Nature Medicine MAY 25, 2024

Effect of semaglutide on kidney outcomes in people with overweight or obesity and established cardiovascular disease in the SELECT trial

Helen M. Colhoun, et al.

Bottom Line

In a pre-specified secondary analysis of the SELECT trial, once-weekly semaglutide 2.4 mg demonstrated a statistically significant 22% reduction in a composite kidney endpoint compared to placebo in adults with overweight or obesity and established cardiovascular disease without diabetes.

Key Findings

1. The primary composite kidney endpoint (death from kidney disease, initiation of chronic kidney replacement therapy, onset of persistent eGFR < 15 ml/min/1.73 m2, persistent ≥50% reduction in eGFR, or onset of persistent macroalbuminuria) occurred in 1.8% of the semaglutide group versus 2.2% in the placebo group (HR 0.78; 95% CI 0.63–0.96; P = 0.02).

2. Treatment with semaglutide resulted in a significantly slower rate of eGFR decline compared with placebo, with a treatment benefit at 104 weeks of 0.75 ml/min/1.73 m2 (95% CI 0.43–1.06; P < 0.001) overall.

3. The benefit on eGFR was more pronounced in patients with a baseline eGFR <60 ml/min/1.73 m2, showing a benefit of 2.19 ml/min/1.73 m2 (95% CI 1.00–3.38; P < 0.001) at 104 weeks.

4. There was no increased risk of acute kidney injury associated with semaglutide treatment compared with placebo.

Study Design

Design

RCT

Double-Blind

Sample

17,604

Patients

Duration

3.5 yr

Median

Setting

Multicenter, International

Population Adults aged 45 years or older with overweight or obesity (BMI ≥27 kg/m2) and established cardiovascular disease, without diabetes.

Intervention Once-weekly subcutaneous semaglutide 2.4 mg

Comparator Matching placebo

Outcome A 5-component composite kidney endpoint (death from kidney disease, initiation of chronic kidney replacement therapy, onset of persistent eGFR < 15 ml/min/1.73 m2, persistent ≥50% reduction in eGFR, or onset of persistent macroalbuminuria).

Study Limitations

• This was a pre-specified secondary analysis rather than the primary goal of the original SELECT trial.

• The study population was restricted to patients with pre-existing cardiovascular disease and excluded those with diabetes, limiting the generalizability to other populations.

• The absolute event rate for the composite kidney outcome was relatively low, which may reflect the inclusion criteria of the parent cardiovascular trial.

• The follow-up period, while sufficient for the primary endpoint of the parent trial, may be short for assessing long-term hard renal outcomes such as end-stage kidney disease.

Clinical Significance

These findings suggest that semaglutide 2.4 mg may provide renal protection in individuals with overweight or obesity and established cardiovascular disease without diabetes, potentially offering a broader metabolic benefit beyond cardiovascular risk reduction alone.

Historical Context

The SELECT trial originally demonstrated that semaglutide 2.4 mg reduced the risk of major adverse cardiovascular events (MACE) by 20% in patients with overweight or obesity and pre-existing cardiovascular disease without diabetes. This secondary analysis extends those findings to renal health, complementing the results from the FLOW trial, which confirmed the efficacy of semaglutide in slowing kidney disease progression in patients with type 2 diabetes and chronic kidney disease.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What are the proposed physiological mechanisms by which GLP-1 receptor agonists provide kidney protection in patients who do not have diabetes mellitus?

Key Response

While GLP-1RAs were initially used for glucose control, their nephroprotective effects in non-diabetic patients are thought to be mediated by the reduction of systemic and local inflammation, decreased oxidative stress, and modulation of glomerular hemodynamics through the inhibition of the sodium-hydrogen exchanger 3 (NHE3) in the proximal tubule, which potentially impacts tubuloglomerular feedback.

Resident

In a patient with obesity and established cardiovascular disease but a normal HbA1c, how should the kidney outcomes from the SELECT trial influence your selection of a weight management agent compared to phentermine/topiramate or orlistat?

Key Response

Unlike other weight-loss medications, semaglutide 2.4 mg is the first to demonstrate significant reductions in a composite kidney endpoint (22% RRR) and major adverse cardiovascular events (MACE) in this specific population. This makes it a preferred first-line agent for patients where long-term organ protection is as critical as weight reduction.

