Weekly Journal Scan: SELECT renoprotective effects of semaglutide in non-diabetic, obese patients with cardiovascular disease

The Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity (SELECT) was a company-funded, double-blind, randomized controlled trial (RCT) demonstrating that the addition of semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, to standard care was associated with a 20% reduction in the risk of major adverse cardiovascular events (MACE) as compared with placebo, among patients with overweight or obesity and established cardiovascular disease (CVD) without diabetes. 1 This secondary analysis of SELECT aimed to evaluate the effects of semaglutide on long-term kidney outcomes. 2The previously defined kidney endpoint was a composite of the first specified death from kidney disease, initiation of chronic kidney replacement therapy (dialysis or transplantation), onset of persistent estimated glomerular filtration rate (eGFR) <15 mL/min/1.73m 2 , persistent 50% reduction in eGFR compared with baseline, or onset of persistent macroalbuminuria.Persistent was defined as 2 new measures at least 4 weeks apart.Other analyses included time to reaching various thresholds of percentage eGFR decline (30%, 40%, 50%, and 57%); the annualized rate of change in eGFR (eGFR slope); and change in eGFR or a urinary albumin-to-creatinine ratio (UACR) from baseline to week 104.End-stage kidney disease or dialysis at baseline was among the exclusion criteria of the trial. From October 2018 through March 2021, a total of 17 604 patients (mean age, 62 years; 28% female) were randomized 1:1 to either onceweekly subcutaneous 2.4 mg semaglutide (to be escalated from a starting dose of 0.24 mg over 16 weeks) or placebo.The mean body mass index (BMI) was 33.3 5.0 kg/m 2 .More than three-quarters of patients had a history of myocardial infarction (MI) and approximately onequarter of chronic heart failure (HF).There were no differences in relatively well-preserved kidney function (mean eGFR, 82.5 17.4 mL/min/ 1.73 m2) and albuminuria status at baseline between the two groups.Only about one-fifth of the trial population had either an eGFR < 60 mL/ min/1.73m2 or an UACR 30 mg/g at baseline. After a median follow-up of 182 weeks, a primary kidney endpoint event occurred in 155 of 8803 patients (1.8%) in the semaglutide group and in 198 of 8801 patients (2.2%) in the placebo group [hazard ratio (HR), 0.78; 95% confidence interval (CI), 0.63-0.96;P-value, not adjusted for multiplicity = .02].There were no specified deaths from kidney disease, and the vast majority of primary kidney endpoint events were represented by the onset of persistent macroalbuminuria [144 in the semaglutide group (1.6%) and 179 in the placebo group (2.0%); HR, 0.80; 95% CI, 0.64-1.00]. At the follow-up time point of 104 weeks, eGFR decline was smaller in the semaglutide group (-0.9 mL/min/1.73m2) than in the placebo group (-1.6 mL/min/1.73m2) with a net treatment benefit of 0.7 mL/min/1.73m2 (95% CI, 0.4-1.1) in the overall population.In the subgroup of patients with baseline eGFR < 60 mL/min/1.73m2, there was a greater increase of eGFR in the semaglutide group (5.3 mL/min/1.73m2) than in the placebo group (3.1 mL/min/1.73m2) with a net treatment benefit of 2.2 mL/min/1.73m2 (95% CI 1.0-3.4).At 104 weeks, UACR increase (expressed as percentage change from baseline) was smaller in the semaglutide group than in the placebo group, resulting in a net treatment benefit of -10.7% (95% CI, -13.2 to -8.2).The mean annual slope of the eGFR was less steep in the semaglutide group than in the placebo group (between-group difference: 0.4 mL/min/1.73m2; 95% CI 0.3-0.5).