The glucagon‐like peptide‐1 receptor agonist semaglutide in diabetic kidney disease: A new kid on the block to afford maximal kidney protection

Chronic kidney disease (CKD) is the most common complication of type 2 diabetes (T2D).1 The co-existence of CKD and T2D is associated with a substantially higher risk for adverse cardiovascular outcomes and faster deterioration of kidney function.2 For almost two decades, the only available pharmacological interventions to mitigate this excess cardiorenal risk included the optimization of blood glucose levels towards an individualized glycaemic target, the adequate blood pressure control and the use of an agent blocking the renin–angiotensin system (RAS) at maximum or maximally tolerated doses.3 Fortunately, this disappointing picture has been modified after the discovery of novel therapies that afford additive cardiorenal protective benefits.3 In a triad of landmark trials conducted specifically in CKD patients who were already treated with a RAS blocker, sodium-glucose co-transporter type 2 (SGLT-2) inhibitors provoked an impressive placebo-subtracted reduction in the risk of kidney failure and death from kidney or cardiovascular causes.4 Similarly, in a large phase 3 clinical trial programme involving 13,026 patients with T2D and a broad spectrum of CKD, the non-steroidal mineralocorticoid receptor antagonist (MRA) finerenone improved the composite kidney and cardiovascular outcomes relative to placebo.5 Once again, these additive effects were demonstrated in patients receiving optimized background therapy with maximally tolerated doses of a RAS blocker before randomization.5 On this scientific basis, both SGLT-2 inhibitors and finerenone have been included as recommended pharmacological interventions for patients with CKD associated with T2D in recently released guidelines.6, 7 However, the residual cardiorenal risk of these patients remains an unresolved issue, generating the need for additional effective therapies. In this Commentary, we discuss the kidney protective effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in patients with diabetic kidney disease, providing a critical evaluation of the results of the FLOW (Evaluate Renal Function with Semaglutide Once Weekly) trial.8, 9 GLP-1RAs are established and guideline-directed therapies for the improvement of glycaemic control and weight loss in patients with T2D.6, 7 Some agents that belong to this novel antidiabetic drug class also mitigate the risk for major adverse cardiovascular events in patients with T2D and established cardiovascular disease or in people with T2D and multiple cardiovascular risk factors.6, 7 However, until recently, the potential kidney protective effects of GLP-1RAs were based mainly on indirect evidence from secondary exploratory analyses of cardiovascular outcome or glycaemic control trials.10-12 In a 2019 meta-analysis of five trials involving a total of 40,302 high-risk patients with T2D, relative to placebo, treatment with GLP-1RAs was associated with a significant 17% reduction in the occurrence of a broader kidney outcome, defined as the composite of new-onset macroalbuminuria, doubling of serum creatinine or sustained ≥40% decrease in estimated glomerular filtration rate (eGFR), incident end-stage kidney disease (ESKD) or renal death hazard ratio (HR): .83; 95% confidence interval (CI): .78–.89.10 Notably, this benefit was primarily driven by a treatment-induced improvement in albuminuria. In contrast, when a narrower composite outcome of worsening of kidney function was analysed, the kidney protective effect of GLP-1RAs did not significantly differ from the effect of placebo (HR: .87; 95% CI: .73–1.03).10 In a 2022 combined analysis incorporating data from 12,637 patients with T2D participating in the SUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) and LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trials,11 relative to placebo, active treatment with semaglutide/liraglutide provoked a 24% reduction in the urinary albumin-to-creatinine ratio (UACR) over a follow-up period of 2 years (95% CI: 20%–27%). As compared with placebo, the GLP-1RAs simaglutide and liraglutide slowed the annual rate of eGFR decline by .87 and .26 mL/min/1.73m2, respectively.11 These effects appeared to be larger in magnitude in patients with established CKD at baseline. Furthermore, simaglutide/liraglutide provoked significant placebo-subtracted reductions in the risks for sustained 40% and 50% eGFR decline over time (HR: .86; 95% CI: .75–.99 and HR: .80; 95% CI: .66–.97, respectively).11 Similar directional, but not statistically significant, effects were evident for 30% and 57% eGFR reductions (HR: .92; 95% CI: .84–1.02 and HR: .89; 95% CI: .69–1.13, respectively). Once again, these benefits appeared to be more pronounced in the subgroup of patients with an eGFR 30–60 mL/min/1.73 m2 at baseline.11 Taken together, these promising preliminary results provided the rationale for the design of the FLOW study, a dedicated phase 3 clinical trial aiming to fully elucidate the kidney protective effect of the GLP-1RA semaglutide versus placebo in patients with CKD and T2D at high risk for kidney injury progression.9 In the FLOW trial, 3533 patients with T2D and albuminuric CKD (defined as an eGFR of 50–75 mL/min/1.73 m2 and UACR of 300–5000 mg/g or an eGFR of 25 to 50% decline in eGFR from baseline, incident ESKD, or death due to renal and cardiovascular causes (HR: .76; 95% CI: .66–.88).8 This benefit was similar in magnitude, when a