The New England Journal of Medicine July 11, 2024

Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes

Vlado Perkovic, Katherine R. Tuttle, Peter Rossing et al.

Bottom Line

In patients with type 2 diabetes and chronic kidney disease, weekly subcutaneous semaglutide significantly reduced the risk of major kidney disease events, cardiovascular events, and all-cause mortality compared to placebo.

Key Findings

1. The trial was stopped early for efficacy after a prespecified interim analysis.

2. The primary composite outcome (kidney failure, ≥50% decline in eGFR, or death from kidney or cardiovascular causes) was reduced by 24% in the semaglutide group compared to placebo (331 vs. 410 events; HR 0.76; 95% CI, 0.66 to 0.88; P=0.0003).

3. Semaglutide significantly slowed the annual rate of eGFR decline by 1.16 ml/min/1.73 m² compared to placebo.

4. The risk of major adverse cardiovascular events (MACE) was reduced by 18% with semaglutide (HR 0.82; 95% CI, 0.68 to 0.98).

5. All-cause mortality was significantly lower in the semaglutide group, demonstrating a 20% relative risk reduction (HR 0.80; 95% CI, 0.67 to 0.95).

6. Serious adverse events were less frequent in the semaglutide group (49.6%) compared to the placebo group (53.8%), primarily driven by reductions in serious infections and cardiovascular disorders.

Study Design

Design

RCT

Double-Blind

Sample

3,533

Patients

Duration

3.4 yr

Median

Setting

28 countries

Population Adults with type 2 diabetes and chronic kidney disease (eGFR 50-75 mL/min/1.73m² with UACR >300 to <5000 mg/g, or eGFR 25 to <50 mL/min/1.73m² with UACR >100 to <5000 mg/g) receiving standard of care, including a maximal tolerated dose of RAS inhibitors.

Intervention Subcutaneous semaglutide 1.0 mg once weekly

Comparator Matched placebo once weekly

Outcome A composite of the onset of kidney failure (dialysis, transplantation, or an eGFR <15 mL/min/1.73m²), at least a 50% reduction in the eGFR from baseline, or death from kidney-related or cardiovascular causes.

Study Limitations

• Early trial cessation due to overwhelming efficacy can sometimes lead to a slight overestimation of the treatment effect magnitude.

• Baseline use of SGLT2 inhibitors (~15%) and non-steroidal MRAs was relatively low, which limits the ability to fully ascertain the additive benefit of semaglutide on top of all contemporary kidney-protective therapies.

• The study population lacked broad demographic diversity (70% men and 66% White), which may limit generalizability to underrepresented groups.

Clinical Significance

The FLOW trial is a landmark study demonstrating that semaglutide provides primary cardio-renal protection in patients with type 2 diabetes and chronic kidney disease. It establishes GLP-1 receptor agonists as a foundational, disease-modifying pillar of therapy—alongside RAS inhibitors, SGLT2 inhibitors, and non-steroidal MRAs—to prevent kidney failure, cardiovascular events, and death in this high-risk population.

Historical Context

While previous cardiovascular outcome trials of GLP-1 receptor agonists (such as SUSTAIN-6 and LEADER) suggested kidney-protective benefits, these were exploratory secondary endpoints largely driven by reductions in albuminuria rather than hard clinical outcomes. FLOW was the first dedicated, adequately powered trial to evaluate a GLP-1 receptor agonist for primary, hard renal outcomes (such as kidney failure and substantial eGFR decline) in a high-risk chronic kidney disease population.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does semaglutide, a GLP-1 receptor agonist, exert renoprotective effects in patients with type 2 diabetes and chronic kidney disease, given that GLP-1 receptors are only minimally expressed in the renal cortex?

Key Response

Students should understand that while semaglutide improves systemic factors like HbA1c, body weight, and blood pressure, its renoprotective mechanisms also involve indirect and systemic effects such as reducing systemic inflammation, lowering oxidative stress, and improving endothelial dysfunction, which collectively reduce hemodynamic stress and structural damage to the glomeruli.

Resident

When managing a patient with type 2 diabetes and stage 3b CKD with albuminuria, how should the findings of the FLOW trial influence your decision to initiate semaglutide, especially if the patient is already taking a maximally tolerated RAS inhibitor and an SGLT2 inhibitor?

Key Response

Residents must navigate guideline-directed medical therapy. The FLOW trial demonstrated significant reductions in composite kidney outcomes and all-cause mortality, including in a subgroup of patients already on SGLT2 inhibitors. This reinforces the clinical application of combining SGLT2 inhibitors and GLP-1 RAs for additive, multi-pathway cardiorenal risk reduction.

