#4441 Kidney Disease Outcomes With Semaglutide Versus Placebo Across Baseline Kdigo Risk Categories: A Post Hoc Analysis of Sustain 6

Abstract

Background and Aims The Kidney Disease: Improving Global Outcomes (KDIGO) risk categories classify risk of progression of chronic kidney disease (CKD) and cardiovascular (CV) complications based on estimated glomerular filtration rate (eGFR) and urinary albumin:creatinine ratio (UACR). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are recommended by the KDIGO 2022 Clinical Practice Guidelines for Diabetes and CKD in patients with type 2 diabetes (T2D) and CKD who need better glycaemic control or CV risk reduction. In patients with T2D, once-weekly (OW) semaglutide, a GLP-1RA, reduces albuminuria and may preserve eGFR compared with placebo, irrespective of baseline eGFR or UACR. The aim of this analysis was to assess the treatment effects on kidney outcomes of OW semaglutide by KDIGO risk category at baseline compared with placebo. Method In a post hoc analysis from the SUSTAIN 6 trial (NCT01720446), randomised patients with T2D (N = 3,297) treated with OW semaglutide (0.5 and 1.0 mg) or placebo were stratified by baseline KDIGO risk category (low, moderate, high, and very high). The median follow-up time was 2.1 years. The treatment effect on the adjudicated endpoint of time to first new or worsening nephropathy (a composite of macroalbuminuria onset, doubling of serum creatinine and eGFR <45 mL/min/1.73 m2, need for kidney replacement therapy, or death due to kidney disease) across KDIGO categories was analysed using Cox regression. Analyses of treatment for eGFR slope and change in UACR (log-transformed) across KDIGO categories were performed using random slope modelling and mixed models adjusted for baseline UACR and assessed at 104 weeks. Results Participants with baseline eGFR and UACR values (N = 3,238) were stratified in to the low (n = 1,596 [49%]; 60% male; mean 64 years), moderate (n = 831 [26%]; 62% male; mean 65 years), high (n = 445 [14%]; 62% male; mean 66 years) and very high (n = 366 [11%]; 59% male; mean 67 years) KDIGO risk categories. Regardless of treatment group, participants in the moderate-, high- and very high-risk groups were more likely to experience the new or worsening nephropathy endpoint vs participants in the low-risk group at end of trial (hazard ratios [95% confidence intervals] 15.7 [8.0;35.7], 15.7 [7.7;36.6] and 23.9 [11.5;55.9], respectively). The treatment effect of OW semaglutide vs placebo was comparable in the low-, moderate-, high- and very high-risk categories (n = 785, 433, 227 and 171 for semaglutide and n = 811, 398, 218 and 195 for placebo, respectively) for new or worsening nephropathy (pinteraction = 0.28), eGFR slope (pinteraction = 0.44) and change in UACR (pinteraction = 0.84; Figure). Conclusion Participants in the higher risk groups had substantially greater hazards of adverse kidney outcomes compared with participants in the low-risk group, as predicted by KDIGO risk category classification. The treatment effect of OW semaglutide vs placebo on risk of new or worsening nephropathy, eGFR slope and change in UACR was consistent across KDIGO risk categories. The ongoing FLOW kidney outcomes trial has a population with T2D and CKD that corresponds to the high- and very high-risk KDIGO categories, and it will provide primary outcome data on potential kidney-protective effects of OW semaglutide; results are anticipated in 2024.