Fellow

The SELECT kidney analysis noted an initial eGFR 'dip' followed by a slower rate of decline compared to placebo. How does this hemodynamic signature compare to SGLT2 inhibitors, and what does it suggest about GLP-1RA effects on the afferent versus efferent arterioles?

Key Response

Similar to SGLT2 inhibitors and ACE inhibitors, GLP-1RAs can cause a modest initial decrease in eGFR. This is likely due to the restoration of tubuloglomerular feedback leading to afferent arteriolar vasoconstriction or potentially efferent vasodilation, reducing glomerular hyperfiltration—a key driver of chronic kidney disease progression in obesity.

Attending

Does the reduction in kidney events observed in SELECT justify the use of semaglutide 2.4 mg primarily for 'renoprotection' in patients with obesity and CVD, or should these findings be viewed strictly as a secondary benefit to weight loss and cardiovascular risk reduction?

Key Response

This question addresses the paradigm shift from treating metabolic diseases as isolated silos to an integrated 'cardio-renal-metabolic' approach. While the study was a secondary analysis, the 22% reduction in kidney events suggests that for high-risk patients, the renal benefits are a primary clinical gain, potentially independent of the total magnitude of weight loss achieved.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Given that the kidney endpoint was a pre-specified secondary outcome in a trial powered for MACE, what are the statistical limitations of using a composite endpoint that includes eGFR slope and macroalbuminuria when the event rates for 'hard' outcomes like end-stage renal disease (ESRD) were low?

Key Response

This critiques the reliance on surrogate or 'soft' markers (like albuminuria and eGFR slope) within a composite. In trials with low event rates for ESRD or death from renal causes, the hazard ratio is often driven by these markers, which may not always translate to a reduction in the need for dialysis or transplantation in shorter follow-up periods.

Journal Editor

In reviewing the SELECT-CKD data, how did the authors account for the competing risk of cardiovascular death, and does the differential mortality between the semaglutide and placebo groups potentially inflate the perceived renal benefit?

Key Response

In high-risk cardiovascular populations, death is a significant competing risk for kidney failure. If the semaglutide group lived longer (as seen in the primary MACE results), they had more time to develop kidney outcomes. A rigorous analysis must use Fine-Gray models or similar methods to ensure the 22% reduction isn't an artifact of the survival benefit.

Guideline Committee

How do the results of the SELECT kidney analysis align with or expand upon the 2024 KDIGO Clinical Practice Guidelines for the Management of CKD in Diabetes, considering this cohort specifically excluded patients with diabetes?

Key Response

Current KDIGO guidelines strongly recommend GLP-1RAs for patients with Type 2 Diabetes and CKD. The SELECT data provides high-quality evidence to support expanding these recommendations to include patients with obesity and CVD even in the absence of diabetes, effectively broadening the clinical indication for GLP-1RAs in the prevention of 'obesity-related glomerulopathy'.

Clinical Landscape

Noteworthy Related Trials

2015

EMPA-REG OUTCOME Trial

n = 7,020 · NEJM

Tested

Empagliflozin 10/25 mg daily

Population

Patients with T2DM and high cardiovascular risk

Comparator

Placebo

Endpoint

3-point MACE

Key result: Empagliflozin significantly reduced cardiovascular death and showed a reduction in the progression of kidney disease.

2016

LEADER Trial

n = 9,340 · NEJM

Tested

Liraglutide 1.8 mg daily

Population

Patients with T2DM and high cardiovascular risk

Comparator

Placebo

Endpoint

3-point MACE

Key result: Liraglutide reduced the rate of first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, and reduced nephropathy events.

2024

FLOW Trial

n = 3,533 · NEJM

Tested

Semaglutide 1.0 mg weekly

Population

Patients with T2DM and chronic kidney disease

Comparator

Placebo

Endpoint

Composite of kidney failure, substantial decline in eGFR, or death from kidney or CV causes

Key result: Semaglutide reduced the risk of clinically important kidney outcomes and death from cardiovascular or kidney causes in patients with T2DM and CKD.

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