kidney-specific composite outcome was explored (HR: .79; 95% CI: .66–.94). Cardiovascular and survival benefits were also demonstrated. Relative to placebo, semaglutide lowered by 18%, the risk for major adverse cardiovascular events (HR: .82; 95% CI: .68–.98) and by 20%, the risk of all-cause mortality (HR: .80; 95% CI: .67–.95).8 With respect to safety of treatment, the incidence of serious adverse events was numerically lower in the semaglutide group than in the placebo group (49.6% vs. 53.8%).8 These strong clinical-trial data directly support a therapeutic role for semaglutide in high-risk patients with albuminuric CKD associated with T2D. The aforementioned results were broadly consistent across several prespecified subgroup analyses.8 For example, 1832 patients (51.8%) were receiving background therapy with metformin. The treatment effect of semaglutide versus placebo on the primary composite outcome was similar in magnitude in metformin users (HR: .71; 95% CI: .57–.88) and in non-users (HR: .80; 95% CI: .66–.97).8 A smaller subset of 550 patients (15.6%) were being treated with an SGLT-2 inhibitor at baseline. Similarly, there was no clear treatment effect modification among the patients receiving background therapy with an SGLT-2 inhibitor (HR: 1.07; 95% CI: .67–1.67) relative to those who were not (HR: .73; 95% CI: .63–.85),8 suggesting a potential synergistic effect of semaglutide when this agent is used in combination with other guideline-directed therapies. It has to be noted, however, that the post hoc nature and the limited statistical power of these data preclude the opportunity to establish direct and causal risk associations. GLP-1RAs exert their glucose-lowering action by binding to the GLP-1 receptor, promoting in this way glucose-dependent insulin section, prolonging gastric emptying and reducing appetite. The mechanisms mediating the kidney protective effect of semaglutide in diabetic kidney disease are not yet fully clear. Mediation analyses of cardiovascular outcome trials are supporting the notion that indirect actions, such as improvement in glycaemic control, weight reduction and decrease in office blood pressure levels, can only partially explain the cardiorenal protection afforded by GLP-1RAs.13, 14 Experimental studies have provided evidence that GLP-1 receptors are expressed in several cell types at the kidney level (i.e. glomerular, tubular and vascular cells), supporting a more direct mechanism of action for these agents.15 Accordingly, on the basis of preclinical and biomarker data, it is speculated that GLP-1RAs directly inhibit the pathogenetic mechanisms implicated in the progression of diabetic kidney disease, such as activation of resident mononuclear phagocytes, infiltration of the kidney by non-resident inflammatory cells and the expression of pro-inflammatory cytokines and adhesion molecules.15 The mechanistic background of kidney protection afforded by the GLP-1RA semaglutide is currently under investigation in the ongoing REMODEL (Renal Mode of Action of Semaglutide in Patients with Type 2 Diabetes and Chronic Kidney Disease) study (NCT04865770). This phase 3 clinical trial is planning to recruit 105 patients with albuminuric CKD and T2D already treated with maximum labelled or tolerated doses of a RAS inhibitor. Patients will be randomly assigned to receive subcutaneous semaglutide (1.0 mg once weekly) or placebo over a follow-up period of 52 weeks. The primary outcome of the REMODEL trial is defined as the between-group difference in the changes of kidney oxygenation, inflammation and global kidney perfusion, assessed with magnetic resonance imaging. In a subset of patients, kidney biopsies will also be performed to investigate changes in gene expression via single-nucleus RNA sequencing and in morphometric parameters. Finally, blood and urine samples will be collected to assess biomarkers of kidney function and kidney injury. The completion of the trial is anticipated on November 2024. In conclusion, despite the improvement in kidney and cardiovascular outcomes with newer therapies, such as SGLT-2 inhibitors and non-steroidal MRA finerenone,4, 5 patients with diabetic kidney disease continue to progress to kidney failure and die early from cardiovascular events. Indirect evidence derived mainly from the secondary analyses of cardiovascular outcome and glycaemic control trials have suggested a potential kidney protective benefit of GLP-1RAs.10-12 However, a dedicated, full-scale, phase 3 clinical trial conducted specifically in patients with CKD and T2D at high risk for kidney disease progression was missing.9 The recently published FLOW trial covers this important scientific gap, providing direct evidence that semaglutide affords substantial kidney, cardiovascular and survival benefits in patients albuminuric CKD associated with T2D, also offering a favourable side effect profile for safe treatment.8 Therefore, apart from the existing therapies, the GLP-1RA semaglutide is now a new kid on the block to afford maximal cardiorenal protection to this high-risk patient population. Literature search: P.I.G.; Drafting the initial version of the manuscript: P.I.G.; Review and revisions on the initial draft: K.L. and V.L.; Supervision: V.L. This work was not supported by any source and represents an original effort of the authors. The authors have no conflicts of interest relevant to this work to disclose. This work does not contain original data. All the information of the presented studies is already included in the main paper.