Obesity is a significant risk factor for chronic kidney disease (CKD), characterized by a decline in glomerular filtration rate (GFR) and increased albuminuria. This association persists even in non-diabetic individuals, highlighting obesity's independent impact on renal function. Studies have shown a causal link between higher BMI and increased odds of CKD, independent of known mediators like diabetes. The mechanisms underlying obesity-related CKD are multifaceted and involve processes such as hyperfiltration, inflammation, oxidative stress, increased tubular sodium reabsorption, and activation of the renin-angiotensin-aldosterone system. Pathological changes in the kidneys, including ectopic lipid accumulation and hyperfiltration-related injury, are also observed. Therefore, effective treatments targeting obesity and its impact on kidney health are crucial. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as potential therapeutic agents. While meta-analyses of GLP-1RA trials in patients with type 2 diabetes showed improvements in kidney outcomes, their impact in non-diabetic, obese individuals with established cardiovascular disease remains unclear. The SELECT trial, which demonstrated a significant reduction in major adverse cardiovascular events (MACE) with semaglutide in this population, provides a unique opportunity to investigate the effects of semaglutide on kidney outcomes.

Existing literature extensively documents the link between obesity and CKD, outlining the independent risk posed by obesity irrespective of diabetic status. Mendelian randomization studies support a causal relationship, emphasizing the importance of addressing obesity to mitigate CKD risk. The mechanisms underlying this association involve a complex interplay of factors affecting renal hemodynamics, inflammation, and tissue structure. GLP-1RAs have shown promise in improving kidney outcomes in patients with type 2 diabetes, but the impact on non-diabetic, obese individuals remains relatively understudied. Prior research on weight-loss interventions has suggested beneficial effects on kidney function; however, the specific effects of GLP-1RAs in the population of interest remain to be explored comprehensively. This trial directly addressed this knowledge gap by specifically focusing on the impact of semaglutide on renal function in overweight/obese individuals with cardiovascular disease but without diabetes.

The SELECT trial was a randomized, double-blind, placebo-controlled, event-driven trial comparing semaglutide 2.4 mg weekly to placebo in 17,604 individuals with established CVD, overweight/obesity (BMI ≥27 kg/m²), and no type 2 diabetes. Patients were aged ≥45 years and had established CVD (prior MI, stroke, or symptomatic PAD). Exclusion criteria included diabetes, HbA1c ≥6.5%, end-stage kidney disease, recent cardiovascular events, or severe heart failure. Patients were randomized 1:1 to receive semaglutide (escalating doses to 2.4 mg over 16 weeks) or placebo. The primary kidney outcome was a composite endpoint including death from kidney disease, initiation of chronic kidney replacement therapy (CKD-RT), persistent eGFR <15 ml/min/1.73 m², persistent ≥50% reduction in eGFR, or persistent macroalbuminuria. Secondary outcomes included individual components of the primary endpoint, other composite kidney endpoints, time to specific eGFR fall thresholds, eGFR slope (total, chronic, and acute), changes in eGFR and UACR at week 104, and adverse events. eGFR was calculated using the CKD-EPI 2009 equation (with sensitivity analyses using the 2021 equation). UACR was calculated from urine samples collected at various time points. All components of the primary endpoint were adjudicated by an independent blinded committee. Statistical analyses included Cox proportional hazards models for time-to-event outcomes and mixed models for repeated measures of continuous outcomes. Subgroup analyses were performed based on baseline characteristics. A mediation analysis was conducted to explore potential mediators of the effect of semaglutide on eGFR, specifically examining the roles of weight change, blood pressure and HbA1c. The study followed the intent-to-treat principle with a sensitivity analysis on the on-treatment population.

