New England Journal of Medicine MAY 24, 2024

Effect of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes (FLOW)

Perkovic V, Tuttle KR, Rossing P, et al.

Bottom Line

In patients with type 2 diabetes and chronic kidney disease, once-weekly subcutaneous semaglutide (1.0 mg) significantly reduced the risk of major kidney disease events and cardiovascular death compared to placebo.

Key Findings

1. The primary composite outcome (kidney failure, ≥50% sustained eGFR reduction, or death from kidney-related or cardiovascular causes) occurred in 331 participants (5.8 per 100 patient-years) in the semaglutide group and 410 participants (7.5 per 100 patient-years) in the placebo group, representing a 24% lower risk (Hazard Ratio 0.76; 95% CI, 0.66 to 0.88; P=0.0003).

2. Semaglutide demonstrated a slower annual rate of eGFR decline compared to placebo, with a mean difference of 1.16 ml/min/1.73 m2 per year (P<0.001).

3. Secondary cardiovascular outcomes were significantly improved, with an 18% lower risk of major adverse cardiovascular events (HR 0.82; 95% CI, 0.68 to 0.98; P=0.029) and a 20% lower risk of all-cause mortality (HR 0.80; 95% CI, 0.67 to 0.95; P=0.01) in the semaglutide arm.

4. Serious adverse events were less frequent in the semaglutide group compared to the placebo group (49.6% vs 53.8%).

Study Design

Design

RCT

Double-Blind

Sample

3,533

Patients

Duration

3.4 yr

Median

Setting

Multicenter, international

Population Adults with type 2 diabetes and chronic kidney disease (eGFR 50 to 75 ml/min/1.73m2 and UACR >300 to <5000 mg/g, or eGFR 25 to <50 ml/min/1.73m2 and UACR >100 to <5000 mg/g) receiving standard care.

Intervention Subcutaneous semaglutide 1.0 mg once weekly.

Comparator Placebo administered once weekly.

Outcome Composite of onset of kidney failure, at least 50% reduction in eGFR from baseline, or death from kidney-related or cardiovascular causes.

Study Limitations

• The study was stopped early for efficacy based on a pre-specified interim analysis, which can sometimes lead to an overestimation of treatment effect.

• SGLT2 inhibitor use at baseline was relatively low (15%), which may limit the generalizability of the findings in settings where SGLT2 inhibitor use is more ubiquitous.

• The trial observed an initial acute drop in eGFR after initiating semaglutide, necessitating careful clinical monitoring during the titration phase.

Clinical Significance

The FLOW trial establishes semaglutide as a potent therapeutic agent to mitigate the progression of kidney disease and cardiovascular death in patients with type 2 diabetes and CKD. This adds a crucial fourth pillar to the standard of care—alongside RAS inhibitors, SGLT2 inhibitors, and finerenone—significantly expanding the options to improve renal and cardiovascular outcomes in this high-risk population.

Historical Context

While GLP-1 receptor agonists had previously shown cardiovascular benefits in large-scale trials, the FLOW trial is the first dedicated renal outcomes study to demonstrate a clear renoprotective benefit for this drug class, shifting the paradigm for the management of diabetic kidney disease.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Beyond its role in glycemic control, what are the primary physiological mechanisms through which GLP-1 receptor agonists like semaglutide exert direct renoprotective effects on the proximal tubule and renal vasculature?

Key Response

Semaglutide reduces glomerular hyperfiltration by inhibiting the sodium-hydrogen exchanger 3 (NHE3) in the proximal tubule, which increases distal sodium delivery and restores tubuloglomerular feedback. Additionally, it has direct anti-inflammatory and anti-fibrotic effects by reducing the expression of proinflammatory cytokines and oxidative stress markers within the renal parenchyma.

Resident

In a patient with Type 2 Diabetes and Stage 3b Chronic Kidney Disease already receiving maximally tolerated doses of an ACE inhibitor and an SGLT2 inhibitor, what specific clinical evidence from the FLOW trial justifies the addition of semaglutide to their regimen?

Key Response

The FLOW trial demonstrated that semaglutide 1.0 mg significantly reduced the risk of a composite primary outcome (kidney failure, 50% eGFR decline, or CV/renal death) by 24% compared to placebo. Importantly, these benefits were observed even in patients already receiving the current standard of care, suggesting an additive nephroprotective effect that targets different pathways than RAS inhibition or SGLT2 inhibition.

