Weekly Journal Scan: SELECT renoprotective effects of semaglutide in non-diabetic, obese patients with cardiovascular disease
Year: 2024
Type: article
Abstract: Comment on the article ‘Long-term kidney outcomes of semaglutide in obesity and cardiovascular disease in the SELECT trial’ published in Nature Medicine. https://doi.org/10.1038/s41591-024-03015-5. 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.2 The 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/1.73 m2, 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 once-weekly 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/m2. More than three-quarters of patients had a history of myocardial infarction (MI) and approximately one-quarter 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/1.73 m2 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/1.73 m2) than in the placebo group (−1.6 mL/min/1.73 m2) with a net treatment benefit of 0.7 mL/min/1.73 m2 (95% CI, 0.4–1.1) in the overall population. In the subgroup of patients with baseline eGFR < 60 mL/min/1.73 m2, there was a greater increase of eGFR in the semaglutide group (5.3 mL/min/1.73 m2) than in the placebo group (3.1 mL/min/1.73 m2) with a net treatment benefit of 2.2 mL/min/1.73 m2 (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/1.73 m2; 95% CI 0.3–0.5). Cardiovascular (CV), kidney, and metabolic (CKM) diseases are pathophysiologically interrelated.3 The American Heart Association recently introduced a novel nomenclature (i.e. CKM syndrome) linking these conditions, with the aim of developing or intensifying multidisciplinary strategies for risk stratification, prevention, and treatment.3 Overweight and obesity are independently associated with an increased risk of CVD and mortality, even after taking into account the influence of metabolic CV risk factors associated with excess body weight, such as diabetes.4 Obesity is also associated with an excess of adverse renal outcomes, including faster eGFR decline and increased albuminuria. Although diabetes is recognized as an important pathogenic link, obesity increases the risk of renal dysfunction even in subjects without diabetes,5 possibly through glomerular hyperfiltration, activation of the renin–angiotensin–aldosterone system (RAAS), heightened inflammation and oxidative stress.6 Emerging evidence suggests that GLP-1 receptor agonists may exert protective renal effects. Yet, the vast majority of data in support of this hypothesis are derived from secondary or post hoc analyses of studies involving diabetic patients, with or without obesity and established CVD.7 Recently, the FLOW (Evaluate Renal Function with Semaglutide Once Weekly) trial showed a significant reduction in the risk of kidney disease–related events in patients with chronic kidney disease (CKD) and type 2 diabetes treated with semaglutide, as compared with placebo.1,8 The present analyses of the SELECT trial provide preliminary evidence supporting the hypothesis that GLP-1 receptor agonists, specifically semaglutide, might have renoprotective effects in the absence of diabetes, among patients with overweight or obesity and established CVD.2 Yet, the SELECT trial was powered for the assessment of MACE and not for the evaluation of renal outcomes that represented one of 25 supportive secondary endpoints listed in the study protocol.1 The number of kidney event endpoints was relatively low [353 in 17 604 patients (2%) after 3.5 years of follow-up], so that the study was definitely underpowered to draw conclusive remarks on the effects of semaglutide on renal outcomes. The observed treatment effect was modest (0.4% absolute difference in the primary kidney endpoint, with a number needed to treat of 250) and was largely driven by a reduction in the onset of persistent macroalbuminuria. The long-term clinical relevance of these findings is uncertain, although albuminuria is a recognized predictor of CKD progression as well as a non-traditional risk factor for CVD, including MI, stroke, HF, and microvascular disease.9 On the other hand, the low renal event rate is likely the result of the enrolment of a population with an expected low risk of kidney disease progression. Patients with end-stage kidney disease or dialysis were excluded from the SELECT trial,1 and nearly 90% of patients had a substantially preserved eGFR (≥60 mL/min/1.73 m2) at baseline, as compared with patients enrolled in the FLOW trial in whom normal baseline eGFR was recorded in only 20% of cases.1 An important limitation of the study was the large prevalence of White individuals (nearly 85%) and the relative underrepresentation of other ethnicities, in particular Black individuals (4%) who are known to be at higher risk of CKD.10 These findings, along with the low proportion of female sex (28%), represent a drawback for the generalizability of the results. The mechanisms by which semaglutide may impact on kidney outcomes remain uncertain. Notably, weak correlations between eGFR changes and individual variations in body weight, glycated haemoglobin (HbA1c), or systolic blood pressure were observed. A mediation analysis suggested that ∼80% of the eGFR change at week 104 could be related directly to changes in body weight. While other interventions leading to substantial weight loss, such as bariatric surgery, are associated with improvements in eGFR and albuminuria, an independent association between body weight loss and benefit on renal function cannot be ascertained from the current analysis, due to the intrinsic limitations of mediation models in a population with low event rates. In addition, two out of three patients enrolled in the SELECT trial met the criterion for pre-diabetes (defined as a mean HbA1c level of 5.7%–6.4%). Therefore, the influence of an improved glucose metabolism on the observed renal benefits in patients treated with semaglutide cannot be excluded, as pre-diabetes may increase the risk of CKD.11 An interesting observation was an early transient reduction of eGFR in the patients treated with semaglutide, which recovered within 20 weeks. The cause of this transient worsening in eGFR is unclear, though changes in glomerular pressure or natriuresis may be contributing factors. Of note, this early decline in eGFR followed by longer-term benefit on renal function has also been observed with sodium-glucose co-transporter-2 inhibitors, RAAS inhibitors, and tirzepatide.12 Within the limitations of statistical uncertainty and limited mechanistic insight, the results of these analyses suggest potential renoprotective effects of semaglutide in a population of overweight or obese patients and established CVD, without history of diabetes. However, these findings, which are consistent with the growing evidence for the beneficial effects of GLP-1 receptor agonists on renal function, need to be confirmed by specifically designed RCTs to test different approaches to the management of the CKM syndrome. R.V. received consulting or lecturing fees from Abbott Vascular, ABIOMED, Amgen, Daiichi Sankyo, and Medtronic, outside the submitted work. M.V. reports personal fees for speaker bureau and/or consulting in Advisory Boards from, Astra Zeneca, Bayer, GSK, Menarini Int, Novartis Pharma, Novo Nordisk, Pfizer, Sanofi Pasteur, Servier. MV is supported by a research grant from Italian Ministry of Health (‘Ricerca corrente’).
Source: European Heart Journal
Authors: Rocco Vergallo, Massimo Volpe
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4402253500