Fellow

In trials assessing renoprotective agents like SGLT2 inhibitors, an initial acute drop in eGFR is predictably observed due to hemodynamic changes. Based on the FLOW trial data, how does the eGFR trajectory with semaglutide compare to this SGLT2 inhibitor 'dip', and what does this imply about their differing intrarenal mechanisms?

Key Response

Fellows should recognize that unlike the pronounced hemodynamic 'dip' seen with SGLT2 inhibitors driven by tubuloglomerular feedback and afferent arteriole constriction, GLP-1 RAs typically show a less pronounced or absent initial eGFR decline. This suggests their renoprotective mechanism relies more heavily on mitigating inflammation and metabolic remodeling rather than purely acute intrarenal hemodynamic shifts.

Attending

Given the significant reduction in all-cause mortality and CKD progression observed in the FLOW trial, how do you practically balance the initiation of semaglutide in patients with advanced CKD (eGFR 25-30) who are highly susceptible to volume depletion and acute kidney injury from gastrointestinal side effects?

Key Response

Attendings must balance long-term trial efficacy with real-world acute safety. GLP-1 RAs frequently cause nausea and vomiting, which can lead to volume depletion and AKI in vulnerable advanced CKD populations. The teaching point is to employ very slow proactive dose titration, implement strict 'sick-day rules', and monitor renal function closely during initiation to secure the long-term dialysis-prevention benefits.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The FLOW trial was stopped early for efficacy based on an interim analysis. How does early termination due to overwhelming benefit potentially impact the estimation of the true treatment effect size, and what statistical methods are essential to account for the competing risk of cardiovascular death when assessing progression to end-stage kidney disease?

Key Response

Researchers must evaluate statistical validity. Early stopping can exaggerate treatment effects (random high phenomenon). Furthermore, in a CKD population, patients frequently die of CV causes before reaching ESKD. Competing risk analyses, such as Fine-Gray models, are essential to prevent overestimating the cumulative incidence of ESKD and accurately measuring the true effect size.

Journal Editor

A relatively low proportion of the FLOW trial population was on baseline SGLT2 inhibitors (approximately 15%), which are now standard of care. As a reviewer evaluating the contemporary relevance of these results, how does this baseline medication profile affect the external validity of the study, and what specific statistical interactions would you demand to see?

Key Response

A critical reviewer would flag that the standard of care has shifted since the trial's inception. If only 15% were on SGLT2i, the absolute benefit of semaglutide might be attenuated in a modern cohort universally treated with SGLT2i. The editor must demand tests for interaction comparing the efficacy of semaglutide in those with versus without baseline SGLT2i use to establish modern external validity.

Guideline Committee

Current KDIGO and ADA guidelines strongly recommend SGLT2 inhibitors as first-line therapy for T2D and CKD, with GLP-1 RAs recommended primarily for cardiovascular or glycemic benefit. Does the FLOW trial provide sufficient Level A evidence to elevate GLP-1 RAs to a concurrent, primary kidney-protective pillar of therapy alongside SGLT2 inhibitors regardless of glycemic control?

Key Response

The committee needs to decide if GLP-1 RAs shift from 'add-on for glycemic/weight/CV control' to 'primary renoprotective agents'. Since FLOW is the first dedicated renal outcomes trial proving that a GLP-1 RA prevents hard kidney endpoints and reduces mortality in this population, guidelines will likely need an update to strongly recommend dual therapy (SGLT2i + GLP-1RA) earlier in the disease course.

Clinical Landscape

Noteworthy Related Trials

2016

SUSTAIN 6 Trial

n = 3,297 · NEJM

Tested

Semaglutide 0.5mg or 1.0mg weekly

Population

T2DM patients with high CV risk

Comparator

Placebo

Endpoint

3-point MACE

Key result: Semaglutide significantly reduced the risk of cardiovascular events and showed an exploratory secondary benefit in reducing new or worsening nephropathy.

2019

CREDENCE Trial

n = 4,401 · NEJM

Tested

Canagliflozin 100mg daily

Population

T2DM patients with albuminuric chronic kidney disease

Comparator

Placebo

Endpoint

Composite of ESKD, doubling of serum creatinine, or renal/CV death

Key result: Canagliflozin significantly reduced the risk of the primary composite outcome by 30% compared to placebo.

2020

DAPA-CKD Trial

n = 4,304 · NEJM

Tested

Dapagliflozin 10mg daily

Population

Patients with CKD, with or without T2DM

Comparator

Placebo

Endpoint

Composite of sustained decline in eGFR of at least 50%, ESKD, or renal/CV death

Key result: Dapagliflozin reduced the primary composite endpoint by 39% across patients with and without type 2 diabetes.

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