#2496 Effect of semaglutide on kidney outcomes in people with overweight or obesity and established cardiovascular disease in the SELECT trial

Abstract Background and Aims Obesity is an important risk factor for declining kidney function and albuminuria. Secondary analyses of cardiovascular outcome trials in people with type 2 diabetes suggest that the glucagon-like peptide-1 receptor agonist semaglutide has the potential to reduce kidney function deterioration. Semaglutide reduced the primary endpoint of major adverse cardiovascular events by 20% in the randomised controlled SELECT trial in people with overweight or obesity without diabetes. The present report is the prespecified analysis on secondary and exploratory kidney outcomes in SELECT. Method The main kidney endpoint was the time from randomisation to first occurrence of a 5-component nephropathy composite comprising: death from kidney causes; initiation of chronic kidney replacement therapy (dialysis or transplantation); onset of persistent estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m2; persistent ≥50% reduction in eGFR compared with baseline; or onset of persistent macroalbuminuria. Persistence was defined as at least two measures at least 4 weeks apart. Patients were randomised to once-weekly subcutaneous semaglutide 2.4 mg or placebo. Blood and urine samples for eGFR and urinary albumin-to-creatinine ratio (UACR) were collected at screening, at 20, 52, 104, 156, 208 weeks of follow-up and at the end of treatment. Analyses were of in-trial data and used Cox regression and mixed models for repeated measures. Results A total of 8803 patients were assigned to semaglutide and 8801 to placebo. The median follow-up was 182 weeks. The main composite nephropathy endpoint occurred in fewer of those assigned semaglutide (1.8% [155/8803]) than placebo (2.2% [198/8801]): hazard ratio 0.78 [95% confidence interval (CI) 0.63, 0.96]; p = 0.02 (Fig. 1). This effect on the main endpoint was driven by the treatment effect on onset of macroalbuminuria and, to a lesser extent, persistent ≥50% reduction in eGFR. At the prespecified 104-week time point, eGFR had declined less in the semaglutide than placebo arm, giving a treatment effect of 0.75 mL/min/1.73 m2 [95% CI 0.43, 1.06]; p < 0.001 (Fig. 2A). The treatment effect on eGFR at 104 weeks was 0.57 mL/min/1.73 m2 [95% CI 0.26, 0.89] among those with eGFR ≥60 mL/min/1.73 m2 (N = 15 638) at baseline and was 2.19 mL/min/1.73 m2 [95% CI 1.00, 3.38] in those with eGFR <60 mL/min/1.73 m2 (N = 1908) at baseline. At 104 weeks the proportionate increase in UACR was less in the semaglutide than the placebo arm, with a treatment effect of –10.7% [95% CI –13.2, –8.2]; p < 0.001 (Fig. 2B). The treatment effect on UACR at 104 weeks was –8.1% [95% CI –10.6, –5.6], –27.2% [95% CI –35.3, –18.1] and –31.4% [95% CI –54.9, 4.3] in those with normo- (N = 14 848), micro- (N =1968) and macroalbuminuria (N = 325) at baseline, respectively. Semaglutide was not associated with any excess of acute kidney injury, regardless of baseline eGFR. Conclusion These prespecified secondary analyses suggest a beneficial effect of once-weekly subcutaneous semaglutide 2.4 mg on a composite kidney endpoint in people with overweight or obesity and established cardiovascular disease. Significant benefits for both eGFR and UACR were found, including clinically relevant lesser eGFR decline in those with baseline eGFR <60 mL/min/1.73 m2.