The study found a statistically significant 22% reduction in the primary composite kidney endpoint with semaglutide versus placebo (hazard ratio 0.78, 95% CI 0.63-0.96, P=0.02). This benefit was largely driven by a reduced incidence of macroalbuminuria and a persistent ≥50% reduction in eGFR. Analysis of individual components of the composite endpoint demonstrated that semaglutide significantly reduced the risk of persistent macroalbuminuria (HR 0.80, P=0.05) and a persistent ≥50% decline in eGFR (HR 0.57, P=0.11). Death from kidney disease or initiation of chronic kidney replacement therapy were rare events and did not contribute significantly to the primary outcome difference. At 104 weeks, semaglutide demonstrated a treatment benefit of 0.75 ml/min/1.73 m² in overall eGFR compared to placebo (P<0.001). This benefit was more pronounced in patients with baseline eGFR <60 ml/min/1.73 m², showing a treatment difference of 2.19 ml/min/1.73 m² (P<0.001). Analysis of the eGFR slope (annualized rate of change) showed a significantly slower decline in eGFR with semaglutide (-0.78 ml/min/1.73 m²/year) compared to placebo (-1.17 ml/min/1.73 m²/year), indicating a treatment benefit of 0.39 ml/min/1.73 m²/year (P<0.001). This effect was consistent across the total and chronic periods (from week 20 onwards). An initial more pronounced decline in eGFR was observed in the semaglutide arm in the first 16 weeks in European patients, but this difference disappeared by week 20. Semaglutide also resulted in a significant 10.7% less increase in UACR at 104 weeks compared to placebo (P<0.001), with larger benefits observed in patients with higher baseline UACR. Subgroup analyses showed consistent treatment effects across various demographic and clinical characteristics. There was little correlation between changes in eGFR and changes in body weight, blood pressure, or HbA1c; however, a mediation analysis suggested that 81% of the change in eGFR at week 104 could be attributed to changes in body weight.

This study provides the first evidence demonstrating the beneficial effects of a GLP-1RA, specifically semaglutide, on kidney outcomes in a population of overweight/obese individuals with established cardiovascular disease but without diabetes. The significant reduction in the primary composite kidney endpoint, driven primarily by the decreased incidence of macroalbuminuria and persistent decline in eGFR, highlights the potential for semaglutide to improve renal health in this high-risk group. The magnitude of the observed effects, particularly the significant improvement in eGFR in patients with impaired baseline renal function, is noteworthy. While the mediation analysis suggests that weight loss likely contributes to some extent to the renal benefits, other potential mechanisms, including direct effects on renal pathways, cannot be ruled out. The study's findings are consistent with prior research suggesting beneficial kidney effects of GLP-1RAs, although the present study is the first large trial to show this in patients without diabetes. These results have important implications for the management of obesity-related CKD, offering a potential therapeutic option beyond weight loss alone.

This pre-specified analysis of the SELECT trial provides compelling evidence that semaglutide offers significant benefits for kidney outcomes in overweight or obese individuals with cardiovascular disease, independent of diabetes. The observed reductions in the composite kidney endpoint and improvements in eGFR, particularly in those with impaired baseline renal function, suggest semaglutide as a promising therapeutic option for this high-risk population. Future research should focus on elucidating the precise mechanisms underlying semaglutide's renoprotective effects and exploring its long-term impact on CKD progression. Investigating the use of alternative methods for assessing GFR, such as cystatin C, in conjunction with creatinine is also needed.

The study used the CKD-EPI creatinine-based eGFR equation, which may not perfectly capture changes in kidney function in individuals with extreme BMIs or those experiencing substantial weight loss. The potential confounding effect of muscle mass changes on serum creatinine levels should be considered. While a mediation analysis was performed, the interpretation of the results should be cautious due to the limitations inherent in such analyses. Although the study had a large sample size, the number of events for some specific kidney outcomes was relatively small, potentially limiting the power of subgroup analyses. The study was primarily focused on cardiovascular outcomes, and other potential mediators of kidney outcomes were not examined. The long term effects of semaglutide on kidney health remain to be fully determined and additional long-term follow up is required.