseline eGFR subgroups, with nominally greater weight loss with lower versus higher eGFR in SUSTAIN 6 and 10 and PIONEER 5 and 6 (interaction P  < 0.05). No new safety concerns with semaglutide were identified., Conclusion: The HbA1c-lowering effect of semaglutide in participants with T2D was comparable irrespective of eGFR, which ranged upwards from eGFR >15 ml/min per 1.73 m 2 ., (© 2022 Published by Elsevier, Inc., on behalf of the International Society of Nephrology.)