Fellow

The FLOW trial included patients with eGFR as low as 25 ml/min/1.73m². How should these results influence the management of patients with advanced CKD (Stage 4) regarding the 'start-stop' criteria for GLP-1RAs, and what was the impact on the slope of eGFR decline observed in this specific sub-population?

Key Response

FLOW provides robust evidence for the safety and efficacy of semaglutide in advanced CKD. The trial showed a significant attenuation in the annual rate of eGFR decline (1.16 ml/min/1.73m² difference favoring semaglutide). Unlike SGLT2 inhibitors, which are often not initiated below an eGFR of 20-25, the FLOW data supports continuing or even initiating semaglutide in Stage 4 CKD to preserve residual renal function, provided GI tolerance is monitored.

Attending

The FLOW trial was terminated early by the Independent Data Monitoring Committee due to clear efficacy. While this is a positive result, what are the practical implications for clinical education regarding the 'legacy effect' and the long-term safety profile of semaglutide in the CKD population?

Key Response

Early termination often leads to an overestimation of the treatment effect size and provides less data on long-term safety (e.g., rare adverse events or durable remission). Clinicians must teach that while the 24% risk reduction is compelling, the shortened follow-up means we must still be vigilant for long-term outcomes like proliferative retinopathy or specific GI complications that may arise over decades of therapy.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Critically analyze the selection of the 50% eGFR decline as a primary endpoint in FLOW versus the traditional 40% decline used in previous CVOTs. How does this higher threshold impact the statistical power, the 'hardness' of the endpoint for regulatory approval, and the clinical meaningfulness of the trial's findings?

Key Response

A 50% eGFR decline is a more conservative and 'harder' endpoint that more closely correlates with the risk of progressing to end-stage kidney disease (ESKD) than a 40% decline. While it requires a larger sample size or longer follow-up to reach the event count (affecting power), the resulting hazard ratios are often more robust and less susceptible to minor fluctuations in serum creatinine, making the evidence for renoprotection more definitive for regulatory bodies like the FDA or EMA.

Journal Editor

Given the high prevalence of cardiovascular death as a competing risk in the CKD population, how does the inclusion of CV death in the primary composite outcome of the FLOW trial potentially mask or enhance the specific 'renal' signal of semaglutide?

Key Response

Editors look for 'competing risk bias.' In CKD patients, many die from CV causes before they ever reach dialysis. Including CV death in the composite (as in FLOW) ensures that the benefit isn't just a result of patients dying before they reach a renal endpoint. However, a rigorous review would also demand a breakdown of the individual components to ensure the 'renal' components (ESKD, 50% decline) independently trended toward significance, which they did in FLOW (p=0.001).

Guideline Committee

Currently, KDIGO and ADA guidelines prioritize SGLT2 inhibitors and RAS inhibitors as first-line therapy for CKD in T2D. Based on FLOW, should semaglutide be elevated to a 'Grade 1A' recommendation for kidney protection specifically, and how does this compare to the evidence level of Finerenone?

Key Response

The FLOW trial provides the first dedicated primary kidney outcome data for a GLP-1RA, similar to the CREDENCE (Canagliflozin) and DAPA-CKD trials. This likely justifies elevating GLP-1RAs from a 'second-line for glucose control' to a 'primary therapy for organ protection' in CKD. This evidence is stronger for semaglutide than for Finerenone (FIDELIO-DKD) in terms of the magnitude of eGFR preservation and the reduction in CV mortality, suggesting a potential shift in the treatment hierarchy.

Clinical Landscape

Noteworthy Related Trials

2016

LEADER Trial

n = 9,340 · NEJM

Tested

Liraglutide 1.8mg daily

Population

T2DM patients with high cardiovascular risk

Comparator

Placebo

Endpoint

Time to first occurrence of CV death, nonfatal MI, or nonfatal stroke

Key result: Liraglutide treatment led to lower rates of major cardiovascular events and secondary analysis suggested beneficial effects on renal outcomes.

2019

CREDENCE Trial

n = 4,401 · NEJM

Tested

Canagliflozin 100mg daily

Population

T2DM patients with CKD and albuminuria

Comparator

Placebo

Endpoint

Composite of end-stage kidney disease, doubling of serum creatinine, or renal/CV death

Key result: Canagliflozin significantly reduced the risk of kidney failure and cardiovascular events in patients with T2DM and albuminuric CKD.

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%, end-stage kidney disease, or renal/CV death

Key result: Dapagliflozin reduced the risk of worsening kidney function and death from cardiovascular or renal causes across a broad population with CKD.

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